ProMod

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
• ProMod (Calcium) reviews

1 INDICATIONS AND USAGE

ProMod (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 ProMod (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 ProMod (Calcium) acetate capsule.

- Capsule: 667 mg ProMod (Calcium) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting ProMod acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of ProMod (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 ProMod (Calcium), including ProMod (Calcium) acetate. Avoid the use of ProMod (Calcium) supplements, including ProMod (Calcium) based nonprescription antacids, concurrently with ProMod (Calcium) acetate.

An overdose of ProMod (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 ProMod (Calcium) levels twice weekly. Should hypercalcemia develop, reduce the ProMod (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 ProMod (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 ProMod (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 ProMod (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 ProMod (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 ProMod (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, ProMod (Calcium) acetate has been generally well tolerated.

ProMod (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 ProMod (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 ProMod (Calcium) concentration could reduce the incidence and severity of ProMod (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 ProMod (Calcium) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

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

There are no empirical data on avoiding drug interactions between ProMod (Calcium) acetate and most concomitant drugs. When administering an oral medication with ProMod (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 ProMod (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 ProMod (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 ProMod (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 ProMod (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:

ProMod acetate capsules contains ProMod (Calcium) acetate. Animal reproduction studies have not been conducted with ProMod (Calcium) acetate, and there are no adequate and well controlled studies of ProMod (Calcium) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with ProMod (Calcium) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum ProMod (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. ProMod (Calcium) acetate treatment, as recommended, is not expected to harm a fetus if maternal ProMod (Calcium) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of ProMod (Calcium) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

ProMod Acetate Capsules contains ProMod (Calcium) acetate and is excreted in human milk. Human milk feeding by a mother receiving ProMod (Calcium) acetate is not expected to harm an infant, provided maternal serum ProMod (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 ProMod (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 ProMod (Calcium) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

ProMod (Calcium) acetate acts as a phosphate binder. Its chemical name is ProMod (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 ProMod (Calcium) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) ProMod (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.

ProMod (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 ProMod resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Orally administered ProMod (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 ProMod (Calcium) acetate.

14 CLINICAL STUDIES

Effectiveness of ProMod (Calcium) acetate in decreasing serum phosphorus has been demonstrated in two studies of the ProMod (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 ProMod (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 ProMod (Calcium) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum ProMod (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 ProMod (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 ProMod (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 ProMod (Calcium) acetate is shown in the Table 3.

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

16 HOW SUPPLIED/STORAGE AND HANDLING

ProMod (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 ProMod (Calcium) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of ProMod (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 ProMod (Calcium) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Potassium:

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

ProMod (Potassium) CHLORIDE EXTENDED RELEASE TABLETS USP 20 mEq K

Rx Only

DESCRIPTION

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

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

ProMod (Potassium) Chloride Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is ProMod (Potassium) chloride, and the structural formula is KCl. ProMod (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.

ProMod (Potassium) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated ProMod (Potassium) chloride crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, ProMod (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 ProMod (Potassium) chloride.

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

CLINICAL PHARMACOLOGY

The ProMod (Potassium) ion is the principal intracellular cation of most body tissues. ProMod (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 ProMod (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.

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

ProMod (Potassium) depletion will occur whenever the rate of ProMod (Potassium) loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of ProMod (Potassium) intake. Such depletion usually develops as a consequence of therapy with diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of ProMod (Potassium) in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. ProMod (Potassium) depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis. ProMod (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 ProMod (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 ProMod (Potassium) in the form of high ProMod (Potassium) food or ProMod (Potassium) chloride may be able to restore normal ProMod (Potassium) levels.

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

INDICATIONS AND USAGE

BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE ProMod (Potassium) CHLORIDE PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT ProMod (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 ProMod (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 ProMod (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 ProMod (Potassium) salts may be indicated.

CONTRAINDICATIONS

ProMod (Potassium) supplements are contraindicated in patients with hyperkalemia since a further increase in serum ProMod (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 ProMod (Potassium) chloride have produced esophageal ulceration in certain cardiac patients with esophageal compression due to enlarged left atrium. ProMod (Potassium) supplementation, when indicated in such patients, should be given as a liquid preparation or as an aqueous (water) suspension of ProMod (Potassium) Chloride (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).

