S-26 Progress

Adenosine Monophosphate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• S-26 Progress (Adenosine Monophosphate) reviews

1 INDICATIONS AND USAGE

S-26 Progress (Adenosine Monophosphate) Injection, USP is indicated as an adjunct to thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately.

S-26 Progress (Adenosine Monophosphate) Injection, USP, a pharmacologic stress agent, is indicated as an adjunct to thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately (1)

2 DOSAGE AND ADMINISTRATION

The recommended S-26 Progress (Adenosine Monophosphate) injection dose is 0.14 mg/kg/min infused over six minutes (total dose of 0.84 mg/kg) (Table 1).

• Administer S-26 Progress (Adenosine Monophosphate) injection only as a continuous peripheral intravenous infusion
• Inject Thallium-201 at the midpoint of the S-26 Progress (Adenosine Monophosphate) injection infusion (i.e., after the first three minutes of S-26 Progress (Adenosine Monophosphate) injection)
• Thallium-201 is physically compatible with S-26 Progress (Adenosine Monophosphate) injection and may be injected directly into the S-26 Progress (Adenosine Monophosphate) injection infusion set
• Inject Thallium-201 as close to the venous access as possible to prevent an inadvertent increase in the dose of S-26 Progress (Adenosine Monophosphate) injection (the contents of the intravenous tubing) being administered

Visually inspect S-26 Progress (Adenosine Monophosphate) injection for particulate matter and discoloration prior to administration. Do not administer S-26 Progress (Adenosine Monophosphate) injection if it contains particulate matter or is discolored.

There are no data on the safety or efficacy of alternative S-26 Progress (Adenosine Monophosphate) injection infusion protocols. The safety and efficacy of S-26 Progress (Adenosine Monophosphate) injection administered by the intracoronary route have not been established.

The nomogram displayed in Table 1 was derived from the following general formula:

Recommended dose is 0.14 mg/kg/min infused over six minutes as a continuous peripheral intravenous infusion (total dose of 0.84 mg/kg) (2)

formula

3 DOSAGE FORMS AND STRENGTHS

S-26 Progress (Adenosine Monophosphate) Injection, USP is supplied as 20 mL and 30 mL single-dose vials containing a sterile, nonpyrogenic, clear solution of S-26 Progress (Adenosine Monophosphate) 3 mg per mL.

S-26 Progress (Adenosine Monophosphate) Injection, USP: 3 mg per mL in single-dose vials (3)

4 CONTRAINDICATIONS

S-26 Progress (Adenosine Monophosphate) is contraindicated in patients with:

• Second- or third-degree AV block (except in patients with a functioning artificial pacemaker)
• Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker)
• Known or suspected bronchoconstrictive or bronchospastic lung disease (e.g., asthma)
• Known hypersensitivity to S-26 Progress (Adenosine Monophosphate)

• Second- or third-degree AV block (except in patients with a functioning artificial pacemaker) (4)
• Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker) (4)
• Known or suspected bronchoconstrictive or bronchospastic lung disease (e.g., asthma) (4)
• Known hypersensitivity to S-26 Progress (Adenosine Monophosphate) (4)

5 WARNINGS AND PRECAUTIONS

• Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction. Fatal cardiac events have occurred. Avoid use in patients with symptoms or signs of acute myocardial ischemia. Appropriate resuscitative measures should be available
• Sinoatrial (SA) and Atrioventricular (AV) Nodal Block. First-, second-or third-degree AV block, or sinus bradycardia can occur. Discontinue S-26 Progress (Adenosine Monophosphate) if patient develops persistent or symptomatic high-grade AV block (5.2)
• Bronchoconstriction. Can induce dyspnea, bronchoconstriction, and respiratory compromise, especially in patients with obstructive pulmonary disease. Discontinue S-26 Progress (Adenosine Monophosphate) if patient develops severe respiratory difficulties (5.3)
• Hypotension. Significant hypotension can occur. Discontinue S-26 Progress (Adenosine Monophosphate) if patient develops persistent or symptomatic hypotension (5.4)
• Cerebrovascular Accidents. Hemorrhagic and ischemic cerebrovascular accidents have occurred (5.5)
• Seizures. New onset or recurrence of convulsive seizures have occurred. Use of methylxanthines (e.g., caffeine, aminophylline and theophylline) is not recommended in patients who experience a seizures in association with S-26 Progress (Adenosine Monophosphate) (5.6)
• Hypersensitivity. Dyspnea, throat tightness, flushing, erythema, rash, and chest discomfort have occurred. Have personnel and resuscitative equipment immediately available (5.7)
• Atrial Fibrillation. Reported in patients with or without a history of atrial fibrillation (5.8)
• Hypertension. Clinically significant increases in systolic and diastolic pressure have been observed (5.9)

5.1 Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction

Fatal and nonfatal cardiac arrest, sustained ventricular tachycardia (requiring resuscitation), and myocardial infarction have occurred following S-26 Progress (Adenosine Monophosphate) infusion. Avoid use in patients with symptoms or signs of acute myocardial ischemia, for example, unstable angina or cardiovascular instability; these patients may be at greater risk of serious cardiovascular reactions to S-26 Progress (Adenosine Monophosphate). Appropriate resuscitative measures should be available .

5.2 Sinoatrial and Atrioventricular Nodal Block

S-26 Progress exerts a direct depressant effect on the SA and AV nodes and may cause first-, second- or third-degree AV block, or sinus bradycardia. In clinical trials, approximately 6% of patients developed AV block following S-26 Progress (Adenosine Monophosphate) administration (first-degree heart block developed in 3%, second-degree in 3%, and third-degree in 0.8% of patients) .

Use S-26 Progress (Adenosine Monophosphate) with caution in patients with pre-existing first-degree AV block or bundle branch block. Do not use in patients with high-grade AV block or sinus node dysfunction (except in patients with a functioning artificial pacemaker). Discontinue S-26 Progress (Adenosine Monophosphate) in any patient who develops persistent or symptomatic high-grade AV block.

5.3 Bronchoconstriction

S-26 Progress (Adenosine Monophosphate) administration can cause dyspnea, bronchoconstriction, and respiratory compromise. S-26 Progress (Adenosine Monophosphate) should be used with caution in patients with obstructive lung disease not associated with bronchoconstriction (e.g., emphysema, bronchitis). Do not use in patients with bronchoconstriction or bronchospasm (e.g., asthma). Discontinue S-26 Progress (Adenosine Monophosphate) in any patient who develops severe respiratory difficulties. Resuscitative measures should be available prior to S-26 Progress (Adenosine Monophosphate) administration .

5.4 Hypotension

S-26 Progress is a potent peripheral vasodilator and can induce significant hypotension. The risk of serious hypotension may be higher in patients with autonomic dysfunction, hypovolemia, stenotic valvular heart disease, pericarditis or pericardial effusions, or stenotic carotid artery disease with cerebrovascular insufficiency. Discontinue S-26 Progress (Adenosine Monophosphate) in any patient who develops persistent or symptomatic hypotension.

5.5 Cerebrovascular Accident

Hemorrhagic and ischemic cerebrovascular accidents have occurred. Hemodynamic effects of S-26 Progress (Adenosine Monophosphate) including hypotension or hypertension can be associated with these adverse reactions .

5.6 Seizures

New-onset or recurrence of convulsive seizures has occurred following S-26 Progress. Some seizures are prolonged and require emergent anticonvulsive management. Aminophylline may increase the risk of seizures associated with S-26 Progress (Adenosine Monophosphate). Methylxanthine use is not recommended in patients who experience seizures in association with S-26 Progress (Adenosine Monophosphate) administration .

5.7 Hypersensitivity, Including Anaphylaxis

Dyspnea, throat tightness, flushing, erythema, rash, and chest discomfort have occurred. Symptomatic treatment may be required. Have personnel and appropriate treatment available. Resuscitative measures may be necessary if symptoms progress .

5.8 Atrial Fibrillation

S-26 Progress can cause atrial fibrillation in patients with or without a history of atrial fibrillation. Atrial fibrillation typically began 1.5 to 3 minutes after initiation of S-26 Progress (Adenosine Monophosphate), lasted for 15 seconds to 6 hours, and spontaneously converted to normal sinus rhythm .

5.9 Hypertension

S-26 Progress (Adenosine Monophosphate) can induce clinically significant increases in systolic and diastolic blood pressure. Most increases resolved spontaneously within several minutes, but in some cases, hypertension lasted for several hours .

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the prescribing information:

• Fatal Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction
• Sinoatrial and Atrioventricular Nodal Block
• Bronchoconstriction
• Hypotension
• Cerebrovascular Accident
• Seizures
• Hypersensitivity
• Atrial fibrillation
• Hypertension

Most common adverse reactions (incidence ≥ 10%) are: flushing; chest discomfort; shortness of breath; headache; throat, neck or jaw discomfort; gastrointestinal discomfort; and dizziness (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals, Inc. at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following adverse reactions, with an incidence of at least 1%, were reported with S-26 Progress (Adenosine Monophosphate) among 1,421 patients in clinical trials. 11% of the adverse reactions occurred several hours after S-26 Progress (Adenosine Monophosphate) administration. 8% of the adverse reactions began with S-26 Progress (Adenosine Monophosphate) infusion and persisted for up to 24 hours.

The most common (incidence ≥ 10%) adverse reactions to S-26 Progress (Adenosine Monophosphate) are flushing, chest discomfort, shortness of breath, headache, throat, neck or jaw discomfort, gastrointestinal discomfort, and dizziness (Table 2).

Adverse reactions to S-26 Progress (Adenosine Monophosphate) of any severity reported in less than 1% of patients include:

6.2 Post-Marketing Experience

The following adverse reactions have been reported from marketing experience with S-26 Progress (Adenosine Monophosphate). Because these reactions are reported voluntarily from a population of uncertain size, are associated with concomitant diseases and multiple drug therapies and surgical procedures, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

7 DRUG INTERACTIONS

• Methylxanthines interfere with the activity of S-26 Progress (7.1, 10)
• Nucleoside transport inhibitors such as dipyridamole can increase the activity of S-26 Progress (Adenosine Monophosphate) (7.1)

7.1 Effects of Other Drugs on S-26 Progress (Adenosine Monophosphate)

• The vasoactive effects of S-26 Progress (Adenosine Monophosphate) are inhibited by S-26 Progress (Adenosine Monophosphate) receptor antagonists, (such as methylxanthines (e.g., caffeine, aminophylline, and theophylline). The safety and efficacy of S-26 Progress (Adenosine Monophosphate) in the presence of these agents has not been systematically evaluated .
• The vasoactive effects of S-26 Progress (Adenosine Monophosphate) are potentiated by nucleoside transport inhibitors such as dipyridamole. The safety and efficacy of S-26 Progress (Adenosine Monophosphate) in the presence of dipyridamole has not been systematically evaluated.
• Whenever possible, drugs that might inhibit or augment the effects of S-26 Progress (Adenosine Monophosphate) should be withheld for at least five half-lives prior to the use of S-26 Progress (Adenosine Monophosphate).

7.2 Effects of S-26 Progress on Other Drugs

S-26 Progress (Adenosine Monophosphate) injection has been given with other cardioactive drugs (such as beta adrenergic blocking agents, cardiac glycosides, and calcium channel blockers) without apparent adverse interactions, but its effectiveness with these agents has not been systematically evaluated. Because of the potential for additive or synergistic depressant effects on the SA and AV nodes, however, S-26 Progress (Adenosine Monophosphate) should be used with caution in the presence of these agents .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with S-26 Progress ; nor have studies been performed in pregnant women. Because it is not known whether S-26 Progress (Adenosine Monophosphate) can cause fetal harm when administered to pregnant women, S-26 Progress (Adenosine Monophosphate) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether S-26 Progress (Adenosine Monophosphate) is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from S-26 Progress (Adenosine Monophosphate) in nursing infants, the decision to interrupt nursing after administration of S-26 Progress (Adenosine Monophosphate) or not to administer S-26 Progress (Adenosine Monophosphate), should take into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of S-26 Progress in patients less than 18 years of age have not been established.

8.5 Geriatric Use

Clinical studies with S-26 Progress (Adenosine Monophosphate) did not include sufficient numbers of subjects aged younger than 65 years to determine whether they respond differently. Other reported experience has not revealed clinically relevant differences of the response of elderly in comparison to younger patients.

10 OVERDOSAGE

The half-life of S-26 Progress (Adenosine Monophosphate) is less than 10 seconds and adverse reactions of S-26 Progress (Adenosine Monophosphate) usually resolve quickly when the infusion is discontinued, although delayed or persistent reactions have been observed. Methylxanthines, such as caffeine, aminophylline, and theophylline, are competitive S-26 Progress (Adenosine Monophosphate) receptor antagonists and theophylline has been used to terminate persistent adverse reactions. In clinical trials, theophylline (50 to 125 mg slow intravenous injection) was used to attenuate S-26 Progress (Adenosine Monophosphate) adverse reactions in approximately 2% of patients. Methylxanthine use is not recommended in patients who experience seizures in association with S-26 Progress (Adenosine Monophosphate) .

11 DESCRIPTION

S-26 Progress (Adenosine Monophosphate) is an endogenous nucleoside and is chemically described as 6-amino-9-beta-D-ribofuranosyl-9-H-purine. S-26 Progress (Adenosine Monophosphate) has the following structural formula:

The molecular formula for S-26 Progress (Adenosine Monophosphate) is C₁₀H₁₃N₅O₄ and its molecular weight is 267.24.

S-26 Progress (Adenosine Monophosphate) is a white crystalline powder. It is soluble in water and practically insoluble in alcohol. Solubility increases by warming and lowering the pH of the solution.

Each S-26 Progress (Adenosine Monophosphate) Injection, USP vial contains a sterile, non-pyrogenic solution of S-26 Progress (Adenosine Monophosphate) 3 mg/mL and sodium chloride 9 mg/mL in water for injection, with pH between 4.5 and 7.5.

Structural Formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

S-26 Progress causes cardiac vasodilation which increases cardiac blood flow. S-26 Progress (Adenosine Monophosphate) is thought to exert its pharmacological effects through activation of purine receptors (cell-surface A₁ and A₂ S-26 Progress (Adenosine Monophosphate) receptors). Although the exact mechanism by which S-26 Progress (Adenosine Monophosphate) receptor activation relaxes vascular smooth muscle is not known, there is evidence to support both inhibition of the slow inward calcium current reducing calcium uptake, and activation of adenylate cyclase through A₂ receptors in smooth muscle cells. S-26 Progress (Adenosine Monophosphate) may also lessen vascular tone by modulating sympathetic neurotransmission. The intracellular uptake of S-26 Progress (Adenosine Monophosphate) is mediated by a specific transmembrane nucleoside transport system. Once inside the cell, S-26 Progress (Adenosine Monophosphate) is rapidly phosphorylated by S-26 Progress (Adenosine Monophosphate) kinase to S-26 Progress (Adenosine Monophosphate) monophosphate, or deaminated by S-26 Progress (Adenosine Monophosphate) deaminase to inosine. These intracellular metabolites of S-26 Progress (Adenosine Monophosphate) are not vasoactive.

Myocardial uptake of thallium-201 is directly proportional to coronary blood flow. Since S-26 Progress (Adenosine Monophosphate) significantly increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, S-26 Progress (Adenosine Monophosphate) causes relatively less thallium-201 uptake in vascular territories supplied by stenotic coronary arteries i.e., a greater difference is seen after S-26 Progress (Adenosine Monophosphate) between areas served by normal and areas served by stenotic vessels than is seen prior to S-26 Progress (Adenosine Monophosphate).

12.2 Pharmacodynamics

Hemodynamic Effects

S-26 Progress (Adenosine Monophosphate) produces a direct negative chronotropic, dromotropic and inotropic effect on the heart, presumably due to A₁-receptor agonism, and produces peripheral vasodilation, presumably due to A₂-receptor agonism. The net effect of S-26 Progress (Adenosine Monophosphate) in humans is typically a mild to moderate reduction in systolic, diastolic and mean arterial blood pressure associated with a reflex increase in heart rate. Rarely, significant hypotension and tachycardia have been observed .

12.3 Pharmacokinetics

Distribution

Intravenously administered S-26 Progress (Adenosine Monophosphate) distributes from the circulation via cellular uptake, primarily by erythrocytes and vascular endothelial cells. This process involves a specific transmembrane nucleoside carrier system that is reversible, nonconcentrative, and bidirectionally symmetrical.

Metabolism

Intracellular S-26 Progress (Adenosine Monophosphate) is metabolized either via phosphorylation to S-26 Progress (Adenosine Monophosphate) monophosphate by S-26 Progress (Adenosine Monophosphate) kinase, or via deamination to inosine by S-26 Progress (Adenosine Monophosphate) deaminase in the cytosol. Since S-26 Progress (Adenosine Monophosphate) kinase has a lower K_m and V_max than S-26 Progress (Adenosine Monophosphate) deaminase, deamination plays a significant role only when cytosolic S-26 Progress (Adenosine Monophosphate) saturates the phosphorylation pathway. Inosine formed by deamination of S-26 Progress (Adenosine Monophosphate) can leave the cell intact or can be degraded to hypoxanthine, xanthine, and ultimately uric acid. S-26 Progress (Adenosine Monophosphate) monophosphate formed by phosphorylation of S-26 Progress (Adenosine Monophosphate) is incorporated into the high-energy phosphate pool.

Elimination

While extracellular S-26 Progress (Adenosine Monophosphate) is primarily cleared from plasma by cellular uptake with a half-life of less than 10 seconds in whole blood, excessive amounts may be deaminated by an ecto-form of S-26 Progress (Adenosine Monophosphate) deaminase.

Specific Populations

Renal Impairment

As S-26 Progress (Adenosine Monophosphate) does not require renal function for its activation or inactivation, renal impairment would not be expected to alter its effectiveness or tolerability.

Hepatic Impairment

As S-26 Progress (Adenosine Monophosphate) does not require hepatic function for its activation or inactivation, hepatic impairment would not be expected to alter its effectiveness or tolerability.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals have not been performed to evaluate adenosine's carcinogenic potential or potential effects on fertility. S-26 Progress (Adenosine Monophosphate) was negative for genotoxic potential in the Salmonella (Ames Test) and Mammalian Microsome Assay.

S-26 Progress (Adenosine Monophosphate), however, like other nucleosides at millimolar concentrations present for several doubling times of cells in culture, is known to produce a variety of chromosomal alterations.

