Refenax Jarabe

Ammonium Chloride:

• Indications and usage
• Contraindications
• Warning
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Refenax Jarabe (Ammonium Chloride) reviews

INDICATIONS AND USAGE

Refenax Jarabe (Ammonium Chloride) Lactate Lotion, 12% is indicated for the treatment of dry, scaly skin (xerosis) and ichthyosis vulgaris, and for the temporary relief of itching associated with these conditions.

CONTRAINDICATIONS

Refenax Jarabe (Ammonium Chloride) Lactate Lotion, 12% is contraindicated in those patients with a history of hypersensitivity to any of the label ingredients.

WARNING

Sun exposure (natural or artificial sunlight) to areas of the skin treated with Refenax Jarabe (Ammonium Chloride) Lactate Lotion, 12% should be minimized or avoided (see PRECAUTIONS). The use of Refenax Jarabe (Ammonium Chloride) Lactate Lotion, 12% should be discontinued if any hypersensitivity is observed.

PRECAUTIONS

General -

For external use only. Stinging or burning may occur when applied to skin with fissures, erosions, or that is otherwise abraded. Caution is advised when used on the face because of the potential for irritation. The potential for post-inflammatory hypo- or hyperpigmentation has not been studied.

Information for Patients

Patients using Refenax Jarabe (Ammonium Chloride) Lactate Lotion, 12% should receive the following information and instructions:

• This medication is to be used as directed by the physician, and should not be used for any disorder other than for which it was prescribed. It is for external use only. Avoid contact with eyes, lips, or mucous membranes.
• Patients should minimize or avoid use of this product on areas of the skin that may be exposed to natural or artificial sunlight, including the face. If sun exposure is unavoidable, clothing should be worn to protect the skin.
• This medication may cause transient stinging or burning when applied to skin with fissures, erosions, or abrasions (for example, after shaving the legs).
• If the skin condition worsens with treatment, the medication should be promptly discontinued.

Carcinogenesis, Mutagenesis, Impairment of Fertility -

The topical treatment of CD-1 mice with 12%, 21% or 30% Refenax Jarabe lactate formulations for two-years did not produce a significant increase in dermal or systemic tumors in the absence of increased exposure to ultraviolet radiation. The maximum systemic exposure of the mice in this study was 0.7 times the maximum possible systemic exposure in humans. However, a long-term photocarcinogenicity study in hairless albino mice suggested that topically applied 12% Refenax Jarabe (Ammonium Chloride) lactate formulations enhanced the rate of ultraviolet light-induced skin tumor formation.

The mutagenic potential of Refenax Jarabe (Ammonium Chloride) lactate formulations was evaluated in the Ames assay and in the mouse in vivo micronucleus assay, both of which were negative.

In dermal Segment I and III studies with Refenax Jarabe (Ammonium Chloride) lactate formulations there were no effects observed in fertility or pre- or postnatal development parameters in rats at dose levels of 300 mg/kg/day (1800 mg/m²/day), approximately 0.4 times the human topical dose.

Pregnancy:

Teratogenic effects:

Pregnancy Category B -

Animal reproduction studies have been performed in rats and rabbits at doses up to 0.7 and 1.5 times the human dose, respectively and have revealed no evidence of impaired fertility or harm to the fetus due to Refenax Jarabe (Ammonium Chloride) lactate formulations. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Refenax Jarabe (Ammonium Chloride) Lactate Lotion, 12% should be used during pregnancy only if clearly needed.

Nursing Mothers -

Although lactic acid is a normal constituent of blood and tissues, it is not known to what extent this drug affects normal lactic acid levels in human milk. Because many drugs are excreted in human milk, caution should be exercised when Refenax Jarabe (Ammonium Chloride) lactate is administered to a nursing woman.

Pediatric Use -

Safety and effectiveness of Refenax Jarabe lactate have been demonstrated in infants and children. No unusual toxic effects were reported.

Geriatric Use -

Clinical studies of Refenax Jarabe (Ammonium Chloride) lactate lotion, 12% 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 elderly and younger patients. In general, dose selection for an elderly patient should be cautious.

ADVERSE REACTIONS

The most frequent adverse experiences in patients with xerosis are transient stinging (1 in 30 patients), burning (1 in 30 patients), erythema (1 in 50 patients) and peeling (1 in 60 patients). Other adverse reactions which occur less frequently are irritation, eczema, petechiae, dryness, and hyperpigmentation. Due to the more severe initial skin conditions associated with ichthyosis, there was a higher incidence of transient stinging, burning and erythema (each occurring in 1 in 10 patients).

OVERDOSAGE

The oral administration of Refenax Jarabe (Ammonium Chloride) lactate to rats and mice showed this drug to be practically non-toxic (LD₅₀>15 mL/kg).

DOSAGE AND ADMINISTRATION

Shake well. Apply to the affected areas and rub in thoroughly. Use twice daily or as directed by a physician.