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

Interaction with Potassium-Sparing Diuretics

Hypokalemia should not be treated by the concomitant administration of ProMod (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 ProMod (Potassium) retention by inhibiting aldosterone production. ProMod (Potassium) supplements should be given to patients receiving ACE inhibitors only with close monitoring.

Gastrointestinal Lesions

Solid oral dosage forms of ProMod (Potassium) chloride can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of ProMod (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. ProMod (Potassium) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated ProMod (Potassium) chloride and thus to minimize the possibility of a high local concentration of ProMod (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 ProMod (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 ProMod (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 ProMod (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. ProMod (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 ProMod (Potassium) salt such as ProMod (Potassium) bicarbonate, ProMod (Potassium) citrate, ProMod (Potassium) acetate, or ProMod (Potassium) gluconate.

PRECAUTIONS

General

The diagnosis of ProMod depletion is ordinarily made by demonstrating hypokalemia in a patient with a clinical history suggesting some cause for ProMod (Potassium) depletion. In interpreting the serum ProMod (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 ProMod (Potassium) while acute acidosis per se can increase the serum ProMod (Potassium) concentration into the normal range even in the presence of a reduced total body ProMod (Potassium). The treatment of ProMod (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 ProMod (Potassium) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending ProMod (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 ProMod 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. ProMod is a normal dietary constituent.

Pregnancy Category C

Animal reproduction studies have not been conducted with ProMod (Potassium) Chloride Extended Release Tablets USP, 20 mEq. It is unlikely that ProMod (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 ProMod ion content of human milk is about 13 mEq per liter. Since oral ProMod (Potassium) becomes part of the body ProMod (Potassium) pool, so long as body ProMod (Potassium) is not excessive, the contribution of ProMod (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 ProMod (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 ProMod (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 ProMod (Potassium) salts to persons with normal excretory mechanisms for ProMod (Potassium) rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if ProMod (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 ProMod (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 ProMod (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 ProMod (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 ProMod (Potassium) by the average adult is 50 to 100 mEq per day. ProMod (Potassium) depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of ProMod (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 ProMod (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 ProMod (Potassium) Chloride Extended Release Tablet USP, 20 mEq provides 20 mEq of ProMod (Potassium) chloride.

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

HOW SUPPLIED

ProMod (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

ProMod (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
• ProMod (Protein) reviews

1 INDICATIONS AND USAGE

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

1.1 Severe Congenital ProMod (Protein) C Deficiency

ProMod (Protein) is indicated for pediatric and adult patients with severe congenital ProMod (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 ProMod 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 ProMod (Protein) under the supervision of a physician experienced in replacement therapy with coagulation factors/inhibitors where monitoring of ProMod (Protein) C activity is feasible.

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

Table 1 provides the ProMod (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 ProMod (Protein) C activity of 100 %. After resolution of the acute episode, continue the patient on the same dose to maintain trough ProMod (Protein) C activity level above 25% for the duration of treatment.

In patients receiving prophylactic administration of ProMod (Protein), higher peak ProMod (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 ProMod (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 ProMod C Activity Monitoring

The measurement of ProMod (Protein) C activity using a chromogenic assay is recommended for the determination of the patient's plasma level of ProMod (Protein) C before and during treatment with ProMod (Protein). The half-life of ProMod (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 ProMod (Protein) C activity measurements be performed immediately before the next injection until the patient is stabilized. After the patient is stabilized, continue monitoring the ProMod (Protein) C levels to maintain the trough ProMod (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 ProMod (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 ProMod C, itself a vitamin K-dependent plasma ProMod (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 ProMod (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 ProMod (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 ProMod (Protein) [Protein C Concentrate (Human)]

Reconstitution: Use Aseptic Technique

• Bring the ProMod (Protein) (powder) and Sterile Water for Injection, USP (diluent) to room temperature.
• Remove caps from the ProMod (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 ProMod (Protein) vial; then rapidly insert the free end of the needle through the ProMod (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 ProMod (Protein) vial. Gently swirl the vial until all powder is dissolved. Be sure that ProMod (Protein) is completely dissolved; otherwise, active materials will be removed by the filter needle.