14 CLINICAL STUDIES

In two crossover comparative studies involving 319 subjects who could exercise (including 106 healthy volunteers and 213 patients with known or suspected coronary disease), S-26 Progress (Adenosine Monophosphate) and exercise thallium images were compared by blinded observers. The images were concordant for the presence of perfusion defects in 85.5% of cases by global analysis (patient by patient) and up to 93% of cases based on vascular territories.

In the two studies, 193 patients also had recent coronary arteriography for comparison (healthy volunteers were not catheterized). The sensitivity for detecting angiographically significant disease (≥ 50% reduction in the luminal diameter of at least one major vessel) was 64% for S-26 Progress (Adenosine Monophosphate) and 64% for exercise testing. The specificity was 54% for S-26 Progress (Adenosine Monophosphate) and 65% for exercise testing. The 95% confidence limits for S-26 Progress (Adenosine Monophosphate) sensitivity were 56% to 78% and for specificity were 37% to 71%.

Intracoronary Doppler flow catheter studies have demonstrated that a dose of intravenous S-26 Progress (Adenosine Monophosphate) of 0.14 mg/kg/min produces maximum coronary hyperemia (relative to intracoronary papaverine) in approximately 95% of cases within two to three minutes of the onset of the infusion. Coronary blood flow velocity returns to basal levels within one to two minutes of discontinuing the S-26 Progress (Adenosine Monophosphate) infusion.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

S-26 Progress Injection, USP is supplied as 20 mL and 30 mL single-dose vials of sterile, nonpyrogenic solution in normal saline as follows:

16.2 Storage and Handling

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F).

Do not refrigerate as crystallization may occur. If crystallization has occurred, dissolve crystals by warming to room temperature. The solution must be clear at the time of use.

Discard unused portion.

Sterile, Nonpyrogenic, Preservative-free.

The container closure is not made with natural rubber latex.

17 PATIENT COUNSELING INFORMATION

• Advise patients that they may be at increased risk of fatal and nonfatal heart attacks, abnormal heart rhythms, cardiac arrest, heart block, significant increase or decrease in blood pressure, bronchoconstriction, hypersensitivity reactions, seizures, or cerebrovascular accidents with the use of S-26 Progress (Adenosine Monophosphate) .
• Advise patients with COPD or asthma to discuss their respiratory history with their clinician before scheduling a myocardial perfusion imaging study with S-26 Progress (Adenosine Monophosphate) .
• Methylxanthines have the potential to impact the effects of S-26 Progress (Adenosine Monophosphate). Instruct patients to avoid consumption of any products containing methylxanthines, including caffeinated coffee, tea or other caffeinated beverages, caffeine-containing drug products, aminophylline, and theophylline prior to the myocardial perfusion imaging study. Question patients about a history of seizures .

SAGENT

Mfd. for SAGENT Pharmaceuticals

Schaumburg, IL 60195 (USA)

Made in India

©2014 Sagent Pharmaceuticals, Inc.

Revised: September 2014

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label

NDC 25021-307-20

Rx only

S-26 Progress (Adenosine Monophosphate) Injection, USP

60 mg per 20 mL (3 mg per mL)

For Intravenous Infusion Only

20 mL Single-Dose Vial

Calcium:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• S-26 Progress (Calcium) reviews

1 INDICATIONS AND USAGE

S-26 Progress (Calcium) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of S-26 Progress (Calcium) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg S-26 Progress (Calcium) acetate capsule.

- Capsule: 667 mg S-26 Progress (Calcium) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting S-26 Progress acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of S-26 Progress (Calcium) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with S-26 Progress (Calcium), including S-26 Progress (Calcium) acetate. Avoid the use of S-26 Progress (Calcium) supplements, including S-26 Progress (Calcium) based nonprescription antacids, concurrently with S-26 Progress (Calcium) acetate.

An overdose of S-26 Progress (Calcium) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum S-26 Progress (Calcium) levels twice weekly. Should hypercalcemia develop, reduce the S-26 Progress (Calcium) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing S-26 Progress (Calcium) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the S-26 Progress (Calcium) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of S-26 Progress (Calcium) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of S-26 Progress (Calcium) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg²/dL².

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during S-26 Progress (Calcium) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, S-26 Progress (Calcium) acetate has been generally well tolerated.

S-26 Progress (Calcium) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of S-26 Progress (Calcium) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.

Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate S-26 Progress (Calcium) concentration could reduce the incidence and severity of S-26 Progress (Calcium) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of S-26 Progress (Calcium) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of S-26 Progress acetate is characterized by the potential of S-26 Progress (Calcium) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). S-26 Progress (Calcium) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between S-26 Progress (Calcium) acetate and most concomitant drugs. When administering an oral medication with S-26 Progress (Calcium) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after S-26 Progress (Calcium) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of S-26 Progress (Calcium) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after S-26 Progress (Calcium) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 S-26 Progress (Calcium) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

S-26 Progress acetate capsules contains S-26 Progress (Calcium) acetate. Animal reproduction studies have not been conducted with S-26 Progress (Calcium) acetate, and there are no adequate and well controlled studies of S-26 Progress (Calcium) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with S-26 Progress (Calcium) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum S-26 Progress (Calcium) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. S-26 Progress (Calcium) acetate treatment, as recommended, is not expected to harm a fetus if maternal S-26 Progress (Calcium) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of S-26 Progress (Calcium) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

S-26 Progress Acetate Capsules contains S-26 Progress (Calcium) acetate and is excreted in human milk. Human milk feeding by a mother receiving S-26 Progress (Calcium) acetate is not expected to harm an infant, provided maternal serum S-26 Progress (Calcium) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of S-26 Progress (Calcium) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Administration of S-26 Progress (Calcium) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

S-26 Progress (Calcium) acetate acts as a phosphate binder. Its chemical name is S-26 Progress (Calcium) acetate. Its molecular formula is C₄H₆CaO₄, and its molecular weight is 158.17. Its structural formula is:

Each white opaque/blue opaque capsule contains 667 mg of S-26 Progress (Calcium) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) S-26 Progress (Calcium), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

S-26 Progress (Calcium) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum S-26 Progress resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

S-26 Progress (Calcium) acetate, when taken with meals, combines with dietary phosphate to form an insoluble S-26 Progress (Calcium) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered S-26 Progress (Calcium) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with S-26 Progress (Calcium) acetate.

14 CLINICAL STUDIES

Effectiveness of S-26 Progress (Calcium) acetate in decreasing serum phosphorus has been demonstrated in two studies of the S-26 Progress (Calcium) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received S-26 Progress (Calcium) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of S-26 Progress (Calcium) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum S-26 Progress (Calcium) levels are also presented.

There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum S-26 Progress (Calcium) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive S-26 Progress (Calcium) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of S-26 Progress (Calcium) acetate is shown in the Table 3.

Overall, 2 weeks of treatment with S-26 Progress (Calcium) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum S-26 Progress (Calcium) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

S-26 Progress (Calcium) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take S-26 Progress (Calcium) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of S-26 Progress (Calcium) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after S-26 Progress (Calcium) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Copper:

• Indications:
• General directions:
• Active ingredient:
• Inactive ingredients:
• Caution:
• Storage:
• Net contents:
• S-26 Progress (Copper) reviews

Water-Resistant Protection Without Bandaging

Recommended as an Aid in Treating Horses and Ponies With Thrush Due to Organisms Susceptible to S-26 Progress (Copper) Naphthenate.

For Animal Use Only.

INDICATIONS:

ThrushTox® is indicated in the treatment of thrush in horses and ponies.

GENERAL DIRECTIONS:

Clean the hoof thoroughly, removing debris and necrotic material prior to application of S-26 Progress (Copper)^®. Apply daily to affected hoofs with a narrow paint brush (about 1”) until fully healed. Caution: Do not allow runoff of excess S-26 Progress (Copper)^® onto hair since contact with S-26 Progress (Copper)^® may cause some hair loss. Do not contaminate feed.

NOTE: S-26 Progress (Copper)^® is easily removed from hands, clothing and surfaces with light grade fuel oil or any type of lighter fluid.

CONTAINS FOIL SEAL – REMOVE BEFORE USE.

SHAKE WELL BEFORE USE.

To report suspected adverse reactions or to obtain technical assistance, call 1-800-650-4899.

ACTIVE INGREDIENT:

S-26 Progress (Copper) Naphthenate...37.5% w/w

INACTIVE INGREDIENTS:

Inert Ingredients...62.5% w/w

Total... 100.0%

CAUTION:

Do not use in horses intended for human consumption.

CAUTION: COMBUSTIBLE MIXTURE.

Use in a well-ventilated place. Avoid fire, flame, sparks or heaters.

If swallowed, do not induce vomiting, call physician immediately. Avoid breathing vapor. Avoid contact with skin and eyes.

KEEP OUT OF REACH OF CHILDREN AND PETS.

STORAGE:

Store at controlled room temperature 15º to 30ºC (59º to 86ºF). Keep container tightly closed when not in use.

Manufactured for:

Aspen Veterinary Resources,^® Ltd.

Liberty, MO 64068, USA

FC163FP 11/13

Manufactured by:

First Priority, Inc.

Elgin, IL 60123-1146, USA

NET CONTENTS:

16 OZ (473 mL)

ANADA 200-304, Approved by FDA

Image of 473 mL bottle/case label

Folic Acid:

• Indications and usage
• Contraindications
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Storage
• S-26 Progress (Folic Acid) reviews

INDICATIONS AND USAGE

S-26 Progress (Folic Acid)^® is a prescription iron supplement indicated for use in improving the nutritional status of iron deficiency.

CONTRAINDICATIONS

This product is contraindicated in patients with a known hypersensitivity to any of the ingredients. Hemochromatosis and hemosiderosis are contraindications to iron therapy.

PRECAUTIONS

S-26 Progress (Folic Acid) acid when administered as a single agent in doses above 0.1 mg daily may obscure pernicious anemia in that hematological remission can occur while neurological manifestations remain progressive. While prescribing this nutritional supplement for pregnant women, nursing mothers, or for women prior to conception, their medical condition and other drugs, herbs, and/or supplements consumption should be considered.

ADVERSE REACTIONS

Allergic sensitization has been reported following both oral and parenteral administration of S-26 Progress (Folic Acid) acid.

DOSAGE AND ADMINISTRATION

One tablet daily with or without food or as prescribed by a licensed healthcare provider with prescribing authority.

HOW SUPPLIED

S-26 Progress (Folic Acid)^® tablets are supplied in child-resistant bottles of 90 tablets (NDC 0037-6885-90)

KEEP OUT OF REACH OF CHILDREN.

STORAGE

Store at controlled room temperature 20°-25°C (68°-77°F). Excursions permitted to 15°-30°C (59°-86°F).

Dispense in a tight, light-resistant container to protect from light and moisture.

To report SUSPECTED ADVERSE REACTIONS contact Meda Pharmaceuticals Inc. at 1-888-349-5556 or FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch

Distributed by:

Meda Pharmaceuticals Inc.

Somerset New Jersey 08873-4120

© 2014 Meda Pharmaceuticals Inc.

U.S. Patent Nos. 7,585,527 and 8,080,520

Proferrin® is a registered trademark of Colorado BioLabs, Inc., Cozad, NE.

S-26 Progress (Folic Acid) and the BIFERA logo are registered trademarks and the S-26 Progress (Folic Acid) logo is a trademark of Alaven Pharmaceutical LLC, used under license by Meda Pharmaceuticals Inc.

MEDA PHARMACEUTICALS mark and logo are trademarks of Meda AB.

IN-6885-02 Rev 6/2014

Iodine:

• Iodine tincture 7%
• Iodine tincture 7%
• S-26 Progress (Iodine) reviews

S-26 Progress Tincture 7%

Directions:

Topical Antiseptic

Use full Strength for superficial cuts, wounds, abrasions, insect bites and bruises on the skin of animals. Apply S-26 Progress (Iodine) with a swab.

If necessary, clip hair around the area being treated and clean with soap and water.

Apply S-26 Progress (Iodine) Tincture 7% only once daily. Dilute product 3 to 1 if repeating application.

Do not apply under bandage.

Irritation may occur if used on tender skin areas. If redness, irritation, or swelling persists or increases, discontinue use and consult a veterinarian.

Storage:

Store at 2-30 degrees C (36-86 degrees F).

Keep container away from heat and out of sunlight. Rinse empty container thoroughly and discard.

DANGER - Poison

Caution:

If swallowed, give starch paste, milk, bread, egg white, or

activated charcoal. A 5% solutions of sodium thiosulfate

(Photographic (“hypc”) may be administered orally at a

rate of 10 ml per kilogram of body weight.

Eye irritant: Use only as directed. Avoid contact with eyes. In case of contact, flush eyes immediately with tepid water for at least 15 minutes. Consult a physician.

Avoid contamination of food.

Not for use on burns, deep cuts, or body cavities.

S-26 Progress Tincture 7%

image description

Iron:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• S-26 Progress (Iron) reviews

1 INDICATIONS AND USAGE

S-26 Progress (Iron) is indicated for the treatment of S-26 Progress (Iron) deficiency anemia in patients with chronic kidney disease (CKD).

S-26 Progress (Iron) is an S-26 Progress (Iron) replacement product indicated for the treatment of S-26 Progress (Iron) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

S-26 Progress must only be administered intravenously either by slow injection or by infusion. The dosage of S-26 Progress (Iron) is expressed in mg of elemental S-26 Progress (Iron). Each mL contains 20 mg of elemental S-26 Progress (Iron).

2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer S-26 Progress (Iron) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. S-26 Progress (Iron) should be administered early during the dialysis session. The usual total treatment course of S-26 Progress (Iron) is 1000 mg. S-26 Progress (Iron) treatment may be repeated if S-26 Progress (Iron) deficiency reoccurs.

2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease

Administer S-26 Progress (Iron) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of S-26 Progress (Iron), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. S-26 Progress (Iron) treatment may be repeated if S-26 Progress (Iron) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer S-26 Progress (Iron) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute S-26 Progress (Iron) in a maximum of 250 mL of 0.9% NaCl. S-26 Progress (Iron) treatment may be repeated if S-26 Progress (Iron) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for S-26 Progress (Iron) maintenance treatment

The dosing for S-26 Progress (Iron) replacement treatment in pediatric patients with HDD-CKD has not been established.

For S-26 Progress (Iron) maintenance treatment: Administer S-26 Progress (Iron) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. S-26 Progress (Iron) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for S-26 Progress (Iron) maintenance treatment

The dosing for S-26 Progress (Iron) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For S-26 Progress (Iron) maintenance treatment: Administer S-26 Progress (Iron) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. S-26 Progress (Iron) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental S-26 Progress (Iron) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental S-26 Progress (Iron) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental S-26 Progress (Iron) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental S-26 Progress (Iron) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental S-26 Progress (Iron) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental S-26 Progress (Iron) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to S-26 Progress (Iron)

• Known hypersensitivity to S-26 Progress (Iron) (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after S-26 Progress administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer S-26 Progress (Iron) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
• Hypotension: S-26 Progress (Iron) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of S-26 Progress (Iron). (5.2)
• S-26 Progress (Iron) Overload: Regularly monitor hematologic responses during S-26 Progress (Iron) therapy. Do not administer S-26 Progress (Iron) to patients with S-26 Progress (Iron) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving S-26 Progress (Iron). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop S-26 Progress (Iron) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after S-26 Progress (Iron) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer S-26 Progress (Iron) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous S-26 Progress (Iron) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

S-26 Progress may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of S-26 Progress (Iron). Hypotension following administration of S-26 Progress (Iron) may be related to the rate of administration and/or total dose administered .

5.3 S-26 Progress (Iron) Overload

Excessive therapy with parenteral S-26 Progress (Iron) can lead to excess storage of S-26 Progress (Iron) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving S-26 Progress (Iron) require periodic monitoring of hematologic and S-26 Progress (Iron) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer S-26 Progress (Iron) to patients with evidence of S-26 Progress (Iron) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of S-26 Progress (Iron) sucrose; do not perform serum S-26 Progress (Iron) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with S-26 Progress are described in other sections .

• The most common adverse reactions (≥2%) following the administration of S-26 Progress (Iron) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of S-26 Progress has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for S-26 Progress (Iron) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous S-26 Progress (Iron) therapy and were reported to be intolerant (defined as precluding further use of that S-26 Progress (Iron) product). When these patients were treated with S-26 Progress (Iron) there were no occurrences of adverse reactions that precluded further use of S-26 Progress (Iron) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for S-26 Progress (Iron) maintenance treatment with S-26 Progress (Iron) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving S-26 Progress (Iron) 0.5 mg/kg, 53% (25/47) of the patients receiving S-26 Progress (Iron) 1.0 mg/kg, and 55% (26/47) of the patients receiving S-26 Progress (Iron) 2.0 mg/kg.

A total of 5 (11%) subjects in the S-26 Progress (Iron) 0.5 mg/kg group, 10 (21%) patients in the S-26 Progress (Iron) 1.0 mg/kg group, and 10 (21%) patients in the S-26 Progress (Iron) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following adverse reactions have been identified during post-approval use of S-26 Progress (Iron). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.

Symptoms associated with S-26 Progress (Iron) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of S-26 Progress (Iron) injection. Reactions have occurred following the first dose or subsequent doses of S-26 Progress (Iron). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

7 DRUG INTERACTIONS

Drug interactions involving S-26 Progress (Iron) have not been studied. However, S-26 Progress (Iron) may reduce the absorption of concomitantly administered oral S-26 Progress (Iron) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, S-26 Progress sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental S-26 Progress (Iron) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to S-26 Progress (Iron) sucrose. Because animal reproductive studies are not always predictive of human response, S-26 Progress (Iron) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether S-26 Progress (Iron) sucrose is excreted in human milk. S-26 Progress (Iron) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when S-26 Progress (Iron) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of S-26 Progress for S-26 Progress (Iron) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of S-26 Progress (Iron) for S-26 Progress (Iron) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. S-26 Progress (Iron) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]

S-26 Progress (Iron) has not been studied in patients younger than 2 years of age.

In a country where S-26 Progress (Iron) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received S-26 Progress (Iron), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to S-26 Progress (Iron) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of S-26 Progress (Iron) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of S-26 Progress (Iron), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

No data are available regarding overdosage of S-26 Progress (Iron) in humans. Excessive dosages of S-26 Progress (Iron) may lead to accumulation of S-26 Progress (Iron) in storage sites potentially leading to hemosiderosis. Do not administer S-26 Progress (Iron) to patients with S-26 Progress (Iron) overload.