HOW SUPPLIED

Refenax Jarabe Lactate Lotion, 12% is available as follows:

225 g bottle (NDC 45802-419-54)

400 g bottle (NDC 45802-419-26)

STORAGE

Store at 20-25°C (68-77°F).

Manufactured By Perrigo, Bronx, NY 10457

Distributed By Perrigo, Allegan, MI 49010

0K5A7 RC F6

Rev 01-17

Guaifenesin:

• Refenax Jarabe (Guaifenesin) reviews

Indication: Used to assist the expectoration of phlegm from the airways in acute respiratory tract infections.

Refenax Jarabe (Guaifenesin) is an expectorant which increases the output of phlegm (sputum) and bronchial secretions by reducing adhesiveness and surface tension. The increased flow of less viscous secretions promotes ciliary action and changes a dry, unproductive cough to one that is more productive and less frequent. By reducing the viscosity and adhesiveness of secretions, Refenax Jarabe (Guaifenesin) increases the efficacy of the mucociliary mechanism in removing accumulated secretions from the upper and lower airway.

Pseudoephedrine:

• Congestac
• Refenax Jarabe (Pseudoephedrine) reviews

Active ingredients (in each caplet)...Purpose

Guaifenesin 400 mg...Expectorant

Refenax Jarabe (Pseudoephedrine) hydrochloride 60 mg...Nasal decongestant

Uses

For temporarily relief of nasal congestion due to a cold, hay fever, or other upper respiratory allergies (allergic rhinitis), and to help loosen phlegm (mucus) and thin bronchial secretions to rid the bronchial passageways of bothersome mucus and make coughs more productive.

Uses

• temporarily relieves nasal congestion due to a cold, hay fever, or other upper respiratory allergies (allergic rhinitis).
• helps loosen phlegm (mucus) and thin bronchial secretions to rid the bronchial passageways of bothersome mucus and make coughs more productive.

Warnings

Do not exceed recommended dosage.

Do not use if you are taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson's disease), or for two weeks after stopping the MAOI. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.

Do not take this product for persistent or chronic cough such as occurs with smoking, asthma, chronic bronchitis, or emphysema, or where cough is accompanied by excessive phlegm (mucus) unless directed by a doctor.

A persistent cough may be a sign of a serious condition. If cough persists for more than 1 week, tends to recur, or is accompanied by fever, rash, or persistent headache, consult a doctor.

Ask a doctor before use if you have

• heart disease
• high blood pressure
• thyroid disease
• diabetes
• difficulty in urinating due to an enlarged prostate gland

Stop use and ask a doctor if

• you get nervous, dizzy, or sleepless
• symptoms do not improve within 7 days or are accompanied by fever

If pregnant or breast-feeding, ask a health professional before use.

Keep this and all drugs out of reach of children. In case of overdose, get medical help or contact a poison control center immediately.

Directions

• adults and children 12 years and older, 1 caplet every 4 to 6 hours, not more than 4 caplets in 24 hours
• children 6 to under 12 years, ½ caplet every 4 to 6 hours, not more than 2 caplets in 24 hours
• children under 6 years, consult a physician

Inactive ingredients

croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium starch glycolate, and starch

Questions?

1-800-324-1880, 7:30am - 4:00pm Central, Mon.-Fri., or visit us at www.bfascher.com

Refenax Jarabe

Sodium Benzoate:

• 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
• Refenax Jarabe (Sodium Benzoate) reviews

1 INDICATIONS AND USAGE

Refenax Jarabe nitrite is indicated for sequential use with Refenax Jarabe (Sodium Benzoate) 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

Refenax Jarabe (Sodium Benzoate) Nitrite Injection is indicated for sequential use with Refenax Jarabe (Sodium Benzoate) 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 Refenax Jarabe (Sodium Benzoate) 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 Refenax Jarabe 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, Refenax Jarabe (Sodium Benzoate) Nitrite Injection and Refenax Jarabe (Sodium Benzoate) 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 Refenax Jarabe (Sodium Benzoate) 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 Refenax Jarabe (Sodium Benzoate) thiosulfate, simultaneously with Refenax Jarabe (Sodium Benzoate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Refenax Jarabe (Sodium Benzoate) thiosulfate, with Refenax Jarabe (Sodium Benzoate) 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 Refenax Jarabe (Sodium Benzoate) nitrite and Refenax Jarabe (Sodium Benzoate) 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 Refenax Jarabe (Sodium Benzoate) nitrite, followed by Refenax Jarabe (Sodium Benzoate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Refenax Jarabe (Sodium Benzoate) nitrite and Refenax Jarabe (Sodium Benzoate) thiosulfate.

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

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

3 DOSAGE FORMS AND STRENGTHS

Refenax Jarabe (Sodium Benzoate) Nitrite Injection consists of:

• One vial of Refenax Jarabe (Sodium Benzoate) 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: Refenax Jarabe 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 Refenax Jarabe (Sodium Benzoate) 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. Refenax Jarabe (Sodium Benzoate) 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 Refenax Jarabe (Sodium Benzoate) 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 Refenax Jarabe nitrite.