2.5 Administration of ProMod [Protein C Concentrate (Human)]

Administration: Use Aseptic Technique

Visually inspect ProMod (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 ProMod (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 ProMod (Protein).
• Inject air into the vial and then withdraw the reconstituted ProMod (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 ProMod (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 ProMod (Protein) is administered to a patient.

Administration by Infusion

Administer ProMod (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

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

ProMod (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

ProMod (Protein) may contain traces of mouse ProMod (Protein) and/or heparin as a result of the manufacturing process. Allergic reactions to mouse ProMod (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 ProMod 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 ProMod (Protein) further contributed to these bleeding events.

Simultaneous administration of ProMod (Protein) and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA.

5.4 Heparin-induced Thrombocytopenia

ProMod (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 ProMod (Protein) C deficiency. Determine the platelet count immediately and consider discontinuation of ProMod (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 ProMod (Protein) exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.

6 ADVERSE REACTIONS

The common adverse reactions related to ProMod 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 ProMod (Protein) was based on 121 patients from clinical studies and compassionate use in severe congenital ProMod (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 ProMod (Protein).

No inhibiting antibodies to ProMod (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 ProMod (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 ProMod (Protein) and tissue plasminogen activator (tPA).

See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3) for information regarding use of ProMod (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 ProMod (Protein). It is also not known whether ProMod (Protein) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ProMod (Protein) should be given to pregnant women only if clearly needed.

8.2 Labor and Delivery

ProMod has not been studied for use during labor and delivery. Use only if clearly needed.

8.3 Nursing Mothers

ProMod (Protein) has not been studied for use in nursing mothers. Use ProMod (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 ProMod (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

ProMod (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 ProMod (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 ProMod (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

ProMod 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 ProMod (Protein) C (APC). APC is a serine protease with potent anticoagulant effects, especially in the presence of its cofactor ProMod (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 ProMod (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 ProMod (Protein) C is not compatible with life. A severe deficiency of this anticoagulant ProMod (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 ProMod (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 ProMod (Protein) C deficiency.

The ProMod (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 ProMod (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 ProMod (Protein).

The pharmacokinetic profile in pediatric patients has not been formally assessed. Limited data suggest that the pharmacokinetics of ProMod (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 ProMod (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 ProMod (Protein) C activity levels. See DOSAGE AND ADMINISTRATION: ProMod (Protein) C Activity Monitoring (2.2).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

Protein C contained in ProMod 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.

ProMod (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 ProMod (Protein) has suggested immunogenic response in heterologous species following repeated dosing of this human derived ProMod (Protein). Thus, the long-term toxicity potential of ProMod (Protein) following repeated dosing in animals is unknown.

Local Tolerance Testing:

Investigation of route of injection tolerance demonstrated that ProMod (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:

ProMod (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 ProMod in subjects with severe congenital ProMod (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 ProMod (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 ProMod (Protein) C deficiency were more effectively treated with ProMod (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 ProMod (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.

ProMod (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 ProMod (Protein) treatment, as shown in Table 6.

Changes in the extent of venous thrombus were also measured for the 5 thromboembolic episodes. ProMod (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 ProMod (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 ProMod (Protein), as shown in Table 8. When not on prophylactic treatment and receiving ProMod (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 ProMod (Protein) C deficiency who were treated with ProMod (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

ProMod (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 ProMod (Protein) C corresponds to the amidolytically measured activity of ProMod (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).

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

NDC 0944-4177-05

ProMod (Protein) C

Concentrate (Human)

ProMod (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

ProMod (Protein) C Concentrate

(Human)

ProMod (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

ProMod (Protein) C

Concentrate (Human)

ProMod (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

ProMod (Protein) C Concentrate (Human)

ProMod (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
• ProMod (Sodium) reviews

1 INDICATIONS AND USAGE

ProMod nitrite is indicated for sequential use with ProMod (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

ProMod (Sodium) Nitrite Injection is indicated for sequential use with ProMod (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 ProMod (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 ProMod 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, ProMod (Sodium) Nitrite Injection and ProMod (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 ProMod (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 ProMod (Sodium) thiosulfate, simultaneously with ProMod (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 ProMod (Sodium) thiosulfate, with ProMod (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 ProMod (Sodium) nitrite and ProMod (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 ProMod (Sodium) nitrite, followed by ProMod (Sodium) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer ProMod (Sodium) nitrite and ProMod (Sodium) thiosulfate.