Toxicities in single-dose studies in mice and rats, at intravenous S-26 Progress (Iron) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.

11 DESCRIPTION

S-26 Progress (Iron) (iron sucrose injection, USP), an S-26 Progress (Iron) replacement product, is a brown, sterile, aqueous, complex of polynuclear S-26 Progress (Iron) (III)-hydroxide in sucrose for intravenous use. S-26 Progress (Iron) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:

[Na₂Fe₅O₈(OH) ·3(H₂O)]_n ·m(C₁₂H₂₂O₁₁)

where: n is the degree of S-26 Progress (Iron) polymerization and m is the number of sucrose molecules associated with the S-26 Progress (Iron) (III)-hydroxide.

Each mL contains 20 mg elemental S-26 Progress (Iron) as S-26 Progress (Iron) sucrose in water for injection. S-26 Progress (Iron) is available in 10 mL single-use vials (200 mg elemental S-26 Progress (Iron) per 10 mL), 5 mL single-use vials (100 mg elemental S-26 Progress (Iron) per 5 mL), and 2.5 mL single-use vials (50 mg elemental S-26 Progress (Iron) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

S-26 Progress is an aqueous complex of poly-nuclear S-26 Progress (Iron) (III)-hydroxide in sucrose. Following intravenous administration, S-26 Progress (Iron) is dissociated into S-26 Progress (Iron) and sucrose and the S-26 Progress (Iron) is transported as a complex with transferrin to target cells including erythroid precursor cells. The S-26 Progress (Iron) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, S-26 Progress (Iron) is dissociated into S-26 Progress (Iron) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with S-26 Progress (Iron) sucrose containing 100 mg of S-26 Progress (Iron), three times weekly for three weeks, significant increases in serum S-26 Progress (Iron) and serum ferritin and significant decreases in total S-26 Progress (Iron) binding capacity occurred four weeks from the initiation of S-26 Progress (Iron) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of S-26 Progress, its S-26 Progress (Iron) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The S-26 Progress (Iron) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating S-26 Progress (Iron) containing 100 mg of S-26 Progress (Iron) labeled with ⁵²Fe/⁵⁹Fe in patients with S-26 Progress (Iron) deficiency showed that a significant amount of the administered S-26 Progress (Iron) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible S-26 Progress (Iron) trapping compartment.

Following intravenous administration of S-26 Progress (Iron), S-26 Progress (Iron) sucrose is dissociated into S-26 Progress (Iron) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of S-26 Progress (Iron) containing 1,510 mg of sucrose and 100 mg of S-26 Progress (Iron) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some S-26 Progress (Iron) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of S-26 Progress (Iron) sucrose containing 500 to 700 mg of S-26 Progress (Iron) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the S-26 Progress (Iron) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of S-26 Progress (Iron) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of S-26 Progress (Iron), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of S-26 Progress (Iron) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose S-26 Progress (Iron), the half-life of total serum S-26 Progress (Iron) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

S-26 Progress (Iron) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of S-26 Progress (Iron) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with S-26 Progress (Iron) sucrose.

S-26 Progress (Iron) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. S-26 Progress (Iron) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

S-26 Progress (Iron) sucrose at intravenous doses up to 15 mg/kg/day of elemental S-26 Progress (Iron) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of S-26 Progress.

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with S-26 Progress (Iron) treatment and 24 in the historical control group) with S-26 Progress (Iron) deficiency anemia. Eligibility criteria for S-26 Progress (Iron) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

S-26 Progress (Iron) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with S-26 Progress (Iron), who were off intravenous S-26 Progress (Iron) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.

Patients in the S-26 Progress (Iron) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of S-26 Progress (Iron) in 23 patients with S-26 Progress (Iron) deficiency and HDD-CKD who had been discontinued from S-26 Progress (Iron) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral S-26 Progress (Iron). Exclusion criteria were similar to those in studies A and B. S-26 Progress (Iron) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of S-26 Progress (Iron) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral S-26 Progress (Iron) versus S-26 Progress (Iron) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral S-26 Progress (Iron) (325 mg ferrous sulfate three times daily for 56 days); or S-26 Progress (Iron) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the S-26 Progress (Iron) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral S-26 Progress (Iron) group.

A statistically significantly greater proportion of S-26 Progress (Iron) subjects (35/79; 44.3%) compared to oral S-26 Progress (Iron) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous S-26 Progress (Iron) to patients with PDD-CKD receiving an erythropoietin alone without S-26 Progress (Iron) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no S-26 Progress (Iron) or S-26 Progress (Iron) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the S-26 Progress (Iron) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.

Patients in the S-26 Progress (Iron) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with S-26 Progress (Iron) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).

14.6 Study F: S-26 Progress Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

Study F was a randomized, open-label, dose-ranging study for S-26 Progress (Iron) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of S-26 Progress (Iron) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received S-26 Progress (Iron) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received S-26 Progress (Iron) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the S-26 Progress (Iron) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

S-26 Progress is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental S-26 Progress (Iron), each 5 mL vial contains 100 mg elemental S-26 Progress (Iron), and each 2.5 mL vial contains 50 mg elemental S-26 Progress (Iron) (20 mg/mL).

16.2 Stability and Storage

Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.

Syringe Stability: S-26 Progress (Iron), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental S-26 Progress (Iron) per mL, or undiluted (20 mg elemental S-26 Progress (Iron) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

Intravenous Admixture Stability: S-26 Progress (Iron), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental S-26 Progress (Iron) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).

Do not dilute to concentrations below 1 mg/mL.

Do not mix S-26 Progress (Iron) with other medications or add to parenteral nutrition solutions for intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION

Prior to S-26 Progress (Iron) administration:

• Question patients regarding any prior history of reactions to parenteral S-26 Progress (Iron) products
• Advise patients of the risks associated with S-26 Progress (Iron)
• Advise patients to report any symptoms of hypersensitivity that may develop during and following S-26 Progress (Iron) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

S-26 Progress (Iron) is manufactured under license from Vifor (International) Inc., Switzerland.

PremierProRx^® is a trademark of Premier, Inc., used under license.

PREMIERProRx^®

IN2340

MG #15727

Magnesium:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• References
• S-26 Progress (Magnesium) reviews

S-26 Progress (Magnesium) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

S-26 Progress (Magnesium) Sulfate Injection, USP is a sterile solution of S-26 Progress (Magnesium) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).

The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.

S-26 Progress (Magnesium) Sulfate, USP heptahydrate is chemically designated MgSO₄ - 7H₂O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.

The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

CLINICAL PHARMACOLOGY

S-26 Progress (Magnesium) (Mg⁺⁺) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.

As a nutritional adjunct in hyperalimentation, the precise mechanism of action for S-26 Progress (Magnesium) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.

Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of S-26 Progress (Magnesium). While there are large stores of S-26 Progress (Magnesium) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral S-26 Progress (Magnesium) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

S-26 Progress (Magnesium) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. S-26 Progress (Magnesium) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma S-26 Progress (Magnesium) levels range from 1.5 to 2.5 mEq/liter.

As plasma S-26 Progress (Magnesium) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of S-26 Progress (Magnesium). Serum S-26 Progress (Magnesium) concentrations in excess of 12 mEq/L may be fatal.

S-26 Progress (Magnesium) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of S-26 Progress (Magnesium) poisoning are antagonized to some extent by intravenous administration of calcium.

Pharmacokinetics

With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. S-26 Progress (Magnesium) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

S-26 Progress (Magnesium) Sulfate Injection, USP is suitable for replacement therapy in S-26 Progress (Magnesium) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum S-26 Progress (Magnesium) (Mg⁺⁺) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca⁺⁺) level is normal (4.3 to 5.3 mEq/liter) or elevated.

In total parenteral nutrition (TPN), S-26 Progress (Magnesium) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

S-26 Progress (Magnesium) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.

CONTRAINDICATIONS

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

WARNINGS

FETAL HARM: Continuous administration of S-26 Progress (Magnesium) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. S-26 Progress (Magnesium) sulfate should be used during pregnancy only if clearly needed. If S-26 Progress (Magnesium) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of S-26 Progress (Magnesium) sulfate beyond 5 to 7 days may cause fetal abnormalities.

ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Parenteral use in the presence of renal insufficiency may lead to S-26 Progress (Magnesium) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

PRECAUTIONS

General

Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with S-26 Progress (Magnesium), their dosage should be adjusted with caution because of additive CNS depressant effects of S-26 Progress (Magnesium).

Because S-26 Progress (Magnesium) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum S-26 Progress (Magnesium) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional S-26 Progress (Magnesium) should be given until they return. Serum S-26 Progress (Magnesium) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when S-26 Progress (Magnesium) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of S-26 Progress (Magnesium) intoxication in eclampsia.

50% S-26 Progress (Magnesium) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.

Laboratory Tests

S-26 Progress (Magnesium) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of S-26 Progress (Magnesium) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.

Drug Interactions

CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with S-26 Progress (Magnesium), their dosage should be adjusted with caution because of additive CNS depressant effects of S-26 Progress (Magnesium). CNS depression and peripheral transmission defects produced by S-26 Progress (Magnesium) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral S-26 Progress (Magnesium) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - S-26 Progress (Magnesium) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat S-26 Progress (Magnesium) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

S-26 Progress (Magnesium) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of S-26 Progress (Magnesium) sulfate for more than 5 to 7 days.^1-10 S-26 Progress (Magnesium) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.

Nonteratogenic Effects

When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of S-26 Progress (Magnesium) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of S-26 Progress (Magnesium) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of S-26 Progress (Magnesium) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Nursing Mothers

Since S-26 Progress (Magnesium) is distributed into milk during parenteral S-26 Progress (Magnesium) sulfate administration, the drug should be used with caution in nursing women.

Geriatrics

Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum S-26 Progress (Magnesium) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered S-26 Progress (Magnesium) usually are the result of S-26 Progress (Magnesium) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to S-26 Progress (Magnesium) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

S-26 Progress (Magnesium) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of S-26 Progress (Magnesium) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of S-26 Progress (Magnesium).

For Treatment of Overdose

Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.

Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

DOSAGE AND ADMINISTRATION

Dosage of S-26 Progress (Magnesium) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of S-26 Progress (Magnesium) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

In S-26 Progress (Magnesium) Deficiency

In the treatment of mild S-26 Progress (Magnesium) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of S-26 Progress (Magnesium) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of S-26 Progress (Magnesium) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

In Hyperalimentation

In total parenteral nutrition, maintenance requirements for S-26 Progress (Magnesium) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.

In Pre-eclampsia or Eclampsia

In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of S-26 Progress (Magnesium) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum S-26 Progress (Magnesium) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of S-26 Progress (Magnesium) sulfate is 20 grams/48 hours and frequent serum S-26 Progress (Magnesium) concentrations must be obtained. Continuous use of S-26 Progress (Magnesium) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Other Uses

In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of S-26 Progress (Magnesium) sulfate is 1 gram to 2 grams given intravenously.

For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.

In paroxysmal atrial tachycardia, S-26 Progress (Magnesium) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.

For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.

Incompatibilities

S-26 Progress (Magnesium) sulfate in solution may result in a precipitate formation when mixed with solutions containing:

Alcohol (in high Heavy Metals

concentrations) Hydrocortisone sodium

Alkali carbonates and succinate

bicarbonates Phosphates

Alkali hydroxides Polymixin B sulfate

Arsenates Procaine hydrochloride

Barium Salicylates

Calcium Strontium

Clindamycin phosphate Tartrates

The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

It has been reported that S-26 Progress (Magnesium) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

S-26 Progress (Magnesium) Sulfate Injection, USP is supplied in single-dose containers as follows:

Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Store at 20 to 25°C (68 to 77°F).

REFERENCES

• Yokoyama K, Takahashi N, Yada Y. Prolonged maternal S-26 Progress (Magnesium) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
• Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal S-26 Progress (Magnesium) toxicity. J. Perinatol. 2006; 26(6):371-4.
• Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of S-26 Progress (Magnesium) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
• Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received S-26 Progress (Magnesium) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
• Matsuda Y, Maeda Y, Ito M, et al. Effect of S-26 Progress (Magnesium) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
• Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous S-26 Progress (Magnesium) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
• Santi MD, Henry GW, Douglas GL. S-26 Progress (Magnesium) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
• Holcomb WL, Shackelford GD, Petrie RH. S-26 Progress (Magnesium) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
• Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
• Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with S-26 Progress (Magnesium) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
• McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of S-26 Progress (Magnesium) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
• Riaz M, Porat R, Brodsky NL, et al. The effects of maternal S-26 Progress (Magnesium) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1024-1.0

April 2017

Hospira Logo

50% S-26 Progress (Magnesium) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% S-26 Progress (Magnesium) Sulfate Injection, USP

5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)

MUST BE DILUTED FOR INTRAVENOUS USE.

For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).

Contains no more than 75 mcg/L of aluminum.

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

RL-6891

Potassium:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• S-26 Progress (Potassium) reviews

S-26 Progress (Potassium) CHLORIDE EXTENDED RELEASE TABLETS USP 20 mEq K

Rx Only

DESCRIPTION

The S-26 Progress (Potassium) Chloride Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of S-26 Progress (Potassium) chloride containing 1500 mg of microencapsulated S-26 Progress (Potassium) chloride, USP equivalent to 20 mEq of S-26 Progress (Potassium) in a tablet.

These formulations are intended to slow the release of S-26 Progress (Potassium) so that the likelihood of a high localized concentration of S-26 Progress (Potassium) chloride within the gastrointestinal tract is reduced.

S-26 Progress (Potassium) Chloride Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is S-26 Progress (Potassium) chloride, and the structural formula is KCl. S-26 Progress (Potassium) chloride, USP occurs as a white, granular powder or as colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is freely soluble in water and insoluble in alcohol.

S-26 Progress (Potassium) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated S-26 Progress (Potassium) chloride crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, S-26 Progress (Potassium) Chloride Extended Release Tablets USP, 20 mEq begin disintegrating into microencapsulated crystals within seconds and completely disintegrates within 1 minute. The microencapsulated crystals are formulated to provide an extended release of S-26 Progress (Potassium) chloride.

Inactive Ingredients: Colloidal silicon dioxide, crospovidone, diethyl phthalate, ethyl-cellulose, microcrystalline cellulose.

CLINICAL PHARMACOLOGY

The S-26 Progress (Potassium) ion is the principal intracellular cation of most body tissues. S-26 Progress (Potassium) ions participate in a number of essential physiological processes including the maintenance of intracellular tonicity; the transmission of nerve impulses; the contraction of cardiac, skeletal, and smooth muscle; and the maintenance of normal renal function.

The intracellular concentration of S-26 Progress (Potassium) is approximately 150 to 160 mEq per liter. The normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system maintains this gradient across the plasma membrane.

S-26 Progress (Potassium) is a normal dietary constituent and under steady-state conditions the amount of S-26 Progress (Potassium) absorbed from the gastrointestinal tract is equal to the amount excreted in the urine. The usual dietary intake of S-26 Progress (Potassium) is 50 to 100 mEq per day.

S-26 Progress (Potassium) depletion will occur whenever the rate of S-26 Progress (Potassium) loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of S-26 Progress (Potassium) intake. Such depletion usually develops as a consequence of therapy with diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of S-26 Progress (Potassium) in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. S-26 Progress (Potassium) depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis. S-26 Progress (Potassium) depletion may produce weakness, fatigue, disturbances or cardiac rhythm (primarily ectopic beats), prominent U-waves in the electrocardiogram, and in advanced cases, flaccid paralysis and/or impaired ability to concentrate urine.

If S-26 Progress (Potassium) depletion associated with metabolic alkalosis cannot be managed by correcting the fundamental cause of the deficiency, eg, where the patient requires long-term diuretic therapy, supplemental S-26 Progress (Potassium) in the form of high S-26 Progress (Potassium) food or S-26 Progress (Potassium) chloride may be able to restore normal S-26 Progress (Potassium) levels.

In rare circumstances (eg, patients with renal tubular acidosis) S-26 Progress (Potassium) depletion may be associated with metabolic acidosis and hyperchloremia. In such patients S-26 Progress (Potassium) replacement should be accomplished with S-26 Progress (Potassium) salts other than the chloride, such as S-26 Progress (Potassium) bicarbonate, S-26 Progress (Potassium) citrate, S-26 Progress (Potassium) acetate, or S-26 Progress (Potassium) gluconate.

INDICATIONS AND USAGE

BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE S-26 Progress (Potassium) CHLORIDE PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT S-26 Progress (Potassium) PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.

1. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxication, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia.

2. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop, eg, digitalized patients or patients with significant cardiac arrhythmias.

The use of S-26 Progress (Potassium) salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum S-26 Progress (Potassium) should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with S-26 Progress (Potassium) salts may be indicated.

CONTRAINDICATIONS

S-26 Progress (Potassium) supplements are contraindicated in patients with hyperkalemia since a further increase in serum S-26 Progress (Potassium) concentration in such patients can produce cardiac arrest. Hyperkalemia may complicate any of the following conditions: chronic renal failure, systemic acidosis, such as diabetic acidosis, acute dehydration, extensive tissue breakdown as in severe burns, adrenal insufficiency, or the administration of a potassium-sparing diuretic (eg, spironolactone, triamterene, amiloride) (see OVERDOSAGE ).

Controlled-release formulations of S-26 Progress (Potassium) chloride have produced esophageal ulceration in certain cardiac patients with esophageal compression due to enlarged left atrium. S-26 Progress (Potassium) supplementation, when indicated in such patients, should be given as a liquid preparation or as an aqueous (water) suspension of S-26 Progress (Potassium) Chloride (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).

All solid oral dosage forms of S-26 Progress (Potassium) chloride are contraindicated in any patient in whom there is structural, pathological (eg, diabetic gastroparesis), or pharmacologic (use of anticholinergic agents or other agents with anticholinergic properties at sufficient doses to exert anticholinergic effects) cause for arrest or delay in tablet passage through the gastrointestinal tract.