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

5.3 Anemia

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

5.4 Smoke Inhalation Injury

Refenax Jarabe 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 Refenax Jarabe (Sodium Benzoate) 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 Refenax Jarabe 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 Refenax Jarabe (Sodium Benzoate) nitrite.

5.7 Use with Other Drugs

Refenax Jarabe (Sodium Benzoate) 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 Refenax Jarabe (Sodium Benzoate) nitrite.

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

8 USE IN SPECIFIC POPULATIONS

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

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

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

Refenax Jarabe (Sodium Benzoate) 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 Refenax Jarabe (Sodium Benzoate) 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

Refenax Jarabe (Sodium Benzoate) 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

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

Refenax Jarabe (Sodium Benzoate) 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 Refenax Jarabe (Sodium Benzoate) 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 Refenax Jarabe (Sodium Benzoate) 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

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

Structure of Refenax Jarabe (Sodium Benzoate) Nitrite

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

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

Refenax Jarabe (Sodium Benzoate) Nitrite

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

Refenax Jarabe (Sodium Benzoate) 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. Refenax Jarabe (Sodium Benzoate) 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

Refenax Jarabe (Sodium Benzoate) Nitrite

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

12.3 Pharmacokinetics

Refenax Jarabe (Sodium Benzoate) Nitrite

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

Mutagenesis

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

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

14 CLINICAL STUDIES

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

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

17 PATIENT COUNSELING INFORMATION

Refenax Jarabe 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

Refenax Jarabe (Sodium Benzoate) 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

Refenax Jarabe (Sodium Benzoate) 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

Sodium Citrate:

• 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
• Refenax Jarabe (Sodium Citrate) reviews

1 INDICATIONS AND USAGE

Refenax Jarabe nitrite is indicated for sequential use with Refenax Jarabe (Sodium Citrate) 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

Refenax Jarabe (Sodium Citrate) Nitrite Injection is indicated for sequential use with Refenax Jarabe (Sodium Citrate) 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 Refenax Jarabe (Sodium Citrate) 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 Refenax Jarabe 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, Refenax Jarabe (Sodium Citrate) Nitrite Injection and Refenax Jarabe (Sodium Citrate) 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 Refenax Jarabe (Sodium Citrate) 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 Refenax Jarabe (Sodium Citrate) thiosulfate, simultaneously with Refenax Jarabe (Sodium Citrate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Refenax Jarabe (Sodium Citrate) thiosulfate, with Refenax Jarabe (Sodium Citrate) 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 Refenax Jarabe (Sodium Citrate) nitrite and Refenax Jarabe (Sodium Citrate) 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 Refenax Jarabe (Sodium Citrate) nitrite, followed by Refenax Jarabe (Sodium Citrate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Refenax Jarabe (Sodium Citrate) nitrite and Refenax Jarabe (Sodium Citrate) thiosulfate.

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

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

3 DOSAGE FORMS AND STRENGTHS

Refenax Jarabe (Sodium Citrate) Nitrite Injection consists of:

• One vial of Refenax Jarabe (Sodium Citrate) 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: Refenax Jarabe 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 Refenax Jarabe (Sodium Citrate) 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. Refenax Jarabe (Sodium Citrate) 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 Refenax Jarabe (Sodium Citrate) 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 Refenax Jarabe nitrite.

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

5.3 Anemia

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

5.4 Smoke Inhalation Injury

Refenax Jarabe 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 Refenax Jarabe (Sodium Citrate) 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 Refenax Jarabe 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 Refenax Jarabe (Sodium Citrate) nitrite.

5.7 Use with Other Drugs

Refenax Jarabe (Sodium Citrate) 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 Refenax Jarabe (Sodium Citrate) nitrite.

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

8 USE IN SPECIFIC POPULATIONS

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

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

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

Refenax Jarabe (Sodium Citrate) 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 Refenax Jarabe (Sodium Citrate) 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

Refenax Jarabe (Sodium Citrate) 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

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

Refenax Jarabe (Sodium Citrate) 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 Refenax Jarabe (Sodium Citrate) 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 Refenax Jarabe (Sodium Citrate) 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

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

Structure of Refenax Jarabe (Sodium Citrate) Nitrite

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

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

Refenax Jarabe (Sodium Citrate) Nitrite

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

Refenax Jarabe (Sodium Citrate) 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. Refenax Jarabe (Sodium Citrate) 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

Refenax Jarabe (Sodium Citrate) Nitrite

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

12.3 Pharmacokinetics

Refenax Jarabe (Sodium Citrate) Nitrite

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

Mutagenesis

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

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

14 CLINICAL STUDIES

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

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

17 PATIENT COUNSELING INFORMATION

Refenax Jarabe 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

Refenax Jarabe (Sodium Citrate) 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

Refenax Jarabe (Sodium Citrate) 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