ProMod (Sodium) nitrite injection and ProMod (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. ProMod (Sodium) nitrite should be administered first, followed immediately by ProMod (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 ProMod (Sodium) nitrite and ProMod (Sodium) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of ProMod (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 ProMod 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 ProMod (Sodium) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of ProMod (Sodium) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to ProMod (Sodium) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of ProMod (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 ProMod (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 ProMod (Sodium) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between ProMod (Sodium) thiosulfate and ProMod (Sodium) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

ProMod (Sodium) Nitrite Injection consists of:

• One vial of ProMod (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: ProMod 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 ProMod (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. ProMod (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 ProMod (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 ProMod nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with ProMod (Sodium) nitrite whenever possible. When ProMod (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 ProMod (Sodium) nitrite administered to an adult. ProMod (Sodium) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. ProMod (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 ProMod (Sodium) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

ProMod (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 ProMod (Sodium) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

ProMod 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 ProMod (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 ProMod 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 ProMod (Sodium) nitrite.

5.7 Use with Other Drugs

ProMod (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 ProMod (Sodium) nitrite.

The medical literature has reported the following adverse events in association with ProMod (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 ProMod (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 ProMod (Sodium) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: ProMod 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. ProMod (Sodium) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

ProMod (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 ProMod (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 ProMod (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, ProMod (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, ProMod (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 ProMod (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 ProMod (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 ProMod (Sodium) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

ProMod (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 ProMod (Sodium) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to ProMod (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, ProMod 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 ProMod (Sodium) nitrite is excreted in human milk. Because ProMod (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 ProMod (Sodium) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of ProMod (Sodium) nitrite. In studies conducted with Long-Evans rats, ProMod (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 ProMod nitrite in conjunction with ProMod (Sodium) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of ProMod (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.

ProMod (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 ProMod (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

ProMod (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

ProMod (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 ProMod (Sodium) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

ProMod (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 ProMod (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 ProMod (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

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

Structure of ProMod (Sodium) Nitrite

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

ProMod (Sodium) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of ProMod (Sodium) nitrite in 10 mL solution (30 mg/mL). ProMod (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 ProMod nitrite and ProMod (Sodium) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

ProMod (Sodium) Nitrite

ProMod (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 ProMod (Sodium) nitrite. It has been suggested that ProMod (Sodium) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, ProMod (Sodium) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

ProMod (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. ProMod (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

ProMod (Sodium) Nitrite

When 4 mg/kg ProMod (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 ProMod (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 ProMod (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 ProMod (Sodium) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

ProMod (Sodium) Nitrite

ProMod (Sodium) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free ProMod (Sodium) nitrite in humans have not been well studied. It has been reported that approximately 40% of ProMod (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 ProMod (Sodium) nitrite and ProMod (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 ProMod nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. ProMod (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. ProMod (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 ProMod (Sodium) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to ProMod (Sodium) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

ProMod (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. ProMod (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. ProMod (Sodium) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of ProMod (Sodium) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, ProMod (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 ProMod (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 ProMod (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 ProMod (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 ProMod (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 ProMod (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 ProMod (Sodium) nitrite and ProMod (Sodium) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) ProMod (Sodium) nitrite or 1 g/kg ProMod (Sodium) thiosulfate alone or in sequence immediately after subcutaneous injection of ProMod (Sodium) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg ProMod (Sodium) nitrite and/or 0.5 g/kg ProMod (Sodium) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of ProMod (Sodium) cyanide required to cause death, and when administered together, ProMod (Sodium) nitrite and ProMod (Sodium) thiosulfate resulted in a synergistic effect in raising the lethal dose of ProMod (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 ProMod (Sodium) nitrite and ProMod (Sodium) thiosulfate in the treatment of cyanide poisoning.

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

14 CLINICAL STUDIES

The human data supporting the use of ProMod (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 ProMod (Sodium) thiosulfate report its use in conjunction with ProMod (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 ProMod (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 ProMod (Sodium) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of ProMod (Sodium) nitrite injection 30 mg/mL (containing 300 mg of ProMod (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: ProMod (Sodium) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

ProMod 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

ProMod (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

ProMod (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