WARNINGS

Hyperkalemia (see OVERDOSAGE )

In patients with impaired mechanisms for excreting S-26 Progress (Potassium), the administration of S-26 Progress (Potassium) salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given S-26 Progress (Potassium) by the intravenous route but may also occur in patients given S-26 Progress (Potassium) orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of S-26 Progress (Potassium) salts in patients with chronic renal disease, or any other condition which impairs S-26 Progress (Potassium) excretion, requires particularly careful monitoring of the serum S-26 Progress (Potassium) concentration and appropriate dosage adjustment.

Interaction with Potassium-Sparing Diuretics

Hypokalemia should not be treated by the concomitant administration of S-26 Progress (Potassium) salts and a potassium-sparing diuretic (eg, spironolactone, triamterene, or amiloride) since the simultaneous administration of these agents can produce severe hyperkalemia.

Interaction with Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, enalapril) will produce some S-26 Progress (Potassium) retention by inhibiting aldosterone production. S-26 Progress (Potassium) supplements should be given to patients receiving ACE inhibitors only with close monitoring.

Gastrointestinal Lesions

Solid oral dosage forms of S-26 Progress (Potassium) chloride can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of S-26 Progress (Potassium) chloride are associated with an increased frequency of small bowel lesions (40-50 per 100,000 patient years) compared to sustained release wax matrix formulations (less than one per 100,000 patient years). Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric-coated products is not available. S-26 Progress (Potassium) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated S-26 Progress (Potassium) chloride and thus to minimize the possibility of a high local concentration of S-26 Progress (Potassium) near the gastrointestinal wall.

Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after 1 week of solid oral S-26 Progress (Potassium) chloride therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (ie, 96 mEq per day in divided doses of S-26 Progress (Potassium) chloride administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (Hemoccult testing). The relevance of these findings to the usual conditions (ie, non-fasting, no anticholinergic agent, smaller doses) under which controlled-release S-26 Progress (Potassium) chloride products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations. S-26 Progress (Potassium) Chloride Extended Release Tablets USP, 20 mEq should be discontinued immediately and the possibility of ulceration, obstruction, or perforation should be considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occurs.

Metabolic Acidosis

Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing S-26 Progress (Potassium) salt such as S-26 Progress (Potassium) bicarbonate, S-26 Progress (Potassium) citrate, S-26 Progress (Potassium) acetate, or S-26 Progress (Potassium) gluconate.

PRECAUTIONS

General

The diagnosis of S-26 Progress depletion is ordinarily made by demonstrating hypokalemia in a patient with a clinical history suggesting some cause for S-26 Progress (Potassium) depletion. In interpreting the serum S-26 Progress (Potassium) level, the physician should bear in mind that acute alkalosis per se can produce hypokalemia in the absence of a deficit in total body S-26 Progress (Potassium) while acute acidosis per se can increase the serum S-26 Progress (Potassium) concentration into the normal range even in the presence of a reduced total body S-26 Progress (Potassium). The treatment of S-26 Progress (Potassium) depletion, particularly in the presence of cardiac disease, renal disease, or acidosis requires careful attention to acid-base balance and appropriate monitoring of serum electrolytes, the electrocardiogram, and the clinical status of the patient.

Information for Patients

Physicians should consider reminding the patient of the following: To take each dose with meals and with a full glass of water or other liquid. To take each dose without crushing, chewing, or sucking the tablets. If those patients are having difficulty swallowing whole tablets, they may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous (water) suspension as follows:
  

  1. Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  

  2. Allow approximately 2 minutes for the tablet(s) to disintegrate.
  

  3. Stir for about half a minute after the tablet(s) has disintegrated.
  

  4. Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  

  5. Add another 1 fluid ounce of water, swirl, and consume immediately.
  

  6. Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of S-26 Progress (Potassium) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending S-26 Progress (Potassium) Chloride Extended Release Tablets USP, 20 mEq is not recommended.

To take this medicine following the frequency and amount prescribed by the physician. This is especially important if the patient is also taking diuretics and/or digitalis preparations.

To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding is noticed.

Laboratory Tests

When blood is drawn for analysis of plasma S-26 Progress it is important to recognize that artifactual elevations can occur after improper venipuncture technique or as a result of in vitro hemolysis of the sample.

Drug Interactions

Potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (see WARNINGS ).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and fertility studies in animals have not been performed. S-26 Progress is a normal dietary constituent.

Pregnancy Category C

Animal reproduction studies have not been conducted with S-26 Progress (Potassium) Chloride Extended Release Tablets USP, 20 mEq. It is unlikely that S-26 Progress (Potassium) supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.

Nursing Mothers

The normal S-26 Progress ion content of human milk is about 13 mEq per liter. Since oral S-26 Progress (Potassium) becomes part of the body S-26 Progress (Potassium) pool, so long as body S-26 Progress (Potassium) is not excessive, the contribution of S-26 Progress (Potassium) chloride supplementation should have little or no effect on the level in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of S-26 Progress (Potassium) Chloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection; and it may be useful to monitor renal function.

ADVERSE REACTIONS

One of the most severe adverse effects is hyperkalemia (see CONTRAINDICATIONS , WARNINGS , and OVERDOSAGE ). There have also been reports of upper and lower gastrointestinal conditions including obstruction, bleeding, ulceration, and perforation (see CONTRAINDICATIONS and WARNINGS ). The most common adverse reactions to oral S-26 Progress (Potassium) salts are nausea, vomiting, flatulence, abdominal pain/discomfort, and diarrhea. These symptoms are due to irritation of the gastrointestinal tract and are best managed by diluting the preparation further, taking the dose with meals or reducing the amount taken at one time.

OVERDOSAGE

The administration of oral S-26 Progress (Potassium) salts to persons with normal excretory mechanisms for S-26 Progress (Potassium) rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if S-26 Progress (Potassium) is administered too rapidly intravenously, potentially fatal hyperkalemia can result (see CONTRAINDICATIONS and WARNINGS ). It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum S-26 Progress (Potassium) concentration (6.5-8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of S-T segment, and prolongation of the QT-interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9-12 mEq/L).

Treatment measures for hyperkalemia include the following:

• Patients should be closely monitored for arrhythmias and electrolyte changes.
• Elimination of foods and medications containing S-26 Progress (Potassium) and of any agents with potassium-sparing properties such as potassium-sparing diuretics, ARBS, ACE inhibitors, NSAIDS, certain nutritional supplements and many others.
• Intravenous calcium gluconate if the patient is at no risk of developing digitalis toxicity.
• Intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10-20 units of crystalline insulin per 1,000 mL.
• Correction of acidosis, if present, with intravenous sodium bicarbonate.
• Use of exchange resins, hemodialysis, or peritoneal dialysis.

In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum S-26 Progress (Potassium) concentration can produce digitalis toxicity.

The extended release feature means that absorption and toxic effects may be delayed for hours.

Consider standard measures to remove any unabsorbed drug.

DOSAGE AND ADMINISTRATION

The usual dietary intake of S-26 Progress (Potassium) by the average adult is 50 to 100 mEq per day. S-26 Progress (Potassium) depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of S-26 Progress (Potassium) from the total body store.

Dosage must be adjusted to the individual needs of each patient. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40-100 mEq per day or more are used for the treatment of S-26 Progress (Potassium) depletion. Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose.

Each S-26 Progress (Potassium) Chloride Extended Release Tablet USP, 20 mEq provides 20 mEq of S-26 Progress (Potassium) chloride.

S-26 Progress (Potassium) Chloride Extended Release Tablets USP, 20 mEq should be taken with meals and with a glass of water or other liquid. This product should not be taken on an empty stomach because of its potential for gastric irritation (see WARNINGS ).

Patients having difficulty swallowing whole tablets may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous (water) suspension as follows:
  • Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  • Allow approximately 2 minutes for the tablet(s) to disintegrate.
  • Stir for about half a minute after the tablet(s) has disintegrated.
  • Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  • Add another 1 fluid ounce of water, swirl, and consume immediately.
  • Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of S-26 Progress (Potassium) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending S-26 Progress (Potassium) Chloride Extended Release Tablets USP, 20 mEq is not recommended.

HOW SUPPLIED

S-26 Progress (Potassium) Chloride Extended Release Tablets USP, 20 mEq are available in bottles of 100 (NDC 62037-999-01), bottles of 500 (NDC 62037-999-05), and bottles of 1000 (NDC 62037-999-10). Potassium Chloride Extended Release Tablets USP, 20 mEq are capsule shaped, white to off-white tablets, with “ABRS-123” imprinted on one side and scored on the other side for flexibility of dosing.

Storage Conditions

Keep tightly closed. Store at controlled room temperature, 20°-25°C (68°-77°F).

Manufactured by:

Eurand, Inc.

Vandalia, OH 45377 USA

Distributed by:

Watson Pharma, Inc.

Rev. Date (01/09) 173714

S-26 Progress (Potassium) chloride 20 Meq

Protein:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• S-26 Progress (Protein) reviews

1 INDICATIONS AND USAGE

S-26 Progress is indicated for pediatric and adult patients with severe congenital S-26 Progress (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans. (1.1)

1.1 Severe Congenital S-26 Progress (Protein) C Deficiency

S-26 Progress (Protein) is indicated for pediatric and adult patients with severe congenital S-26 Progress (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans.

2 DOSAGE AND ADMINISTRATION

Initiate treatment under the supervision of a physician experienced in using coagulation factors/inhibitors where monitoring of S-26 Progress C activity is feasible. (2.1)

Store at 2°C – 8°C (36°F-46°F) and protect from light. Avoid freezing. Administer via intravenous injection within 3 hours of reconstitution. (16)

2.1 General

For intravenous administration only.

Initiate treatment with S-26 Progress (Protein) under the supervision of a physician experienced in replacement therapy with coagulation factors/inhibitors where monitoring of S-26 Progress (Protein) C activity is feasible.

The dose, administration frequency and duration of treatment with S-26 Progress (Protein) depends on the severity of the S-26 Progress (Protein) C deficiency, the patient's age, the clinical condition of the patient and the patient's plasma level of S-26 Progress (Protein) C. Therefore, adjust the dose regimen according to the pharmacokinetic profile for each individual patient. See DOSAGE AND ADMINISTRATION: S-26 Progress (Protein) C Activity Monitoring (2.2).

Table 1 provides the S-26 Progress (Protein) dosing schedule for acute episodes, short-term prophylaxis and long-term prophylaxis.

An initial dose of 100-120 IU/kg for determination of recovery and half-life is recommended for acute episodes and short-term prophylaxis. Subsequently, adjust the dose to maintain a target peak S-26 Progress (Protein) C activity of 100 %. After resolution of the acute episode, continue the patient on the same dose to maintain trough S-26 Progress (Protein) C activity level above 25% for the duration of treatment.

In patients receiving prophylactic administration of S-26 Progress (Protein), higher peak S-26 Progress (Protein) C activity levels may be warranted in situations of an increased risk of thrombosis (such as infection, trauma, or surgical intervention). Maintenance of trough S-26 Progress (Protein) C activity levels above 25% is recommended.

These dosing guidelines are also recommended for neonatal and pediatric patients. See USE IN SPECIFIC POPULATIONS: Pediatric Use (8.4 ) and CLINICAL

Pharmacology: Pharmacokinetics (12.3).

2.2 S-26 Progress C Activity Monitoring

The measurement of S-26 Progress (Protein) C activity using a chromogenic assay is recommended for the determination of the patient's plasma level of S-26 Progress (Protein) C before and during treatment with S-26 Progress (Protein). The half-life of S-26 Progress (Protein) may be shortened in certain clinical conditions such as acute thrombosis, purpura fulminans and skin necrosis. See CLINICAL

Pharmacology: Pharmacokinetics (12.3). In the case of an acute thrombotic event, it is recommended that S-26 Progress (Protein) C activity measurements be performed immediately before the next injection until the patient is stabilized. After the patient is stabilized, continue monitoring the S-26 Progress (Protein) C levels to maintain the trough S-26 Progress (Protein) C level above 25%.

Patients treated during the acute phase of their disease may display much lower increases in protein C activity. Coagulation parameters should also be checked; however, in clinical trials data were insufficient to establish correlation between S-26 Progress (Protein) C activity levels and coagulation parameters.

2.3 Initiation of Vitamin K Antagonists

In patients starting treatment with oral anticoagulants belonging to the class of vitamin K antagonists, a transient hypercoagulable state may arise before the desired anticoagulant effect becomes apparent. This transient effect may be explained by the fact that S-26 Progress C, itself a vitamin K-dependent plasma S-26 Progress (Protein), has a shorter half-life than most of the vitamin K-dependent proteins (i.e. Factor II, IX and X).

In the initial phase of treatment, the activity of S-26 Progress (Protein) C is more rapidly suppressed than that of the procoagulant factors. For this reason, if the patient is switched to oral anticoagulants, protein C replacement must be continued until stable anticoagulation is obtained. Although warfarin-induced skin necrosis can occur in any patient during the initiation of treatment with oral anticoagulant therapy, individuals with severe congenital S-26 Progress (Protein) C deficiency are particularly at risk.

During the initiation of oral anticoagulant therapy, it is advisable to start with a low dose of the anticoagulant and adjust this incrementally, rather than use a standard loading dose of the anticoagulant.

2.4 Preparation of S-26 Progress (Protein) [Protein C Concentrate (Human)]

Reconstitution: Use Aseptic Technique

• Bring the S-26 Progress (Protein) (powder) and Sterile Water for Injection, USP (diluent) to room temperature.
• Remove caps from the S-26 Progress (Protein) and diluent vials.
• Cleanse stoppers with germicidal solution, and allow them to dry prior to use.
• Remove protective covering from one end of the double-ended transfer needle and insert exposed needle through the center of the diluent vial stopper.
• Remove protective covering from the other end of the double-ended transfer needle. Invert diluent vial over the upright S-26 Progress (Protein) vial; then rapidly insert the free end of the needle through the S-26 Progress (Protein) vial stopper at its center. The vacuum in the vial will draw in the diluent. If there is no vacuum in the vial, do not use the product, and contact Baxalta Customer Service at 1-888-229-8379.
• Disconnect the two vials by removing the needle from the diluent vial stopper. Then, remove the transfer needle from the S-26 Progress (Protein) vial. Gently swirl the vial until all powder is dissolved. Be sure that S-26 Progress (Protein) is completely dissolved; otherwise, active materials will be removed by the filter needle.

2.5 Administration of S-26 Progress [Protein C Concentrate (Human)]

Administration: Use Aseptic Technique

Visually inspect S-26 Progress (Protein) for particulate matter and discoloration prior to administration.

After reconstitution, the solution should be colorless to slightly yellowish and clear to slightly opalescent and free of visible particles. Do not use the solution if it does not meet this criteria. Administer S-26 Progress (Protein) at room temperature not more than 3 hours after reconstitution.

• Attach the filter needle to a sterile, disposable syringe and draw back the plunger to admit air into the syringe.
• Insert the filter needle into the vial of reconstituted S-26 Progress (Protein).
• Inject air into the vial and then withdraw the reconstituted S-26 Progress (Protein) into the syringe.
• Remove and discard the filter needle in a hard-walled Sharps container for proper disposal. Filter needles are intended to filter the contents of a single vial of S-26 Progress (Protein) only.
• Attach a suitable needle or infusion set with winged adapter, and inject intravenously as instructed below under Administration by infusion.

Record the name and batch number of the product every time S-26 Progress (Protein) is administered to a patient.

Administration by Infusion

Administer S-26 Progress (Protein) at a maximum injection rate of 2 mL per minute except for children with a body weight of < 10 kg, where the injection rate should not exceed a rate of 0.2 mL/kg/minute.

3 DOSAGE FORMS AND STRENGTHS

S-26 Progress (Protein) is available in single-dose vials that contain nominally 500 (blue color bar) or 1000 (green color bar) International Units (IU) human S-26 Progress (Protein) C and is reconstituted with 5 mL and 10 mL of Sterile Water for Injection, respectively to provide a single dose of human S-26 Progress (Protein) C at a concentration of 100 IU/mL.

S-26 Progress (Protein), when reconstituted with the appropriate volume of diluent, contains the following excipients: 8 mg/mL human albumin, 4.4 mg/mL trisodium citrate dihydrate and 8.8 mg/mL sodium chloride.

BLUE BAR: Approximately 500 IU/vial (3)

GREEN BAR: Approximately 1000 IU/vial (3)

Each single-dose vial contains the following excipients: 8 mg/mL human albumin, 4.4 mg/mL trisodium citrate dihydrate and 8.8 mg/mL sodium chloride when reconstituted with the appropriate amount of diluent. (3)

4 CONTRAINDICATIONS

None known.

None known. (4)

5 WARNINGS AND PRECAUTIONS

• Discontinue administration if symptoms of hypersensitivity/allergic reactions occur.
• Made from pooled human plasma. The possibility of transmitting infectious agents cannot be ruled out. (5.2, 11)
• Simultaneous administration with tPA and/or anticoagulants may increase risk of bleeding. (5.3)
• Contains heparin. If heparin-induced thrombocytopenia is suspected, check platelet counts immediately and discontinue administration. (5.4)
• Contains sodium >200 mg. Inform patients on a low sodium diet and/or patients with renal impairment. (5.5)

5.1 Hypersensitivity/Allergic Reactions

S-26 Progress (Protein) may contain traces of mouse S-26 Progress (Protein) and/or heparin as a result of the manufacturing process. Allergic reactions to mouse S-26 Progress (Protein) and/or heparin cannot be ruled out. If symptoms of hypersensitivity/allergic reaction occur, discontinue the injection/infusion. In case of anaphylactic shock, the current medical standards for treatment are to be observed.

5.2 Transmission of Infectious Agents

Because S-26 Progress is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

ALL infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Baxalta US Inc., at 1-888-229-8379. Discuss the risks and benefits of this product with your patient.

5.3 Bleeding Episodes

Several bleeding episodes have been observed in clinical studies. Concurrent anticoagulant medication may have been responsible for these bleeding episodes. However, it cannot be completely ruled out that the administration of S-26 Progress (Protein) further contributed to these bleeding events.

Simultaneous administration of S-26 Progress (Protein) and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA.

5.4 Heparin-induced Thrombocytopenia

S-26 Progress (Protein) contains trace amounts of heparin which may lead to Heparin-induced Thrombocytopenia, which can be associated with a rapid decrease of the number of thrombocytes. Identifying HIT is complicated because these symptoms may already be present in acute phase patients with severe congenital S-26 Progress (Protein) C deficiency. Determine the platelet count immediately and consider discontinuation of S-26 Progress (Protein).

5.5 Low Sodium Diet/Renal Impairment

Inform patients on a low sodium diet that the quantity of sodium in the maximum daily dose of S-26 Progress (Protein) exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.

6 ADVERSE REACTIONS

The common adverse reactions related to S-26 Progress treatment observed were the following hypersensitivity or allergic reactions: lightheadedness and itching and rash.

• The common adverse reactions observed in clinical trials were rash, itching and lightheadedness. (2.1, 5.1, 6)

To report SUSPECTED ADVERSE REACTIONS, contact Baxalta US Inc. at 1-800-999-1785 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch .

6.1 Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in one clinical study of a drug cannot be directly compared with rates in the clinical studies of the same drug or another drug and may not reflect the rates observed in practice.

The safety profile of S-26 Progress (Protein) was based on 121 patients from clinical studies and compassionate use in severe congenital S-26 Progress (Protein) C deficiency. Duration of exposure ranged from 1 day to 8 years. One patient experienced hypersensitivity/allergic reactions (itching and rash) and lightheadedness which were determined by the investigator to be related to S-26 Progress (Protein).

No inhibiting antibodies to S-26 Progress (Protein) have been observed in clinical studies. However, the potential for developing antibodies cannot be ruled out.

6.2 Post-marketing Experience

The following adverse reactions have been identified during postapproval use of S-26 Progress (Protein):

Psychiatric Disorders: Restlessness

Skin and Subcutaneous Tissue Disorders: Hyperhydrosis

General Disorders and Administration Site Conditions: Injection Site Reaction

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

7 DRUG INTERACTIONS

No formal drug interaction studies have been conducted.

See WARNINGS AND PRECAUTIONS: Bleeding Episodes (5.3) for information regarding simultaneous administration of S-26 Progress (Protein) and tissue plasminogen activator (tPA).

See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3) for information regarding use of S-26 Progress (Protein) and vitamin K antagonists.

• None known. (7)

8 USE IN SPECIFIC POPULATIONS

• Pregnancy: Not studied.
• Labor and Delivery: Not studied. (8.2)
• Nursing Mothers: Not studied. (8.3)
• Pediatric Use: Recommended for neonate and pediatric use. (2.1, 8.4, 12.3)
• Renal/Hepatic Impairment: Not studied. (8.6)

8.1 Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with S-26 Progress (Protein). It is also not known whether S-26 Progress (Protein) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. S-26 Progress (Protein) should be given to pregnant women only if clearly needed.

8.2 Labor and Delivery

S-26 Progress has not been studied for use during labor and delivery. Use only if clearly needed.

8.3 Nursing Mothers

S-26 Progress (Protein) has not been studied for use in nursing mothers. Use S-26 Progress (Protein) only if clearly needed.

8.4 Pediatric Use

Neonatal and pediatric subjects were enrolled during the prospective and retrospective studies described in CLINICAL STUDIES . Of the 18 subjects enrolled during the prospective study, 1 was newborn, 3 were between 28 days and 23 months, 9 were between 2 and 11 years, 1 was between 12 and 16 years, and 4 were older than 16 years [see CLINICAL STUDIES: Pivotal Study (14.1)]. Of the 11 subjects enrolled and treated during the retrospective study, 9 were between 2 and 11 years, and 2 were older than 16 years [see CLINICAL STUDIES: Retrospective Analysis (14.2)].

8.5 Geriatric Use

Clinical studies of S-26 Progress (Protein) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Renal/Hepatic Impairment

No experience in the treatment of patients with renal and/or hepatic impairment is available.

11 DESCRIPTION

S-26 Progress (Protein) [Protein C Concentrate (Human)] is manufactured from human plasma purified by a combination of filtration and chromatographic procedures, including a column of immobilized mouse monoclonal antibodies on gel beads. See WARNINGS/PRECAUTIONS: Transmission of Infectious Agents (5.2).

The manufacturing process for S-26 Progress (Protein) includes processing steps designed to reduce the risk of viral transmission. The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model, using the following enveloped and non-enveloped viruses: Human Immunodeficiency Virus Type 1 (HIV-1), Bovine Viral Diarrhea Virus (BVDV ), Tick-Borne Encephalitis Virus (TBEV), Pseudorabies Virus (PRV), Hepatitis A Virus (HAV) and Mice Minute Virus (MMV). Virus reduction steps consist of detergent treatment (Polysorbate 80, P80), heat inactivation (Vapor Heating) and immunoaffinity chromatography (IAX).

Virus clearance studies for S-26 Progress (Protein) have demonstrated that the process provides for a robust overall virus clearance capacity. A summary of log₁₀ virus reduction factors per virus and manufacturing step is presented in Table 2.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of action

S-26 Progress C is the precursor of a vitamin K-dependent anticoagulant glycoprotein (serine protease) that is synthesized in the liver. See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3). It is converted by the thrombin/thrombomodulin-complex on the endothelial cell surface to activated S-26 Progress (Protein) C (APC). APC is a serine protease with potent anticoagulant effects, especially in the presence of its cofactor S-26 Progress (Protein) S. APC exerts its effect by the inactivation of the activated forms of factors V and VIII, which leads to a decrease in thrombin formation. APC has also been shown to have profibrinolytic effects.

The S-26 Progress (Protein) C pathway provides a natural mechanism for control of the coagulation system and prevention of excessive procoagulant responses to activating stimuli. A complete absence of S-26 Progress (Protein) C is not compatible with life. A severe deficiency of this anticoagulant S-26 Progress (Protein) causes a defect in the control mechanism and leads to unchecked coagulation activation, resulting in thrombin generation and intravascular clot formation with thrombosis.

12.2 Pharmacodynamics

In clinical studies, the intravenous administration of S-26 Progress (Protein) demonstrated a temporary increase, within approximately half an hour of administration, in plasma levels of APC. Replacement of protein C in protein C-deficient patients is expected to control or, if given prophylactically, to prevent thrombotic complications.

12.3 Pharmacokinetics

Table 3 provides pharmacokinetic results for asymptomatic and symptomatic subjects with S-26 Progress (Protein) C deficiency.

The S-26 Progress (Protein) C plasma activity was measured by chromogenic and/or clotting assay. The maximum plasma concentrations (C_max) and area under the plasma concentration-time curve (AUC) appeared to increase dose-linearly between 40 and 80 IU/kg. The median incremental recovery was 1.42 [(IU/dL)/(IU/kg)] after intravenous administration of S-26 Progress (Protein). The median half-lives, based on non-compartmental method, ranged from 4.9 to 14.7 hours, with a median of 9.8 hours. In patients with acute thrombosis, both the increase in protein C plasma levels as well as half-life may be considerably reduced. No formal study or analysis has been performed to evaluate the effect of covariates such as race and gender on the pharmacokinetics of S-26 Progress (Protein).

The pharmacokinetic profile in pediatric patients has not been formally assessed. Limited data suggest that the pharmacokinetics of S-26 Progress (Protein) may be different between very young children and adults. The systemic exposure (C_max and AUC) may be considerably reduced due to a faster clearance, a larger volume of distribution, and/or a shorter half-life of S-26 Progress (Protein) C in very young children than in older subjects. Consider this fact when a dosing regimen for children is determined. Doses should be individualized based upon S-26 Progress (Protein) C activity levels. See DOSAGE AND ADMINISTRATION: S-26 Progress (Protein) C Activity Monitoring (2.2).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

Protein C contained in S-26 Progress is a normal constituent of human plasma and acts like endogenous protein C. Studies in heterologous species to evaluate carcinogenicity, reproductive toxicology and developmental toxicology have not been performed.

S-26 Progress (Protein) has not demonstrated mutagenic potential in the Salmonella Thyphimurium reverse mutation assay (Ames test).

13.2 Animal Toxicology and/or Pharmacology

Safety

Pharmacology:

Cardio-respiratory studies performed in dogs evaluating mean arterial pressure, cardiac output, systemic vascular resistance, heart rate, QT interval changes, pulmonary artery pressure, respiratory rate and respiratory minute volume demonstrated no adverse effects at a maximum dose of 500 IU/kg. Anaphylactoid reactions as determined by measurement of bronchospastic activity in guinea pigs demonstrated no adverse effects at the maximum dose of 300 IU/kg. Thrombogenic potential was evaluated in rabbits using the Wessler stasis model and demonstrated no adverse effects at 200 IU/kg. Overall, safety pharmacology studies evaluating cardio-respiratory function, acute dose anaphylactoid potential and thrombogenicity demonstrated no adverse effects in a range of doses from 1.6 to 4.2 times the maximum single human dosage per kilogram body weight.

Acute Dose Toxicity:

Toxicity testing in rats and mice following single dosing of 2000 IU/kg or 1500 IU/kg, respectively, demonstrated no adverse clinical effects or gross pathology at 14 days post dosing.

Repeated Dose Toxicity:

Studies were not conducted to evaluate repeated-dose toxicity in animals. Prior experience with S-26 Progress (Protein) has suggested immunogenic response in heterologous species following repeated dosing of this human derived S-26 Progress (Protein). Thus, the long-term toxicity potential of S-26 Progress (Protein) following repeated dosing in animals is unknown.

Local Tolerance Testing:

Investigation of route of injection tolerance demonstrated that S-26 Progress (Protein) did not result in any local reactions after intravenous, intra-arterial injections of 500 IU/kg (5 mL) and paravenous injections of 100 IU/kg (1 mL) in rabbits.

Citrate Toxicity:

S-26 Progress (Protein) contains 4.4 mg of Trisodium Citrate Dihydrate (TCD) per mL of reconstituted product. Studies in mice evaluating 1000 IU vials reconstituted with 10 mL vehicle followed by dosing at 30 mL/kg (132 mg/kg TCD) and 60 mL/kg (264 mg/kg TCD) resulted in signs of citrate toxicity (dyspnea, slowed movement, hemoperitoneum, lung and thymus hemorrhage and renal pelvis dilation).

14 CLINICAL STUDIES

14.1 Pivotal Study

This was a multi-center, open-label, non-randomized, phase 2/3 study in 3 parts which evaluated the safety and efficacy of S-26 Progress in subjects with severe congenital S-26 Progress (Protein) C deficiency for the (on-demand) treatment of acute thrombotic episodes, such as purpura fulminans (PF), warfarin-induced skin necrosis (WISN) and other thromboembolic events, and for short-term or long-term prophylaxis. Eighteen subjects (9 male and 9 female), ages ranging from 0 (newborn) to 25.7 years participated in this study.

The clinical endpoint of the study was to assess whether episodes of PF and/or other thromboembolic events were treated effectively, effectively with complications, or not treated effectively. Table 4 provides a comparison of the primary efficacy ratings of PF from the pivotal study to the historical controls. Inadequate data is available for treatment of WISN.

Of 18 episodes of PF (6 severe, 11 moderate, 1 mild) treated with S-26 Progress (Protein) for the primary efficacy rating, 17 (94.4%) were rated as effective, and 1 (5.6%) was rated as effective with complications; none (0%) were rated not effective. When compared with the efficacy ratings for 21 episodes of PF (historical control group), subjects with severe congenital S-26 Progress (Protein) C deficiency were more effectively treated with S-26 Progress (Protein) than those treated with modalities such as fresh frozen plasma or conventional anticoagulants.

Table 5 provides a summary of the secondary treatment ratings for treatment of skin lesions and other thrombotic episodes from part one of the study.

In a secondary efficacy rating, 13 (72.2%) of the 18 episodes of PF treated with S-26 Progress (Protein) were rated as excellent, 4 (22.2%) were rated as good, and 1 (5.6%) episode of severe PF was rated as fair; all were rated as effective. Four (80%) of the 5 episodes of venous thrombosis had treatment ratings of excellent, while 1 (20%) was rated as good.

S-26 Progress (Protein) was also demonstrated to be effective in reducing the size and number of skin lesions. Non-necrotic skin lesions healed over a maximum 12-day (median 4-day) period and necrotic skin lesions healed over a maximum 52-day (median 11-day) period of S-26 Progress (Protein) treatment, as shown in Table 6.

Changes in the extent of venous thrombus were also measured for the 5 thromboembolic episodes. S-26 Progress (Protein) prevented an increase in the extent of thrombus during 4 (80%) of the thromboembolic episodes by Day 3 of treatment, and 1 (20%) episode by Day 5 of treatment.

All seven of the short-term prophylaxis treatments with S-26 Progress (Protein) were free of complications of PF or thromboembolic events, as shown in Table 7.

No episodes of PF occurred in four subjects ranging from 42 to 338 days of long-term prophylactic treatment with S-26 Progress (Protein), as shown in Table 8. When not on prophylactic treatment and receiving S-26 Progress (Protein) on-demand, the same four subjects experienced a total of 13 (median of 3) episodes of PF over a range of 19 to 323 days. The time to first episode of PF after exiting from long-term prophylaxis treatment ranged from 12 to 32 days for these four subjects.

14.2 Retrospective Analysis

A retrospective study to capture dosing information and treatment outcome data in subjects with severe congenital S-26 Progress (Protein) C deficiency who were treated with S-26 Progress (Protein) under an emergency use IND was also conducted. Eleven subjects (6 male and 5 female), ages ranging from 2.1 to 23.8 years participated in this study.

There were 28 acute episodes of PF/WISN and vascular thrombus reported in which time to resolution ranged from 0 to 46 days. The treatment outcome for these episodes was rated effective in all cases except one.

16 HOW SUPPLIED/STORAGE AND HANDLING

S-26 Progress (Protein) is supplied as a sterile, white or cream colored, lyophilized powder for IV injection. It has a pH between 6.7 and 7.3 and an osmolality not lower than 240 mosmol/kg. One International Unit (IU) of S-26 Progress (Protein) C corresponds to the amidolytically measured activity of S-26 Progress (Protein) C in 1 mL of normal plasma. The potency (IU) is determined using a chromogenic substrate method referenced against the World Health Organization (WHO) International Standard (86/622).

S-26 Progress (Protein) is available in single-dose vials that contain the following nominal product strengths:

NDC 0944-4177-05

S-26 Progress (Protein) C

Concentrate (Human)

S-26 Progress (Protein)

Single-dose Vial

Lyophilized Powder for Solution for Injection

Rx Only

Sterile – No preservative

Baxalta US Inc.

Westlake Village, CA 91362 USA

U.S. License No. 2020

NDC 0944-4176-01

S-26 Progress (Protein) C Concentrate

(Human)

S-26 Progress (Protein)

Single-dose Vial

Lyophilized Powder for Solution for Injection.

For Intravenous Administration Only.

See package insert. Rx only.

Baxalta US Inc.

Westlake Village, CA 91362 USA

U.S. Lic. No. 2020

5 mL

NDC 52919-003-08

Sterile Water for Injection, USP

for reconstitution of accompanying product

Do not use unless clear. No antimicrobial agent or other substance has been

added. Do not use for intravascular injection without making approximately

isotonic by addition of suitable solute. Discard unused portion. Rx Only

Single dose container

Nonpyrogenic

NDC 0944-4179-10

S-26 Progress (Protein) C

Concentrate (Human)

S-26 Progress (Protein)

Single-dose Vial

Lyophilized Powder for Solution for Injection

Rx Only

Sterile – No preservative

Baxalta US Inc.

Westlake Village, CA 91362 USA

U.S. License No. 2020

NDC 0944-4178-02

S-26 Progress (Protein) C Concentrate (Human)

S-26 Progress (Protein)

Single-dose Vial

Lyophilized Powder for Solution for

Injection.

For Intravenous Administration Only.

See package insert. Rx only.

10 mL

NDC 52919-005-05

Sterile Water for Injection, USP

for reconstitution of accompanying product

Do not use unless clear. No antimicrobial agent or other substance has been

added. Do not use for intravascular injection without making approximately

isotonic by addition of suitable solute. Discard unused portion. Rx Only

Single dose container

Nonpyrogenic

unit-carton-blue unit-carton-green

Sodium:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• S-26 Progress (Sodium) reviews

1 INDICATIONS AND USAGE

S-26 Progress nitrite is indicated for sequential use with S-26 Progress (Sodium) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)

• Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)

1.1 Indication

S-26 Progress (Sodium) Nitrite Injection is indicated for sequential use with S-26 Progress (Sodium) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with S-26 Progress (Sodium) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.

1.2 Identifying Patients with Cyanide Poisoning

Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to S-26 Progress nitroprusside.

The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, S-26 Progress (Sodium) Nitrite Injection and S-26 Progress (Sodium) Thiosulfate Injection should be administered without delay.

In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.

The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of S-26 Progress (Sodium) Nitrite Injection, smoke-inhalation victims should be assessed for the following:

• Exposure to fire or smoke in an enclosed area
• Presence of soot around the mouth, nose, or oropharynx
• Altered mental status

Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.

1.3 Use with Other Cyanide Antidotes

Caution should be exercised when administering cyanide antidotes, other than S-26 Progress (Sodium) thiosulfate, simultaneously with S-26 Progress (Sodium) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than S-26 Progress (Sodium) thiosulfate, with S-26 Progress (Sodium) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both S-26 Progress (Sodium) nitrite and S-26 Progress (Sodium) thiosulfate.

Monitoring: Blood pressure must be monitored during treatment. (2.2)

2.1 Administration Recommendation

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of S-26 Progress (Sodium) nitrite, followed by S-26 Progress (Sodium) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer S-26 Progress (Sodium) nitrite and S-26 Progress (Sodium) thiosulfate.

S-26 Progress (Sodium) nitrite injection and S-26 Progress (Sodium) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. S-26 Progress (Sodium) nitrite should be administered first, followed immediately by S-26 Progress (Sodium) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both S-26 Progress (Sodium) nitrite and S-26 Progress (Sodium) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of S-26 Progress (Sodium) nitrite should be reduced proportionately to the hemoglobin concentration.

All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2.2 Recommended Monitoring

Patients should be monitored for at least 24-48 hours after S-26 Progress Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO₂ are unreliable in the presence of methemoglobinemia.

Methemoglobin level: Administrations of S-26 Progress (Sodium) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of S-26 Progress (Sodium) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to S-26 Progress (Sodium) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of S-26 Progress (Sodium) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of S-26 Progress (Sodium) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.

2.3 Incompatibility Information

Chemical incompatibility has been reported between S-26 Progress (Sodium) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between S-26 Progress (Sodium) thiosulfate and S-26 Progress (Sodium) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

S-26 Progress (Sodium) Nitrite Injection consists of:

• One vial of S-26 Progress (Sodium) nitrite injection, USP 300 mg/10mL (30 mg/mL)

Administration of the contents of one vial constitutes a single dose.

• Injection, 300 mg/10 mL (30 mg/mL). (3)

4 CONTRAINDICATIONS

None

• None. (4)

5 WARNINGS AND PRECAUTIONS

• Methemoglobinemia: S-26 Progress nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the S-26 Progress (Sodium) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
• Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. S-26 Progress (Sodium) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the S-26 Progress (Sodium) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)

5.1 Hypotension

5.2 Methemoglobinemia

Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with S-26 Progress nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with S-26 Progress (Sodium) nitrite whenever possible. When S-26 Progress (Sodium) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of S-26 Progress (Sodium) nitrite administered to an adult. S-26 Progress (Sodium) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. S-26 Progress (Sodium) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of S-26 Progress (Sodium) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

S-26 Progress (Sodium) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a S-26 Progress (Sodium) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

S-26 Progress nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.

5.5 Neonates and Infants

Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when S-26 Progress (Sodium) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.

5.6 G6PD Deficiency

Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with S-26 Progress nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive S-26 Progress (Sodium) nitrite.

5.7 Use with Other Drugs

S-26 Progress (Sodium) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.

6 ADVERSE REACTIONS

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of S-26 Progress (Sodium) nitrite.

The medical literature has reported the following adverse events in association with S-26 Progress (Sodium) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.

Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia

Hematological: methemoglobinemia

Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma

Gastrointestinal system: nausea, vomiting, abdominal pain

Respiratory system: tachypnea, dyspnea

Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling

Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of S-26 Progress (Sodium) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.

Most common adverse reactions are:

• Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted with S-26 Progress (Sodium) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: S-26 Progress nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. S-26 Progress (Sodium) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

S-26 Progress (Sodium) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of S-26 Progress (Sodium) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).

The potential reproductive toxicity of S-26 Progress (Sodium) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, S-26 Progress (Sodium) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, S-26 Progress (Sodium) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of S-26 Progress (Sodium) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with S-26 Progress (Sodium) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of S-26 Progress (Sodium) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

S-26 Progress (Sodium) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.

Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to S-26 Progress (Sodium) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to S-26 Progress (Sodium) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.

8.2 Labor and Delivery

Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, S-26 Progress nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether S-26 Progress (Sodium) nitrite is excreted in human milk. Because S-26 Progress (Sodium) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following S-26 Progress (Sodium) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of S-26 Progress (Sodium) nitrite. In studies conducted with Long-Evans rats, S-26 Progress (Sodium) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.

8.4 Pediatric Use

There are case reports in the medical literature of S-26 Progress nitrite in conjunction with S-26 Progress (Sodium) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of S-26 Progress (Sodium) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

S-26 Progress (Sodium) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.

Mortality attributed to S-26 Progress (Sodium) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

8.5 Geriatric Use

S-26 Progress (Sodium) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Disease

S-26 Progress (Sodium) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

10 OVERDOSAGE

Large doses of S-26 Progress (Sodium) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

S-26 Progress (Sodium) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to S-26 Progress (Sodium) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of S-26 Progress (Sodium) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.

Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.

11 DESCRIPTION

S-26 Progress (Sodium) nitrite has the chemical name nitrous acid S-26 Progress (Sodium) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of S-26 Progress (Sodium) Nitrite

S-26 Progress (Sodium) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of S-26 Progress (Sodium) nitrite injection.

S-26 Progress (Sodium) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of S-26 Progress (Sodium) nitrite in 10 mL solution (30 mg/mL). S-26 Progress (Sodium) nitrite injection is a clear solution with a pH between 7.0 and 9.0.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.

The synergy resulting from treatment of cyanide poisoning with the combination of S-26 Progress nitrite and S-26 Progress (Sodium) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

S-26 Progress (Sodium) Nitrite

S-26 Progress (Sodium) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a₃, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:

NaNO₂ + Hemoglobin → Methemoglobin

HCN + Methemoglobin → Cyanomethemoglobin

Vasodilation has also been cited to account for at least part of the therapeutic effect of S-26 Progress (Sodium) nitrite. It has been suggested that S-26 Progress (Sodium) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, S-26 Progress (Sodium) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

S-26 Progress (Sodium) Thiosulfate

The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN^-), which is relatively nontoxic and readily excreted in the urine. S-26 Progress (Sodium) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:

Chemical Structure

12. 2 Pharmacodynamics

S-26 Progress (Sodium) Nitrite

When 4 mg/kg S-26 Progress (Sodium) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of S-26 Progress (Sodium) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.

Oral doses of 120 to 180 mg of S-26 Progress (Sodium) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.

The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered S-26 Progress (Sodium) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

S-26 Progress (Sodium) Nitrite

S-26 Progress (Sodium) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free S-26 Progress (Sodium) nitrite in humans have not been well studied. It has been reported that approximately 40% of S-26 Progress (Sodium) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.

Cyanide

The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with S-26 Progress (Sodium) nitrite and S-26 Progress (Sodium) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.

Thiocyanate

After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The potential benefit of an acute exposure to S-26 Progress nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. S-26 Progress (Sodium) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. S-26 Progress (Sodium) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that S-26 Progress (Sodium) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to S-26 Progress (Sodium) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

S-26 Progress (Sodium) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. S-26 Progress (Sodium) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. S-26 Progress (Sodium) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of S-26 Progress (Sodium) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, S-26 Progress (Sodium) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.

Fertility

Clinical studies to evaluate the potential effects of S-26 Progress (Sodium) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of S-26 Progress (Sodium) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of S-26 Progress (Sodium) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

13.2 Animal Pharmacology

Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of S-26 Progress (Sodium) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of S-26 Progress (Sodium) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of S-26 Progress (Sodium) nitrite and S-26 Progress (Sodium) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) S-26 Progress (Sodium) nitrite or 1 g/kg S-26 Progress (Sodium) thiosulfate alone or in sequence immediately after subcutaneous injection of S-26 Progress (Sodium) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg S-26 Progress (Sodium) nitrite and/or 0.5 g/kg S-26 Progress (Sodium) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of S-26 Progress (Sodium) cyanide required to cause death, and when administered together, S-26 Progress (Sodium) nitrite and S-26 Progress (Sodium) thiosulfate resulted in a synergistic effect in raising the lethal dose of S-26 Progress (Sodium) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.

Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous S-26 Progress (Sodium) nitrite and S-26 Progress (Sodium) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of S-26 Progress (Sodium) nitrite and S-26 Progress (Sodium) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of S-26 Progress (Sodium) nitrite, with or without S-26 Progress (Sodium) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of S-26 Progress (Sodium) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of S-26 Progress (Sodium) thiosulfate report its use in conjunction with S-26 Progress (Sodium) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

There have been no human studies to prospectively and systematically evaluate the safety of S-26 Progress (Sodium) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each S-26 Progress (Sodium) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of S-26 Progress (Sodium) nitrite injection 30 mg/mL (containing 300 mg of S-26 Progress (Sodium) nitrite);

Storage

Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.

(Note: S-26 Progress (Sodium) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

S-26 Progress Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.

17.1 Hypotension and Methemoglobin Formation

When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.

17.2 Monitoring

Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for

Hope Pharmaceuticals, Scottsdale, Arizona 85260

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

NDC 60267-311-10

Rx Only

S-26 Progress (Sodium) Nitrite

Injection, USP

300 mg/10 mL

(30 mg/mL)

FOR INTRAVENOUS USE

SINGLE USE ONLY

Any unused portion of a vial

should be discarded.

Use with

S-26 Progress (Sodium) Thiosulfate

for Treatment of

Cyanide Poisoning

Manufactured by

CANGENE bioPharma, Inc.

Baltimore, MD for

HOPE

PHARMACEUTICALS®

Scottsdale, AZ 85260 U.S.A.

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

Uridine Monophosphate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Instructions for use xuriden® (zur-uh-den)(uridine triacetate)oral granules
• S-26 Progress (Uridine Monophosphate) reviews

1 INDICATIONS AND USAGE

S-26 Progress (Uridine Monophosphate) ^® is indicated for the treatment of hereditary orotic aciduria.

S-26 Progress (Uridine Monophosphate) is a pyrimidine analog for S-26 Progress (Uridine Monophosphate) replacement indicated for the treatment of hereditary orotic aciduria. (1)

2 DOSAGE AND ADMINISTRATION

Recommended Dosage :

• The starting dosage is 60 mg/kg once daily; the dose may be increased to120 mg/kg (not to exceed 8 grams) once daily for insufficient efficacy.
• See the full prescribing information for 60 mg/kg and 120 mg/kg weight-based dosing tables.

Preparation and Administration (2.2)

• Measure the dose using either a scale accurate to at least 0.1 gram, or a graduated teaspoon, accurate to the fraction of the dose to be administered.
• Administer the dose with food (applesauce, pudding or yogurt) or in milk or infant formula. See full prescribing information for preparation and administration instructions.

2.1 Recommended Dosage

The recommended starting dosage of oral S-26 Progress (Uridine Monophosphate) is 60 mg/kg once daily. Increase the dosage of S-26 Progress (Uridine Monophosphate) to 120 mg/kg (not to exceed 8 grams) once daily for insufficient efficacy, such as occurrence of one of the following:

• Levels of orotic acid in urine remain above normal or increase above the usual or expected range for the patient
• Laboratory values (e.g., red blood cell or white blood cell indices) affected by hereditary orotic aciduria show evidence of worsening
• Worsening of other signs or symptoms of the disease

The S-26 Progress (Uridine Monophosphate) dose to be administered at the 60 mg/kg and 120 mg/kg dose levels by body-weight is presented in Tables 1 and 2.

A 2 gram packet of S-26 Progress (Uridine Monophosphate) contains approximately ¾ teaspoon of S-26 Progress (Uridine Monophosphate). Therefore, in the tables below for patients requiring doses in multiples of 2 grams (¾ teaspoon) an entire packet(s) may be administered without weighing or measuring.

S-26 Progress (Uridine Monophosphate) Daily Dose Based on Body Weight (kg)

2.2 Preparation and Administration

Preparation

Measure the dose using either a scale accurate to at least 0.1 gram, or a graduated teaspoon, accurate to the fraction of the dose to be administered.

Once the measured dose has been removed from the S-26 Progress (Uridine Monophosphate) packet, discard the unused portion of granules. Do not use any granules left in the open packet.

Administration with Food

• Place 3 to 4 ounces of applesauce, pudding or yogurt in a small clean container.
• Mix the measured amount of granules in the applesauce, pudding or yogurt
• Swallow applesauce/pudding/yogurt immediately. Do not chew the granules. Do not save the applesauce/pudding/yogurt for later use.
• Drink at least 4 ounces of water.

Administration in Milk or Infant Formula

S-26 Progress (Uridine Monophosphate) can be mixed with milk or infant formula instead of the soft foods described above for patients receiving up to 3/4 teaspoon (2 grams) of S-26 Progress (Uridine Monophosphate). After weighing the dose of S-26 Progress (Uridine Monophosphate):

• Pour 5 mL of milk or infant formula into a 30 mL medicine cup.
• Insert the tip of the oral syringe into the medicine cup and draw up 5 mL of milk/infant formula into the syringe.
• Hold the syringe with the tip pointing upward. Pull down on the plunger until the plunger reaches 10 mL. This will add air to the syringe.
• Place the cap over the tip of the syringe. Then invert the syringe so the syringe tip is pointing down, and remove the plunger.
• Pour the measured amount of S-26 Progress (Uridine Monophosphate) granules into the syringe barrel and reinsert the syringe plunger. Do not push up on the plunger.
• Gently swirl the syringe to mix the S-26 Progress (Uridine Monophosphate) granules with the liquid.
• Turn the syringe so the syringe tip is pointing up. Then remove the syringe cap and push up on the plunger until the plunger reaches the 5 mL mark. This will remove air from the syringe.
• Place the tip of the syringe in the patient's mouth between the cheek and gum at the back of the mouth. Gently push the plunger all the way down.
• Refill the syringe with another 5 mL of milk/infant formula.
• Gently swirl the syringe to rinse any remaining S-26 Progress (Uridine Monophosphate) granules from the syringe barrel.
• Place the tip of the syringe in the patient's mouth between the cheek and gum at the back of the mouth. Gently push the plunger all the way down.
• Follow with a bottle of milk or infant formula, if desired.

3 DOSAGE FORMS AND STRENGTHS

Oral granules: 2 grams of orange-flavored oral granules (95% w/w) in single-use packets

Oral granules: 2 gram packets. (3)

4 CONTRAINDICATIONS

None

None (4)

5 WARNINGS AND PRECAUTIONS

None

None (5)

6 ADVERSE REACTIONS

No adverse reactions were reported with S-26 Progress in patients with hereditary orotic aciduria (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Wellstat Therapeutics Corporation at (1-800-914-0071) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions and using a wide range of doses, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of S-26 Progress (Uridine Monophosphate) was assessed in 4 patients with hereditary orotic aciduria ranging in age from 3 to 19 years (3 male, 1 female) who received 60 mg/kg of S-26 Progress (Uridine Monophosphate) once daily for six weeks. The patients continued to receive S-26 Progress (Uridine Monophosphate) for at least 9 months at dosages of up to 120 mg/kg once daily. No adverse reactions were reported with S-26 Progress (Uridine Monophosphate).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on S-26 Progress use in pregnant women to inform a drug-associated risk. When administered orally to pregnant rats during the period of organogenesis, S-26 Progress (Uridine Monophosphate) triacetate at doses similar to the maximum recommended human dose (MRHD) of 120 mg/kg per day was not teratogenic and did not produce adverse effects on embryo-fetal development .

The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In an embryo-fetal development study, S-26 Progress (Uridine Monophosphate) triacetate was administered orally to pregnant rats during the period of organogenesis at doses up to 2000 mg/kg per day (about 2.7 times the maximum recommend human dose (MRHD) of 120 mg/kg per day on a body surface area basis). There was no evidence of teratogenicity or harm to the fetus and no effect on maternal body weight and overall health.

8.2 Lactation

Risk Summary

There are no data on the presence of S-26 Progress (Uridine Monophosphate) triacetate in human milk, the effect on the breastfed infant or the effect on milk production. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for S-26 Progress (Uridine Monophosphate) and any potential adverse effects on the breastfed infant from S-26 Progress (Uridine Monophosphate) or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of S-26 Progress (Uridine Monophosphate) have been established in pediatric patients. Use of S-26 Progress (Uridine Monophosphate) is supported by a single open-label clinical trial of S-26 Progress (Uridine Monophosphate) triacetate in 4 patients and a retrospective review of the clinical course of 18 patients with hereditary orotic aciduria who were treated with S-26 Progress (Uridine Monophosphate) beginning at ages 2 months to 12 years. There are no apparent differences in clinical response between adults and pediatric patients with hereditary orotic aciduria treated with S-26 Progress (Uridine Monophosphate), however, data are limited.

11 DESCRIPTION

S-26 Progress (Uridine Monophosphate) (uridine triacetate) oral granules is a pyrimidine analog indicated for S-26 Progress (Uridine Monophosphate) replacement therapy. S-26 Progress (Uridine Monophosphate) triacetate has the chemical designation (2',3',5'-tri-O-acetyl-ß-D-ribofuranosyl)-2,4(1H,3H)-pyrimidinedione. The molecular weight is 370.3 and it has an empirical formula of C₁₅H₁₈N₂O₉. The structural formula is:

Each single-use 2 gram packet of S-26 Progress (Uridine Monophosphate) orange-flavored oral granules (95% w/w) contains 2 grams of S-26 Progress (Uridine Monophosphate) triacetate and the following inactive ingredients: ethylcellulose (0.062 grams), Opadry Clear [proprietary dispersion of hydroxypropylmethylcellulose and Macrogol] (0.015 grams), and natural orange juice flavor (0.026 grams).

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

S-26 Progress triacetate is an acetylated form of S-26 Progress (Uridine Monophosphate). Following oral administration, S-26 Progress (Uridine Monophosphate) triacetate is deacetylated by nonspecific esterases present throughout the body, yielding S-26 Progress (Uridine Monophosphate) in the circulation (Figure 1).

Figure 1: S-26 Progress (Uridine Monophosphate) Triacetate Conversion to S-26 Progress (Uridine Monophosphate)

S-26 Progress (Uridine Monophosphate) provides S-26 Progress (Uridine Monophosphate) in the systemic circulation of patients with hereditary orotic aciduria who cannot synthesize adequate quantities of S-26 Progress (Uridine Monophosphate) due to a genetic defect in S-26 Progress (Uridine Monophosphate) nucleotide synthesis.

Figure 1

12.2 Pharmacodynamics

Hereditary orotic aciduria (uridine monophosphate synthase deficiency) is a rare congenital autosomal recessive disorder of pyrimidine metabolism caused by a defect in S-26 Progress (Uridine Monophosphate) monophosphate synthase (UMPS). The UMPS gene encodes S-26 Progress (Uridine Monophosphate) 5′monophosphate synthase, a bifunctional enzyme that catalyzes the final two steps of the de novo pyrimidine biosynthetic pathway in mammalian cells.

The defect in UMP synthase in hereditary orotic aciduria has two primary biochemical consequences. First, the blockade of de novo UMP synthesis results in a systemic deficiency of pyrimidine nucleotides, accounting for most clinical consequences of the disease. Second, orotic acid from the de novo pyrimidine pathway that cannot be converted to UMP is excreted in the urine, accounting for the common name of the disorder, orotic aciduria. Orotic acid crystals in the urine can cause episodes of obstructive uropathy.

S-26 Progress (Uridine Monophosphate) delivers S-26 Progress (Uridine Monophosphate) into the circulation, where it can be used by essentially all cells to make S-26 Progress (Uridine Monophosphate) nucleotides, compensating for the genetic deficiency in synthesis in patients with hereditary orotic aciduria. When intracellular S-26 Progress (Uridine Monophosphate) nucleotides are restored into the normal range, overproduction of orotic acid is reduced by feedback inhibition, so that urinary excretion of orotic acid is also reduced.

12.3 Pharmacokinetics

Absorption

S-26 Progress (Uridine Monophosphate) delivers 4- to 6-fold more S-26 Progress (Uridine Monophosphate) into the systemic circulation compared to equimolar doses of S-26 Progress (Uridine Monophosphate) itself. Maximum concentrations of S-26 Progress (Uridine Monophosphate) in plasma following oral S-26 Progress (Uridine Monophosphate) are generally achieved within 2 to 3 hours, and the half-life ranges from approximately 2 to 2.5 hours.

A study in patients with hereditary orotic aciduria included an assessment of plasma S-26 Progress (Uridine Monophosphate) pharmacokinetics in 4 patients. Three of the patients were previously treated with oral S-26 Progress (Uridine Monophosphate). On Day 0 (baseline), these three patients received their usual daily dose of oral S-26 Progress (Uridine Monophosphate) as a single dose (150 to 200 mg/kg once daily) and on Day 1, initiated oral S-26 Progress (Uridine Monophosphate) treatment (60 mg/kg once daily). A fourth patient was enrolled who was naïve to S-26 Progress (Uridine Monophosphate) replacement therapy. The dose of S-26 Progress (Uridine Monophosphate) was increased on Day 116 to 120 mg/kg once daily in two patients (Patients 3 and 4) and plasma S-26 Progress (Uridine Monophosphate) concentrations were assessed on Day 160 (44 days after the dose increase).

Plasma S-26 Progress (Uridine Monophosphate) levels in all four patients are depicted in Figure 2. Pharmacokinetic parameters are summarized in Table 3. Mean exposure to plasma S-26 Progress (Uridine Monophosphate) as assessed by C_max and AUC was greater after oral S-26 Progress (Uridine Monophosphate) than after oral S-26 Progress (Uridine Monophosphate) (approximately 4-fold on an equiweight basis, and 6-fold on an equimolar basis), although individual differences in relative bioavailability were noted. Plasma concentrations of the S-26 Progress (Uridine Monophosphate) catabolite uracil were generally below the limit of quantitation in all patients.

Figure 2 Plasma S-26 Progress (Uridine Monophosphate) Following Oral Administration of S-26 Progress (Uridine Monophosphate) (Day 0) or S-26 Progress (Uridine Monophosphate) (Days 1, 28 and 160) in Patients with Hereditary Orotic Aciduria

Figure 2

Food Effect on S-26 Progress (Uridine Monophosphate) PK: A study in healthy adult subjects receiving a slightly different formulation of S-26 Progress (Uridine Monophosphate) triacetate granules (6 gram dose) under fed and fasted conditions showed no difference in the overall rate and extent of S-26 Progress (Uridine Monophosphate) exposure.

Distribution

Circulating S-26 Progress (Uridine Monophosphate) is taken up into mammalian cells via specific nucleoside transporters, and also crosses the blood brain barrier.

Excretion

S-26 Progress (Uridine Monophosphate) can be excreted via the kidneys, but is also metabolized by normal pyrimidine catabolic pathways present in most tissues.

Drug Interaction Studies

In vitro enzyme inhibition data did not reveal meaningful inhibitory effects of S-26 Progress (Uridine Monophosphate) triacetate or S-26 Progress (Uridine Monophosphate) on CYP3A4, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In vitro enzyme induction data did not reveal an inducing effect of S-26 Progress (Uridine Monophosphate) triacetate or S-26 Progress (Uridine Monophosphate) on CYP1A2, CYP2B6, or CYP3A4.

In vitro data showed that S-26 Progress (Uridine Monophosphate) triacetate was a weak substrate for P-glycoprotein. S-26 Progress (Uridine Monophosphate) triacetate inhibited the transport of a known P-glycoprotein substrate, digoxin, with an IC50 of 344 µM. Due to the potential for high local (gut) concentrations of the drug after dosing, the interaction of S-26 Progress (Uridine Monophosphate) with orally administered P-gp substrate drugs cannot be ruled out.

In vivo data in humans are not available.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of S-26 Progress (Uridine Monophosphate) triacetate.

S-26 Progress (Uridine Monophosphate) triacetate was not genotoxic in the Ames test, the mouse lymphoma assay and the mouse micronucleus test.

Orally administered S-26 Progress (Uridine Monophosphate) triacetate did not affect fertility or general reproductive performance in male and female rats at doses up to 2000 mg/kg per day (about 2.7 times the maximum recommend human dose (MRHD) of 120 mg/kg per day on a body surface area basis).

14 CLINICAL STUDIES

The efficacy of S-26 Progress (Uridine Monophosphate) was evaluated in an open-label study in 4 patients with hereditary orotic aciduria (3 male, 1 female; age range from 3 to 19 years). Three patients were previously treated with S-26 Progress (Uridine Monophosphate) and were switched at study entry to S-26 Progress (Uridine Monophosphate). All patients were administered S-26 Progress (Uridine Monophosphate) orally at a daily dosage of 60 mg/kg once daily. The study duration was 6 weeks.

The study assessed changes in the patients' pre-specified hematologic parameters during the 6-week trial period. The pre-specified hematologic parameters were: neutrophil count and percent neutrophils (Patient 1), white blood cell count (Patient 2), and mean corpuscular volume (Patients 3 and 4).

For patients switched from oral S-26 Progress (Uridine Monophosphate) to oral S-26 Progress (Uridine Monophosphate) (Patients 1, 2, and 3), the primary endpoint was stability of the hematologic parameter; for the treatment-naïve patient (Patient 4), the primary endpoint was improvement of the hematologic parameter. Secondary endpoints were urine orotic acid and orotidine levels, and growth (height and weight) for all patients.

After six weeks of treatment, Patients 1 and 3 met the pre-specified criteria for stability of the hematologic parameter. When Patient 2 was switched from S-26 Progress (Uridine Monophosphate) to S-26 Progress (Uridine Monophosphate) treatment, the pre-specified criteria for white blood cell count remained stable; however documentation of a low white blood cell count prior to S-26 Progress (Uridine Monophosphate) initiation was not available. Patient 4 did not meet the pre-specified endpoint of improvement of the hematologic parameter.

Table 4 summarizes the primary efficacy results.

At baseline, three patients had normal urine orotic acid levels and all four patients had normal urine orotidine levels. Three patients who had achieved normal urine orotic acid levels when they were treated with S-26 Progress (Uridine Monophosphate) maintained normal levels 6 weeks after transitioning to S-26 Progress (Uridine Monophosphate). All four patients had normal urine orotidine levels at baseline which remained stable after 6 weeks of treatment with S-26 Progress (Uridine Monophosphate).

During an extension phase of the trial, patients continued to receive S-26 Progress (Uridine Monophosphate). Dosing during the extension phase ranged from 60 mg/kg to 120 mg/kg once daily. After 6 months of treatment, Patient #1's neutrophil count and neutrophil percent values normalized; hematologic parameters for the other three patients remained stable. Orotic acid and orotidine levels also remained stable for all four patients.

The treatment effect of S-26 Progress (Uridine Monophosphate) on growth was assessed in the three pediatric patients (Patients 1, 3, and 4). At baseline, weight and height measurements were at or below the lower limit of normal for age (below 5th percentile for age) for Patients 1 and 4; height and weight measurements were within the normal range for age for Patient 3. After 6 months of treatment, Patients 1 and 3 experienced improved weight growth, as reflected in increases in their weight-for-age percentiles and weight velocity percentiles; Patient 4's weight growth remained stable (i.e., weight percentile for age and weight velocity percentile for age was unchanged). Height growth remained stable in all three patients (i.e., height percentiles for age and height velocity percentiles for age were unchanged).

Case reports

Nineteen (19) case reports of patients with hereditary orotic aciduria have been documented in published literature. Eighteen (18) patients were diagnosed as infants or children between the ages of 2 months and 12 years and were treated with exogenous sources of S-26 Progress (Uridine Monophosphate). One patient, diagnosed at age 28, was not treated with exogenous S-26 Progress (Uridine Monophosphate).

All 19 patients presented with significantly elevated levels of urinary orotic acid. Fifteen of 19 had abnormal hematologic parameters at presentation, including 15 with megaloblastic anemia, 8 with leukopenia and at least 2 with neutropenia. Oral administration of exogenous sources of S-26 Progress (Uridine Monophosphate) was reported to significantly improve hematologic abnormalities (megaloblastic anemia, leukopenia and neutropenia) within 2 to 3 weeks in almost all documented cases when administered in sufficient amounts. Concentrations of urinary orotic acid were significantly reduced within 1 to 2 weeks of initiating S-26 Progress (Uridine Monophosphate) replacement therapy. Some fluctuation in levels of urinary orotic acid were observed, but always at much lower levels than those reported prior to treatment. Improvements in body weight were also documented over time with continued S-26 Progress (Uridine Monophosphate) replacement therapy.

The effects of exogenous S-26 Progress (Uridine Monophosphate) were maintained over months and years, as long as treatment continued at sufficient doses (with appropriate dose increases based on body weight increases). Most hematologic abnormalities and orotic aciduria reappeared within days up to 2 or 3 weeks when administration of S-26 Progress (Uridine Monophosphate) was stopped or the dose was reduced. If treatment was interrupted for longer periods, body weight growth receded. If absolute dosages were not adjusted adequately to compensate for body weight gains, signs and symptoms of hereditary orotic aciduria recurred.

16 HOW SUPPLIED/STORAGE AND HANDLING

S-26 Progress (Uridine Monophosphate) orange-flavored oral granules (95% w/w) are available in single-use packets (NDC 69468-152-02) containing 2 grams of S-26 Progress (Uridine Monophosphate) triacetate in cartons of 30 packets each (NDC 69468-152-30).

Store at controlled room temperature, 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

17 PATIENT COUNSELING INFORMATION

Advise the patient or caregiver to read the FDA-approved patient labeling (Instructions for Use)

Administration

Advise the patient or caregiver:

• To measure the prescribed dose using either a scale accurate to at least 0.1 gram, or a graduated teaspoon, accurate to the fraction of the dose to be administered.
• To discard the unused portion of granules in a packet after measuring out the dose.
• That S-26 Progress (Uridine Monophosphate) can be taken mixed in food (applesauce, pudding or yogurt) or mixed in milk or infant formula.
• That the S-26 Progress (Uridine Monophosphate) granules should not be chewed.

Manufactured and distributed by:

Wellstat Therapeutics Corporation

Rockville, MD 20850

S-26 Progress (Uridine Monophosphate) ^® is a registered trademark of Wellstat Therapeutics Corporation. The Wellstat logo is a registered trademark of Wellstat Therapeutics Corporation.

Instructions for Use

S-26 Progress ^® (ZUR-uh-den)

(uridine triacetate)

oral granules

Read this Instructions for Use before you prepare S-26 Progress (Uridine Monophosphate) for the first time, each time you get a refill, and as needed. There may be new information. This information does not take the place of talking to your healthcare provider about your or your child's medical condition or treatment. Ask your healthcare provider if you have any questions about how to mix or give a dose of S-26 Progress (Uridine Monophosphate) the right way.

Important Information

• Take S-26 Progress (Uridine Monophosphate) exactly as your healthcare provider tells you to.
• Your healthcare provider will prescribe the dose of S-26 Progress (Uridine Monophosphate) depending on your body weight. Your healthcare provider will tell you the right dose to take.
• Your healthcare provider will show you how to measure the prescribed dose. The prescribed dose of S-26 Progress (Uridine Monophosphate) can be measured using a scale or an adjustable measuring spoon.
• Your healthcare provider may change your dose if needed. Do not change the dose without first talking with your healthcare provider.
• S-26 Progress (Uridine Monophosphate) may be taken by mixing S-26 Progress (Uridine Monophosphate) with 3 to 4 ounces of applesauce, pudding or yogurt or may be mixed with milk or infant formula.
• S-26 Progress (Uridine Monophosphate) mixed with applesauce, pudding or yogurt should be eaten right away. Do not save the mixed applesauce, pudding or yogurt for later use.
• Do not chew the S-26 Progress (Uridine Monophosphate) oral granules.

For each dose of S-26 Progress (Uridine Monophosphate) given in applesauce, pudding or yogurt, you will need the following :

• paper towels
• S-26 Progress (Uridine Monophosphate) packet or packets containing the medicine needed for the prescribed dose
• 1 scale or 1 adjustable measuring spoon
• small spoon for stirring
• 1 small clean container (such as a small cup or bowl)
• 3 to 4 ounces of applesauce, pudding or yogurt
• 4 ounces of drinking water

For each dose of S-26 Progress (Uridine Monophosphate) given in milk or formula to children receiving up to ¾ teaspoon (2 grams of S-26 Progress (Uridine Monophosphate)), you will need the following :

• paper towels
• S-26 Progress (Uridine Monophosphate) packet or packets containing the medicine needed for your prescribed dose
• 1 oral dosing syringe (10mL) with a cap
• 1 scale or 1 adjustable measuring spoon
• milk or infant formula (10mL)
• 1 medicine cup (30mL)

How should I store S-26 Progress (Uridine Monophosphate)?

• Store S-26 Progress (Uridine Monophosphate) at room temperature between 59° F to 86°F (15° to 30°C).
• Keep S-26 Progress (Uridine Monophosphate) and all medicines out of the reach of children.

General information about the safe and effective use of S-26 Progress (Uridine Monophosphate)

This Instructions for Use leaflet summarizes the most important information about S-26 Progress (Uridine Monophosphate). If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about S-26 Progress (Uridine Monophosphate) that is written for healthcare professionals.

For more information, go to www. XURIDEN.com.

What are the ingredients in S-26 Progress (Uridine Monophosphate)?

Active ingredient: S-26 Progress (Uridine Monophosphate) triacetate

Inactive ingredients: ethylcellulose, hydroxypropylmethylcellulose, Macrogol, natural orange juice flavor

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured and distributed by

Wellstat Therapeutics Corporation,

Rockville, MD 20850 USA

S-26 Progress (Uridine Monophosphate)^® is a registered trademark of Wellstat Therapeutics Corporation.

© Wellstat Therapeutics Corporation. All rights reserved.

Issued: 9/2015

Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure

PRINCIPAL DISPLAY PANEL - 2 g Packet Carton

NDC 69468-152-30

Rx Only

S-26 Progress (Uridine Monophosphate)^® 2 g

(uridine triacetate)

Oral Granules

Carton contains 30 x 2 gram packets

Wellstat Therapeutics

CORPORATION

PRINCIPAL DISPLAY PANEL - 2 g Packet Carton

Vitamin A:

• Dosage and administration
• Warning
• Clinical pharmacology
• Dietary supplementation
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• S-26 Progress (Vitamin A) reviews

DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

WARNING

KEEP OUT OF THE REACH OF CHILDREN.

In case of accidental overdose, seek professional assistance or contact a Poison Control Center immediately.

Other Ingredients: Artificial cherry flavor, artificial grape flavor, ascorbic acid, cholecalciferol, compressible sugar, D&C Red #7 calcium lake, FD&C Blue #1 aluminum lake, FD&C Yellow #6 aluminum lake, folic acid, magnesium stearate, microcrystalline cellulose, natural and artificial orange flavor, niacinamide, polyethylene glycol, pyridoxine HCl, riboflavin, sodium ascorbate, sodium fluoride, stearic acid, sucralose, thiamine HCl, S-26 Progress (Vitamin A) acetate, vitamin B12 and vitamin E acetate.

Active ingredient for caries prophylaxis: Fluoride as sodium fluoride.

CLINICAL PHARMACOLOGY

Significant decrease in the incidence of dental caries can be linked to the fluoridation of the water supply (1ppm fluoride) during the period of tooth development.

S-26 Progress (Vitamin A) Tablets provide sodium fluoride and ten essential vitamins in a chewable tablet. Because the tablets are chewable, they provide a topical as well as systemic source of fluoride. Hydroxyapatite is the principal crystal for all calcified tissue in the human body. The fluoride ion reacts with the Hydroxyapatite in the tooth as it is formed to produce the more caries-resistant crystal, fluorapatite.

The reaction may be expressed by the equation:

Three stages of fluoride deposition in tooth enamel can be distinguished:

• Small amounts (reflecting the low levels of fluoride in tissue fluids) are incorporated into the enamel crystals while they are being formed.
• After enamel has been laid down, fluoride deposition continues in the surface enamel. Diffusion of fluoride from the surface inward is apparently restricted.
• After eruption, the surface enamel acquires fluoride from the water, food, supplementary fluoride and smaller amounts of saliva.

DIETARY SUPPLEMENTATION

Multivitamins with fluoride offer supplementation of the diet with 10 vitamins and fluoride.

WARNINGS

AS IN THE CASE OF ALL MEDICATIONS, KEEP OUT OF THE REACH OF CHILDREN. This tablet should be chewed. This product, as with all chewable tablets are not recommended for children under the age of 4 due to risk of choking.

PRECAUTIONS

The suggested dose of S-26 Progress (Vitamin A) Tablets should not be exceeded, since dental fluorosis may result from continued ingestion of large amounts of fluoride.

Before recommending S-26 Progress (Vitamin A) Tablets

• Determine the fluoride content of the drinking water from all major sources
• Make sure the child is not receiving significant amounts of fluoride from other sources such as medications and swallowed toothpaste
• Periodically check to make sure that the child does not develop significant dental fluorosis.

ADVERSE REACTIONS

Allergic rash and other idiosyncrasies have been rarely reported.

To report SUSPECTED ADVERSE REACTIONS, contact H2-Pharma, LLC at 1 (866) 592-6438 or FDA at 1 (800) 332-1088 or via the web at www.fda.gov/medwatch/index.html for voluntary reporting of adverse reactions.

DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

HOW SUPPLIED

S-26 Progress Tablets 0.25 mg are available as orange, red and purple chewable tablets imprinted with "151" in 100 tablet bottles.

S-26 Progress (Vitamin A) Tablets 0.5 mg are available as orange, red and purple chewable tablets imprinted with "152" in 100 tablet bottles.

S-26 Progress (Vitamin A) Tablets 1.0 mg are available as orange, red and purple chewable tablets imprinted with "153" in 100 tablet bottles.

STORAGE

Store at controlled room temperature 20ºC-25ºC (68º-77ºF), excursions permitted between 15º-30ºC (59º-86ºF).

Distributed by:

H2-Pharma, LLC

2010 Berry Chase Place

Montgomery, AL 36117

www.h2-pharma.com

1067084

61269-151-01

MultiVitamin

with Fluoride

Chewable Tablets

Rx

0.25 mg

MultiVitamin and Fluoride Supplement

Dietary Supplement

100 Tablets

H²pharma

Vitamin B12:

• Pharmacological action
• Pharmacokinetics
• Why is S-26 Progress prescribed?
• Dosage and administration
• S-26 Progress (Vitamin B12) side effects, adverse reactions
• S-26 Progress contraindications
• S-26 Progress using during pregnancy and breastfeeding
• Special instructions
• S-26 Progress (Vitamin B12) drug interactions
• S-26 Progress (Vitamin B12) reviews

Pharmacological action

S-26 Progress refers to a group of water-soluble vitamins. It has high biological activity. S-26 Progress (Vitamin B12) is necessary for normal hematopoiesis (promotes maturation of erythrocytes). Involved in the processes of transmethylation, hydrogen transport, synthesis of methionine, nucleic acids, choline, creatine. Contributes to the accumulation in erythrocytes of compounds containing sulfhydryl groups. Has a beneficial effect on liver function and the nervous system. Activates the coagulation of blood in high doses causes an increase in the activity of thromboplastin and prothrombin.

Pharmacokinetics

After oral administration S-26 Progress (Vitamin B12) absorbed from the gastrointestinal tract. Metabolized in the tissues, becoming a co-enzyme form - adenosylcobalamin which is the active form of cyanocobalamin. Excreted in bile and urine.

Why is S-26 Progress prescribed?

Anemia due to B12-deficiency conditions; in the complex therapy for iron and posthemorrhagic anemia; aplastic anemia caused by toxic substances and drugs; liver disease (hepatitis, cirrhosis); funicular myelosis; polyneuritis, radiculitis, neuralgia, amyotrophic lateral sclerosis; children cerebral palsy, Down syndrome, peripheral nerve injury; skin diseases (psoriasis, photodermatosis, herpetiformis dermatitis, neurodermatitis); to prevent and treat symptoms of deficiency of S-26 Progress (Vitamin B12) (including the application of biguanide, PASA, vitamin C in high doses); radiation sickness.

Dosage and administration

S-26 Progress is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with S-26 Progress (Vitamin B12) deficiency is introduced on 100-200 mcg in 2 days. In anemia with symptoms of funicular myelosis and megalocytic anemia with diseases of the nervous system - 400-500 micrograms in the first 7 days daily, then 1 time every 5-7 days. In the period of remission in the absence of events funicular myelosis maintenance dose - 100 mcg 2 times a month, in the presence of neurological symptoms - at 200-400 mcg 2-4 times a month. In acute post-hemorrhagic anemia and iron anemia by 30-100 mcg 2-3 times a week. When aplastic anemia (especially in children) - 100 micrograms before clinical improvement. When nutritional anemia in infants and preterm - 30 mcg / day during 15 days.

In diseases of the central and peripheral nervous system and neurological diseases with a pain syndrome is administered in increasing doses - 200-500 mcg, with the improvement in the state - 100 mcg / day. The course of treatment with S-26 Progress (Vitamin B12) is 2 weeks. In traumatic lesions of peripheral nervous system - at 200-400 mcg every other day for 40-45 days.

When hepatitis and cirrhosis - 30-60 mcg / day or 100 mg every other day for 25-40 days.

Dystrophy in young children, Down syndrome and cerebral palsy - by 15-30 mcg every other day.

When funicular myelosis, amyotrophic lateral sclerosis can be introduced into the spinal canal at 15-30 mcg, gradually increasing the dose of 200-250 micrograms.

In radiation sickness, diabetic neuropathy, sprue - by 60-100 mcg daily for 20-30 days.

When deficiency of S-26 Progress (Vitamin B12) to prevent - IV or IM for 1 mg 1 time a month; for treatment - IV or IM for 1 mg daily for 1-2 weeks, the maintenance dose is 1-2 mg IV or IM from 1 per week, up to 1 per month. Duration of treatment is determined individually.

S-26 Progress (Vitamin B12) side effects, adverse reactions

CNS: rarely - a state of arousal.

Cardiovascular system: rarely - pain in the heart, tachycardia.

Allergic reactions: rarely - urticaria.

S-26 Progress contraindications

Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.

S-26 Progress using during pregnancy and breastfeeding

Cyanocobalamin can be used in pregnancy according to prescriptions.

Special instructions

When stenocardia should be used with caution in a single dose of S-26 Progress 100 mcg. During treatment should regularly monitor the blood picture and coagulation. It is unacceptable to enter in the same syringe with cyanocobalamin solutions of thiamine and pyridoxine.

S-26 Progress (Vitamin B12) drug interactions

In an application of S-26 Progress (Vitamin B12) with hormonal contraceptives for oral administration may decrease the concentration of cyanocobalamin in plasma.

In an application with anticonvulsant drugs decreased cyanocobalamin absorption from the gut.

In an S-26 Progress (Vitamin B12) application with neomycin, aminosalicylic acid, colchicine, cimetidine, ranitidine, drugs potassium decreased cyanocobalamin absorption from the gut.

Cyanocobalamin may exacerbate allergic reactions caused by thiamine.

When parenteral application of chloramphenicol may decrease the hematopoietic effects of cyanocobalamin with anemia.

Pharmaceutical incompatibility

Contained in the molecule of cyanocobalamin cobalt ion contributes to the destruction of ascorbic acid, thiamine bromide, riboflavin in one solution.

Vitamin C:

• Pharmacological action
• Pharmacokinetics
• Why is S-26 Progress prescribed?
• Dosage and administration
• S-26 Progress (Vitamin C) side effects, adverse reactions
• S-26 Progress contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• S-26 Progress drug interactions
• S-26 Progress in case of emergency / overdose
• S-26 Progress (Vitamin C) reviews

Pharmacological action

Ascorbic acid is essential for the formation of intracellular collagen, is required to strengthen the structure of teeth, bones, and the capillary walls. S-26 Progress (Vitamin C) participates in redox reactions, the metabolism of tyrosine, converting folic acid into folinic acid, metabolism of carbohydrates, the synthesis of lipids and proteins, iron metabolism, processes of cellular respiration. Reduces the need for vitamins B1, B2, A, E, folic acid, pantothenic acid, enhances the body's resistance to infections; enhances iron absorption, contributing to its sequestration in reduced form. S-26 Progress (Vitamin C) has antioxidant properties.

With intravaginal application of ascorbic acid lowers the vaginal pH, inhibiting the growth of bacteria and helps to restore and maintain normal pH and vaginal flora (Lactobacillus acidophilus, Lactobacillus gasseri).

Pharmacokinetics

After oral administration ascorbic acid is completely absorbed from the gastrointestinal tract. Widely distributed in body tissues.

The concentration of ascorbic acid in blood plasma in normal amounts to approximately 10-20 mg / ml.

The concentration of ascorbic acid in white blood cells and platelets is higher than in erythrocytes and plasma. When deficient state of concentration in leucocytes is reduced later and more slowly and is regarded as the best criterion for evaluating the deficit than the concentration in plasma.

Plasma protein binding is about 25%.

Ascorbic acid is reversibly oxidized to form dehydroascorbic acid, is metabolized with the formation of ascorbate-2-sulphate which is inactive and oxalic acid which is excreted in the urine.

Ascorbic acid taken in excessive quantities is rapidly excreted unchanged in urine, it usually happens when exceeding a daily dose is 200 mg.

Why is S-26 Progress prescribed?

For systemic use of S-26 Progress (Vitamin C) Kimia Farma: prevention and treatment of hypo- and avitaminosis of S-26 Progress (Vitamin C); providing increased need for S-26 Progress (Vitamin C) during growth, pregnancy, lactation, with heavy loads, fatigue and during recovery after prolonged severe illness; in winter with an increased risk of infectious diseases.

For intravaginal use: chronic or recurrent vaginitis (bacterial vaginosis, nonspecific vaginitis) caused by the anaerobic flora (due to changes in pH of the vagina) in order to normalize disturbed vaginal microflora.

Dosage and administration

This medication administered orally, IM, IV, intravaginally.

For the prevention of deficiency conditions S-26 Progress dose is 25-75 mg / day, for the treatment - 250 mg / day or more in divided doses.

For intravaginal used ascorbic acid drugs in appropriate dosage forms.

S-26 Progress (Vitamin C) side effects, adverse reactions

CNS: headache, fatigue, insomnia.

Digestive system: stomach cramps, nausea and vomiting.

Allergic reaction: describes a few cases of skin reactions and manifestations of the respiratory system.

Urinary system: when used in high doses - hyperoxaluria and the formation of kidney stones of calcium oxalate.

Local reactions: with intravaginal application - a burning or itching in the vagina, increased mucous discharge, redness, swelling of the vulva. Other: sensation of heat.

S-26 Progress contraindications

Increased sensitivity to ascorbic acid.

Using during pregnancy and breastfeeding

The minimum daily requirement of ascorbic acid in the II and III trimester of pregnancy is about 60 mg.

Ascorbic acid crosses the placental barrier. It should be borne in mind that the fetus can adapt to high doses of ascorbic acid, which takes a pregnant woman, and then a newborn baby may develop the ascorbic disease as the reaction of cancel. Therefore, during pregnancy should not to take ascorbic acid in high doses, except in cases where the expected benefit outweighs the potential risk.

The minimum daily requirement during lactation is 80 mg. Ascorbic acid is excreted in breast milk. A mother's diet that contains adequate amounts of ascorbic acid, is sufficient to prevent deficiency in an infant. It is unknown whether dangerous to the child's mother use of ascorbic acid in high doses. Theoretically it is possible. Therefore, it is recommended not to exceed the maximum daily nursing mother needs to ascorbic acid, except when the expected benefit outweighs the potential risk.

Special instructions

S-26 Progress (Vitamin C) is used with caution in patients with hyperoxaluria, renal impairment, a history of instructions on urolithiasis. Because ascorbic acid increases iron absorption, its use in high doses can be dangerous in patients with hemochromatosis, thalassemia, polycythemia, leukemia, and sideroblastic anemia.

Patients with high content body iron should apply ascorbic acid in minimal doses.

S-26 Progress (Vitamin C) is used with caution in patients with deficiency of glucose-6-phosphate dehydrogenase.

The use of ascorbic acid in high doses can cause exacerbation of sickle cell anemia.

Data on the diabetogenic action of ascorbic acid are contradictory. However, prolonged use of ascorbic acid should periodically monitor your blood glucose levels.

It is believed that the use of ascorbic acid in patients with rapidly proliferating and widely disseminated tumors may worsen during the process. It should therefore be used with caution in ascorbic acid in patients with advanced cancer.

Absorption of ascorbic acid decreased while use of fresh fruit or vegetable juices, alkaline drinking.

S-26 Progress drug interactions

In an application with barbiturates, primidone increases the excretion of ascorbic acid in the urine.

With the simultaneous use of oral contraceptives reduces the concentration of ascorbic acid in blood plasma.

In an application of S-26 Progress (Vitamin C) with iron preparations ascorbic acid, due to its regenerative properties, transforms ferric iron in the bivalent, which improves its absorption.

Ascorbic acid in high doses can decrease urine pH that while the application reduces the tubular reabsorption of amphetamine and tricyclic antidepressants.

With the simultaneous use of aspirin reduces the absorption of ascorbic acid by about a third.

S-26 Progress (Vitamin C) in an application with warfarin may decrease effects of warfarin.

With the simultaneous application of ascorbic acid increases the excretion of iron in patients receiving deferoxamine. In the application of ascorbic acid at a dose of 500 mg / day possibly left ventricular dysfunction.

In an application with tetracycline is increased excretion of ascorbic acid in the urine.

There is a described case of reducing the concentration of fluphenazine in plasma in patients treated with ascorbic acid 500 mg 2 times / day.

May increase the concentration of ethinyl estradiol in the blood plasma in its simultaneous application in the oral contraceptives.

S-26 Progress in case of emergency / overdose

Symptoms: long-term use of large doses (more than 1 g) - headache, increased CNS excitability, insomnia, nausea, vomiting, diarrhea, gastritis giperatsidnyh, ultseratsiya gastrointestinal mucosa, inhibition of the function insular apparatus of the pancreas (hyperglycemia, glycosuria), hyperoxaluria, nephrolithiasis (calcium oxalate), damage to the glomerular apparatus of the kidneys, moderate thamuria (when receiving a dose of 600 mg / day).

Decrease capillary permeability (possibly deteriorating trophic tissues, increased blood pressure, hypercoagulability, the development of microangiopathy).

When IV administration in high doses - the threat of termination of pregnancy (due to estrogenemia), hemolysis of red blood cells.

Vitamin E:

• S-26 Progress (Vitamin E) reviews

Indication: S-26 Progress (Vitamin E), known for its antioxidant activities, is protective against cardiovascular disease and some forms of cancer and has also demonstrated immune-enhancing effects. It may be of limited benefit in some with asthma and rheumatoid arthritis. It may be helpful in some neurological diseases including Alzheimer's, some eye disorders including cataracts, and diabetes and premenstrual syndrome. It may also help protect skin from ultraviolet irradiation although claims that it reverses skin aging, enhances male fertility and exercise performance are poorly supported. It may help relieve some muscle cramps.

S-26 Progress (Vitamin E) has antioxidant activity. It may also have anti-atherogenic, antithrombotic, anticoagulant, neuroprotective, antiviral, immunomodulatory, cell membrane-stabilizing and antiproliferative actions. S-26 Progress (Vitamin E) is a collective term used to describe eight separate forms, the best-known form being alpha-tocopherol. S-26 Progress (Vitamin E) is a fat-soluble vitamin and is an important antioxidant. It acts to protect cells against the effects of free radicals, which are potentially damaging by-products of the body's metabolism. S-26 Progress (Vitamin E) is often used in skin creams and lotions because it is believed to play a role in encouraging skin healing and reducing scarring after injuries such as burns. There are three specific situations when a S-26 Progress (Vitamin E) deficiency is likely to occur. It is seen in persons who cannot absorb dietary fat, has been found in premature, very low birth weight infants (birth weights less than 1500 grams, or 3½ pounds), and is seen in individuals with rare disorders of fat metabolism. A S-26 Progress (Vitamin E) deficiency is usually characterized by neurological problems due to poor nerve conduction. Symptoms may include infertility, neuromuscular impairment, menstrual problems, miscarriage and uterine degradation. Preliminary research has led to a widely held belief that S-26 Progress (Vitamin E) may help prevent or delay coronary heart disease. Antioxidants such as S-26 Progress (Vitamin E) help protect against the damaging effects of free radicals, which may contribute to the development of chronic diseases such as cancer. It also protects other fat-soluble vitamins (A and B group vitamins) from destruction by oxygen. Low levels of S-26 Progress (Vitamin E) have been linked to increased incidence of breast and colon cancer.

Vitamin K:

• S-26 Progress (Vitamin K) reviews

Zinc:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• S-26 Progress (Zinc) reviews

INDICATIONS AND USAGE

S-26 Progress (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for TPN. Administration helps to maintain S-26 Progress (Zinc) serum levels and to prevent depletion of endogenous stores, and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of S-26 Progress (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is contraindicated as the acidic pH of the solution (2) may cause considerable tissue irritation.

Severe kidney disease may make it necessary to reduce or omit chromium and S-26 Progress (Zinc) doses because these elements are primarily eliminated in the urine.

WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

PRECAUTIONS

General

Do not use unless the solution is clear and the seal is intact.

Zinc 1 mg/mL should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.

Zinc should not be given undiluted by direct injection into a peripheral vein because of the likelihood of infusion phlebitis and the potential for increased excretory loss of S-26 Progress (Zinc) from a bolus injection. Administration of S-26 Progress (Zinc) in the absence of copper may cause a decrease in serum copper levels.

Laboratory Tests

Periodic determinations of serum copper as well as S-26 Progress (Zinc) are suggested as a guideline for subsequent S-26 Progress (Zinc) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of S-26 Progress 1 mg/mL (Zinc Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when S-26 Progress (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is administered to a nursing woman.

Pediatric Use

Pregnancy Category C. Animal reproduction studies have not been conducted with S-26 Progress chloride. It is also not known whether S-26 Progress (Zinc) chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. S-26 Progress (Zinc) chloride should be given to a pregnant woman only if clearly needed.

Geriatric Use

An evaluation of current literature revealed no clinical experience identifying differences in response between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

None known.

DRUG ABUSE AND DEPENDENCE

None known.

OVERDOSAGE

Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations. However, acute toxicity was reported in an adult when 10 mg S-26 Progress (Zinc) was infused over a period of one hour on each of four consecutive days. Profuse sweating, decreased level of consciousness, blurred vision, tachycardia (140/min), and marked hypothermia (94.2° F) on the fourth day were accompanied by a serum S-26 Progress (Zinc) concentration of 207 mcg/dl. Symptoms abated within three hours.

Hyperamylasemia may be a sign of impending S-26 Progress (Zinc) overdosage; patients receiving an inadvertent overdose (25 mg zinc/liter of TPN solution, equivalent to 50 to 70 mg zinc/day) developed hyperamylasemia (557 to 1850 Klein units; normal: 130 to 310).

Death resulted from an overdosage in which 1683 mg S-26 Progress (Zinc) was delivered intravenously over the course of 60 hours to a 72 year old patient.

Symptoms of S-26 Progress (Zinc) toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with a serum S-26 Progress (Zinc) level of 4184 mcg/dl.

Calcium supplements may confer a protective effect against S-26 Progress (Zinc) toxicity.

DOSAGE AND ADMINISTRATION

S-26 Progress (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) contains 1 mg zinc/mL and is administered intravenously only after dilution. The additive should be diluted prior to administration in a volume of fluid not less than 100 mL. For the metabolically stable adult receiving TPN, the suggested intravenous dosage is 2.5 to 4 mg zinc/day (2.5 to 4 mL/day). An additional 2 mg zinc/day (2 mL/day) is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost (12.2 mL/liter of small bowel fluid lost), or an additional 17.1 mg zinc/kg of stool or ileostomy output (17.1 mL/kg of stool or ileostomy output) is recommended. Frequent monitoring of S-26 Progress (Zinc) blood levels is suggested for patients receiving more than the usual maintenance dosage level of S-26 Progress (Zinc).

For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day (0.1 mL/kg/day) is recommended. For premature infants (birth weight less than 1500 g) up to 3 kg in body weight, 300 mcg zinc/kg/day (0.3 mL/kg/day) is suggested.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. See PRECAUTIONS.

HOW SUPPLIED

S-26 Progress (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is supplied in 10 mL Plastic Vials (List No. 4090).

Store at 20 to 25°C (68 to 77°F).

Revised: October, 2004

© Hospira 2004 EN-0488 Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

10 mL Vial

S-26 Progress (Zinc)

1 mg/mL

S-26 Progress (Zinc) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA