GP-2 Ban

Sodium Chloride:

• 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
• GP-2 Ban (Sodium Chloride) reviews

1 INDICATIONS AND USAGE

GP-2 Ban nitrite is indicated for sequential use with GP-2 Ban (Sodium Chloride) 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

GP-2 Ban (Sodium Chloride) Nitrite Injection is indicated for sequential use with GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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 GP-2 Ban 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, GP-2 Ban (Sodium Chloride) Nitrite Injection and GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) thiosulfate, simultaneously with GP-2 Ban (Sodium Chloride) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than GP-2 Ban (Sodium Chloride) thiosulfate, with GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) nitrite and GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) nitrite, followed by GP-2 Ban (Sodium Chloride) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer GP-2 Ban (Sodium Chloride) nitrite and GP-2 Ban (Sodium Chloride) thiosulfate.

GP-2 Ban (Sodium Chloride) nitrite injection and GP-2 Ban (Sodium Chloride) 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. GP-2 Ban (Sodium Chloride) nitrite should be administered first, followed immediately by GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) nitrite and GP-2 Ban (Sodium Chloride) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of GP-2 Ban (Sodium Chloride) 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 GP-2 Ban 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 GP-2 Ban (Sodium Chloride) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of GP-2 Ban (Sodium Chloride) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to GP-2 Ban (Sodium Chloride) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between GP-2 Ban (Sodium Chloride) thiosulfate and GP-2 Ban (Sodium Chloride) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

GP-2 Ban (Sodium Chloride) Nitrite Injection consists of:

• One vial of GP-2 Ban (Sodium Chloride) 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: GP-2 Ban 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 GP-2 Ban (Sodium Chloride) 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. GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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 GP-2 Ban nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with GP-2 Ban (Sodium Chloride) nitrite whenever possible. When GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) nitrite administered to an adult. GP-2 Ban (Sodium Chloride) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

GP-2 Ban 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 GP-2 Ban (Sodium Chloride) 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 GP-2 Ban 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 GP-2 Ban (Sodium Chloride) nitrite.

5.7 Use with Other Drugs

GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) nitrite.

The medical literature has reported the following adverse events in association with GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: GP-2 Ban 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. GP-2 Ban (Sodium Chloride) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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, GP-2 Ban (Sodium Chloride) 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, GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to GP-2 Ban (Sodium Chloride) 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, GP-2 Ban 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 GP-2 Ban (Sodium Chloride) nitrite is excreted in human milk. Because GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of GP-2 Ban (Sodium Chloride) nitrite. In studies conducted with Long-Evans rats, GP-2 Ban (Sodium Chloride) 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 GP-2 Ban nitrite in conjunction with GP-2 Ban (Sodium Chloride) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of GP-2 Ban (Sodium Chloride) 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.

GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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

GP-2 Ban (Sodium Chloride) 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

GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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

GP-2 Ban (Sodium Chloride) nitrite has the chemical name nitrous acid GP-2 Ban (Sodium Chloride) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of GP-2 Ban (Sodium Chloride) Nitrite

GP-2 Ban (Sodium Chloride) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of GP-2 Ban (Sodium Chloride) nitrite injection.

GP-2 Ban (Sodium Chloride) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of GP-2 Ban (Sodium Chloride) nitrite in 10 mL solution (30 mg/mL). GP-2 Ban (Sodium Chloride) 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 GP-2 Ban nitrite and GP-2 Ban (Sodium Chloride) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

GP-2 Ban (Sodium Chloride) Nitrite

GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) nitrite. It has been suggested that GP-2 Ban (Sodium Chloride) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, GP-2 Ban (Sodium Chloride) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

GP-2 Ban (Sodium Chloride) 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. GP-2 Ban (Sodium Chloride) 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

GP-2 Ban (Sodium Chloride) Nitrite

When 4 mg/kg GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

GP-2 Ban (Sodium Chloride) Nitrite

GP-2 Ban (Sodium Chloride) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free GP-2 Ban (Sodium Chloride) nitrite in humans have not been well studied. It has been reported that approximately 40% of GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) nitrite and GP-2 Ban (Sodium Chloride) 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 GP-2 Ban nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. GP-2 Ban (Sodium Chloride) 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. GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to GP-2 Ban (Sodium Chloride) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

GP-2 Ban (Sodium Chloride) 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. GP-2 Ban (Sodium Chloride) 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. GP-2 Ban (Sodium Chloride) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of GP-2 Ban (Sodium Chloride) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) nitrite and GP-2 Ban (Sodium Chloride) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) GP-2 Ban (Sodium Chloride) nitrite or 1 g/kg GP-2 Ban (Sodium Chloride) thiosulfate alone or in sequence immediately after subcutaneous injection of GP-2 Ban (Sodium Chloride) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg GP-2 Ban (Sodium Chloride) nitrite and/or 0.5 g/kg GP-2 Ban (Sodium Chloride) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of GP-2 Ban (Sodium Chloride) cyanide required to cause death, and when administered together, GP-2 Ban (Sodium Chloride) nitrite and GP-2 Ban (Sodium Chloride) thiosulfate resulted in a synergistic effect in raising the lethal dose of GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) nitrite and GP-2 Ban (Sodium Chloride) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of GP-2 Ban (Sodium Chloride) nitrite and GP-2 Ban (Sodium Chloride) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of GP-2 Ban (Sodium Chloride) nitrite, with or without GP-2 Ban (Sodium Chloride) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) thiosulfate report its use in conjunction with GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) 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 GP-2 Ban (Sodium Chloride) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of GP-2 Ban (Sodium Chloride) nitrite injection 30 mg/mL (containing 300 mg of GP-2 Ban (Sodium Chloride) 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: GP-2 Ban (Sodium Chloride) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

GP-2 Ban 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

GP-2 Ban (Sodium Chloride) 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

GP-2 Ban (Sodium Chloride) 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

Tirofiban:

• 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
• Insert
• Container
• Carton
• Carton 3.75 mg/15 ml
• Carton 5 mg/100 ml
• GP-2 Ban (Tirofiban) reviews

1 INDICATIONS AND USAGE

GP-2 Ban (Tirofiban) is indicated to reduce the rate of thrombotic cardiovascular events (combined endpoint of death, myocardial infarction, or refractory ischemia/repeat cardiac procedure) in patients with non-ST elevation acute coronary syndrome (NSTE-ACS).

GP-2 Ban (Tirofiban)^® is a platelet aggregation inhibitor indicated to reduce the rate of thrombotic cardiovascular events (combined endpoint of death, myocardial infarction, or refractory ischemia/repeat cardiac procedure) in patients with non-ST elevation acute coronary syndrome (NSTE-ACS).

2 DOSAGE AND ADMINISTRATION

• Administer intravenously 25 mcg/kg within 5 minutes and then 0.15 mcg/kg/min for up to 18 hours. In patients with creatinine clearance ≤60 mL/min, give 25 mcg/kg within 5 minutes and then 0.075 mcg/kg/min.

2.1 Recommended Dosage

The recommended dosage is 25 mcg/kg administered intravenously within 5 minutes and then 0.15 mcg/kg/min for up to 18 hours.

2.2 Administration

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

To open the 250 mL premixed bag, first tear off its foil overpouch. The plastic may be somewhat opaque because of moisture absorption during sterilization; the opacity will diminish gradually. Check for leaks by squeezing the inner bag firmly; if any leaks are found or sterility is suspect then the solution should be discarded. Do not use unless the solution is clear and the seal is intact.

Administration Instructions

• Withdraw the bolus dose of GP-2 Ban from the 15 mL premixed bolus vial into a syringe. Alternatively, the bolus dose of GP-2 Ban (Tirofiban) may be administered from the 100 mL premixed vial or from the 250 mL premixed bag. Do not dilute. Administer the bolus dose within 5 minutes via a syringe or IV pump.
• Immediately following the bolus dose administration, administer the maintenance infusion from the 100 mL premixed vial or 250 mL premixed bag via an IV pump.
• Discard any unused portion left in the vial or bag.

The recommended bolus volume using the 15 mL premixed bolus vial can be calculated using the following equation:

The recommended bolus volume using the 100 mL premixed vial or 250 mL premixed bag can be calculated using the following equation:

The recommended infusion rate for patients with CrCl (Creatinine Clearance) >60 mL/min using the 100 mL premixed vial or 250 mL premixed bag can be calculated using the following equation:

Example calculation of infusion rate for 60 kg patient with CrCl >60 mL/min using the 100 mL premixed vial or 250 mL premixed bag:

Drug Compatibilities

GP-2 Ban (Tirofiban) can be administered in the same intravenous line as heparin, atropine sulfate, dobutamine, dopamine, epinephrine hydrochloride (HCl), famotidine injection, furosemide, lidocaine, midazolam HCl, morphine sulfate, nitroglycerin, potassium chloride, and propranolol HCl. Do not administer GP-2 Ban (Tirofiban) through the same IV line as diazepam. Do not add other drugs or remove solution directly from the bag with a syringe.

equation-1 equation-2 equation-3 equation-4

2.3 Dose Adjustment for Renal Impairment

The recommended dosage in patients with CrCl ≤60 mL/min is 25 mcg/kg intravenously within 5 minutes and then 0.075 mcg/kg/min, for up to 18 hours.

The recommended infusion rate for patients with CrCl ≤60 mL/min using the 100 mL premixed vial or 250 mL premixed bag can be calculated using the following equation:

equation-5

3 DOSAGE FORMS AND STRENGTHS

GP-2 Ban (Tirofiban) is a clear, non-preserved, colorless, isosmotic, sterile premixed injection with sodium chloride for tonicity adjustment available in the following presentations:

• Injection: 12.5 mg/250mL (50 mcg/mL) in 250 mL bag. (3)
• Injection: 5 mg/100mL (50 mcg/mL) in 100 mL vial. (3)
• Injection: 3.75 mg/15mL (250 mcg/mL) in 15 mL bolus vial. (3)

4 CONTRAINDICATIONS

GP-2 Ban (Tirofiban) is contraindicated in patients with:

• Severe hypersensitivity reaction to GP-2 Ban (Tirofiban) (i.e., anaphylactic reactions) .
• A history of thrombocytopenia following prior exposure to GP-2 Ban (Tirofiban) .
• Active internal bleeding or a history of bleeding diathesis, major surgical procedure or severe physical trauma within the previous month [see Adverse Reactions (6.1)].

• Known hypersensitivity to any component of GP-2 Ban (Tirofiban). (4)
• History of thrombocytopenia with prior exposure to GP-2 Ban (Tirofiban). (4)
• Active internal bleeding, or history of bleeding diathesis, major surgical procedure or severe physical trauma within the previous month. (4)

5 WARNINGS AND PRECAUTIONS

• GP-2 Ban can cause serious bleeding. If bleeding cannot be controlled discontinue GP-2 Ban (Tirofiban). (5.1)
• Thrombocytopenia: Discontinue GP-2 Ban (Tirofiban) and heparin. (5.2)

5.1 General Risk of Bleeding

Bleeding is the most common complication encountered during therapy with GP-2 Ban (Tirofiban). Most bleeding associated with GP-2 Ban (Tirofiban) occurs at the arterial access site for cardiac catheterization. Minimize the use of traumatic or potentially traumatic procedures such as arterial and venous punctures, intramuscular injections, nasotracheal intubation, etc.

Concomitant use of fibrinolytics, anticoagulants and antiplatelet drugs increases the risk of bleeding.

5.2 Thrombocytopenia

Profound thrombocytopenia has been reported with GP-2 Ban (Tirofiban). Monitor platelet counts beginning about 6 hours after treatment initiation and daily thereafter. If the platelet count decreases to <90,000/mm³, monitor platelet counts to exclude pseudothrombocytopenia. If thrombocytopenia is confirmed, discontinue GP-2 Ban (Tirofiban) and heparin. Previous exposure to a glycoprotein (GP) IIb/IIIa receptor antagonist may increase the risk of developing thrombocytopenia .

6 ADVERSE REACTIONS

Bleeding is the most commonly reported adverse reaction.

To report SUSPECTED ADVERSE REACTIONS, contact Medicure at 1-800-509-0544 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 clinical practice.

In the PRISM (Platelet Receptor Inhibition for Ischemic Syndrome Management), PRISM-PLUS (Platelet Receptor Inhibition for Ischemic Syndrome Management - Patients Limited by Unstable Signs and Symptoms) and RESTORE (Randomized Efficacy Study of GP-2 Ban (Tirofiban) for Outcomes and Restenosis) trials, 1946 patients received GP-2 Ban (Tirofiban) in combination with heparin and 2002 patients received GP-2 Ban (Tirofiban) alone for about 3 days. Forty-three percent of the population was >65 years of age and approximately 30% of patients were female. In clinical studies with the recommended regimen (25 mcg/kg bolus followed by a 0.15 mcg/kg/min maintenance infusion), GP-2 Ban (Tirofiban) was administered in combination with aspirin, clopidogrel and heparin or bivalirudin to over 8000 patients for typically ≤24 hours. Approximately 30% of the population was >65 years of age and approximately 25% were female.

Bleeding

PRISM-PLUS Regimen

The incidences of major and minor bleeding using the TIMI criteria in the PRISM-PLUS study are shown below.

The incidence rates of TIMI major bleeding in patients undergoing percutaneous procedures in PRISM-PLUS are shown below.

The incidence rates of TIMI major bleeding in patients undergoing coronary artery bypass graft surgery (CABG) in PRISM-PLUS within one day of discontinuation of GP-2 Ban (Tirofiban) were 17% on GP-2 Ban (Tirofiban) plus heparin (N=29) and 35% on heparin alone (N=31).

Recommended (“High-Dose Bolus”) Regimen

Rates of major bleeds (including any intracranial, intraocular or retroperitoneal hemorrhage, clinically overt signs of hemorrhage associated with a drop in hemoglobin of >3 g/dL or any drop in hemoglobin by 4g/dL, bleeding requiring transfusion of ≥2U blood products, bleeding directly resulting in death within 7 days or hemodynamic compromise requiring intervention) were consistent with the rates observed in subjects administered the PRISM-PLUS regimen of GP-2 Ban (Tirofiban). There was a trend toward greater bleeding in ST segment elevation myocardial infarction (STEMI) patients treated with fibrinolytics prior to administration of GP-2 Ban (Tirofiban) using the recommended regimen during rescue PCI.

Non-Bleeding

The incidences of non-bleeding adverse events that occurred at an incidence of >1% and numerically higher than control, regardless of drug relationship, are shown below:

Thrombocytopenia

Patients treated with GP-2 Ban plus heparin, were more likely to experience decreases in platelet counts than were those on heparin alone. These decreases were reversible upon discontinuation of GP-2 Ban (Tirofiban). The percentage of patients with a decrease of platelets to <90,000/mm³ was 1.5%, compared with 0.6% in the patients who received heparin alone. The percentage of patients with a decrease of platelets to <50,000/mm³ was 0.3%, compared with 0.1% of the patients who received heparin alone.

6.2 Post-Marketing Experience

The following additional adverse reactions have been identified during post-approval use of GP-2 Ban (Tirofiban). 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 the drug exposure.

Hypersensitivity: Severe allergic reactions including anaphylactic reactions have occurred during the first day of GP-2 Ban (Tirofiban) infusion, during initial treatment, and during readministration of GP-2 Ban (Tirofiban). Some cases have been associated with severe thrombocytopenia (platelet counts <10,000/mm³). No information is available on the formation of antibodies to GP-2 Ban (Tirofiban).

7 DRUG INTERACTIONS

Concomitant use of fibrinolytics, anticoagulants and antiplatelet drugs increases the risk of bleeding.

• Coadministration of fibrinolytics, anticoagulants and antiplatelet agents, increases the risk of bleeding. (7)

8 USE IN SPECIFIC POPULATIONS

• Renal Insufficiency: Reduce the dose in patients with severe renal insufficiency.

8.1 Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. GP-2 Ban (Tirofiban) has been shown to cross the placenta in pregnant rats and rabbits. Studies with GP-2 Ban (Tirofiban) HCl at intravenous doses up to 5 mg/kg/day (about 5 and 13 times the maximum recommended daily human dose for rat and rabbit, respectively, when compared on a body surface area basis) have revealed no harm to the fetus.

8.3 Nursing Mothers

It is not known whether GP-2 Ban is excreted in human milk. However, significant levels of GP-2 Ban (Tirofiban) were shown to be present in rat milk. Because many drugs are excreted in human milk, and because of the potential for adverse effects on the nursing infant, discontinue nursing or discontinue GP-2 Ban (Tirofiban).

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of patients in controlled clinical studies of GP-2 Ban, 43% were 65 years and over, while 12% were 75 and over. With respect to efficacy, the effect of GP-2 Ban (Tirofiban) in the elderly (≥65 years) appeared similar to that seen in younger patients (<65 years). Elderly patients receiving GP-2 Ban (Tirofiban) with heparin or heparin alone had a higher incidence of bleeding complications than did younger patients, but the incremental risk of bleeding in patients treated with GP-2 Ban (Tirofiban) in combination with heparin compared to the risk in patients treated with heparin alone was similar regardless of age. No dose adjustment is recommended for the elderly population .

8.6 Renal Insufficiency

Patients with moderate to severe renal insufficiency have decreased plasma clearance of GP-2 Ban (Tirofiban). Reduce the dosage of GP-2 Ban (Tirofiban) in patients with severe renal insufficiency .

Safety and efficacy of GP-2 Ban (Tirofiban) has not been established in patients on hemodialysis.

10 OVERDOSAGE

In clinical trials, inadvertent overdosage with GP-2 Ban (Tirofiban) occurred in doses up to 2 times the recommended dose for initial infusion doses. Inadvertent overdosage occurred in doses up to 9.8 times the 0.15 mcg/kg/min maintenance infusion rate.

The most frequently reported manifestation of overdosage was bleeding, primarily minor mucocutaneous bleeding events and minor bleeding at the sites of cardiac catheterization .

Overdosage of GP-2 Ban (Tirofiban) should be treated by assessment of the patient’s clinical condition and cessation or adjustment of the drug infusion as appropriate.

GP-2 Ban (Tirofiban) can be removed by hemodialysis.

11 DESCRIPTION

GP-2 Ban (Tirofiban) contains GP-2 Ban (Tirofiban) hydrochloride, a non-peptide antagonist of the platelet GP IIb/IIIa receptor, which inhibits platelet aggregation.

GP-2 Ban (Tirofiban) hydrochloride monohydrate is chemically described as N(butylsulfonyl)-O-[4-(4-piperidinyl)butyl]-L-tyrosine monohydrochloride monohydrate.

Its molecular formula is C₂₂H₃₆N₂O₅S-HCl-H₂O and its structural formula is:

GP-2 Ban (Tirofiban) hydrochloride monohydrate is a white to off-white, non-hygroscopic, free-flowing powder, with a molecular weight of 495.08. It is very slightly soluble in water.

GP-2 Ban (Tirofiban) Injection Premixed is supplied as a sterile solution in water for injection, for intravenous use. The pH of the solution ranges from 5.5 to 6.5 adjusted with hydrochloric acid and/or sodium hydroxide.

Each 100 mL of the premixed, isosmotic intravenous injection contains 5.618 mg GP-2 Ban (Tirofiban) hydrochloride monohydrate equivalent to 5 mg GP-2 Ban (Tirofiban) (50 mcg/mL) and the following inactive ingredients: 0.9 g sodium chloride, 54 mg sodium citrate dihydrate, and 3.2 mg citric acid anhydrous.

Each 250 mL of the premixed, isosmotic intravenous injection contains 14.045 mg GP-2 Ban (Tirofiban) hydrochloride monohydrate equivalent to 12.5 mg GP-2 Ban (Tirofiban) (50 mcg/mL) and the following inactive ingredients: 2.25 g sodium chloride, 135 mg sodium citrate dihydrate, and 8 mg citric acid anhydrous.

GP-2 Ban (Tirofiban) Injection Premixed Bolus Vial is supplied as a sterile, isosmotic, concentrated solution for intravenous bolus injection, in 15 mL vials. No dilution is required. Each 15 mL of the premixed, isosmotic intravenous injection bolus vial contains 4.215 mg of GP-2 Ban (Tirofiban) hydrochloride monohydrate equivalent to 3.75 mg of GP-2 Ban (Tirofiban) and the following inactive ingredients: 120 mg sodium chloride, 40.5 mg sodium citrate dihydrate, and 2.4 mg citric acid anhydrous and water for injection.

structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

GP-2 Ban is a reversible antagonist of fibrinogen binding to the GP IIb/IIIa receptor, the major platelet surface receptor involved in platelet aggregation. When administered intravenously, GP-2 Ban (Tirofiban) inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner.

When given according to the PRISM-PLUS regimen of 0.4 mcg/kg/min over 30 minutes followed by a 0.1 mcg/kg/min maintenance infusion, >90% inhibition of platelet aggregation is attained by the end of the 30-minute infusion. When given according to the recommended regimen of 25 mcg/kg followed by a 0.15 mcg/kg/min maintenance infusion, >90% inhibition of platelet aggregation is attained within 10 minutes. Platelet aggregation inhibition is reversible following cessation of the infusion of GP-2 Ban (Tirofiban).

12.2 Pharmacodynamics

GP-2 Ban (Tirofiban) inhibits platelet function, as demonstrated by its ability to inhibit ex vivo adenosine phosphate (ADP)-induced platelet aggregation and prolong bleeding time in healthy subjects and patients with coronary artery disease. The time course of inhibition parallels the plasma concentration profile of the drug.

Following discontinuation of an infusion of GP-2 Ban (Tirofiban) 0.10 mcg/kg/min, ex vivo platelet aggregation returns to near baseline in 4 to 8 hours in approximately 90% of patients with coronary artery disease. The addition of heparin to this regimen does not significantly alter the percentage of subjects with >70% inhibition of platelet aggregation (IPA), but does increase the average bleeding time, as well as the number of patients with bleeding times prolonged to >30 minutes. Similar platelet aggregation recovery rates are observed following discontinuation of a 0.15 mcg/kg/min infusion.

12.3 Pharmacokinetics

GP-2 Ban has a half-life of approximately 2 hours. It is cleared from the plasma largely by renal excretion, with about 65% of an administered dose appearing in urine and about 25% in feces, both largely as unchanged GP-2 Ban (Tirofiban). Metabolism appears to be limited.

GP-2 Ban (Tirofiban) is not highly bound to plasma proteins and protein binding is concentration independent over the range of 0.01 to 25 mcg/mL. The unbound fraction in human plasma is 35%. The steady state volume of distribution of GP-2 Ban (Tirofiban) ranges from 22 to 42 liters.

In healthy subjects, the plasma clearance of GP-2 Ban (Tirofiban) ranges from 213 to 314 mL/min. Renal clearance accounts for 39 to 69% of plasma clearance.

Specific Populations

There is no effect on clearance of GP-2 Ban (Tirofiban) by sex, race, age, or hepatic impairment.

Renal Insufficiency

Plasma clearance of GP-2 Ban (Tirofiban) is decreased about 40% in subjects with creatinine clearance <60 mL/min and >50% in patients with creatinine clearance <30 mL/min, including patients requiring hemodialysis . GP-2 Ban (Tirofiban) is removed by hemodialysis.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of GP-2 Ban (Tirofiban) has not been evaluated.

GP-2 Ban (Tirofiban) HCl was negative in the in vitro microbial mutagenesis and V-79 mammalian cell mutagenesis assays. In addition, there was no evidence of direct genotoxicity in the in vitro alkaline elution and in vitro chromosomal aberration assays. There was no induction of chromosomal aberrations in bone marrow cells of male mice after the administration of intravenous doses up to 5 mg tirofiban/kg (about 3 times the maximum recommended daily human dose when compared on a body surface area basis).

Fertility and reproductive performance were not affected in studies with male and female rats given intravenous doses of GP-2 Ban (Tirofiban) up to 5 mg/kg/day (about 5 times the maximum recommended daily human dose when compared on a body surface area basis).

14 CLINICAL STUDIES

Two large-scale clinical studies established the efficacy of GP-2 Ban (Tirofiban) in the treatment of patients with NSTE-ACS (unstable angina/non-ST elevation MI). The two studies examined GP-2 Ban (Tirofiban) alone and added to heparin, prior to and after percutaneous coronary revascularization (if indicated) (PRISM-PLUS) and in comparison to heparin in a similar population (PRISM). These trials are discussed in detail below.

PRISM-PLUS (Platelet Receptor Inhibition for Ischemic Syndrome Management - Patients Limited by Unstable Signs and Symptoms)

In the double-blind PRISM-PLUS trial, 1570 patients with documented NSTE-ACS within 12 hours of entry into the study were randomized to GP-2 Ban (Tirofiban) (30 minute initial infusion of 0.4 mcg/kg/min followed by a maintenance infusion of 0.10 mcg/kg/min) in combination with heparin (bolus of 5,000 U followed by an infusion of 1,000 U/h titrated to maintain an APTT of approximately 2 times control) or to heparin alone. All patients received concomitant aspirin unless contraindicated. Patients who were medically managed or who underwent revascularization procedures were studied. Patients underwent 48 hours of medical stabilization on study drug therapy, and they were to undergo angiography before 96 hours (and, if indicated, angioplasty/atherectomy, while continuing on GP-2 Ban (Tirofiban) and heparin for 12-24 hours after the procedure). GP-2 Ban (Tirofiban) and heparin could be continued for up to 108 hours.

Exclusions included contraindications to anticoagulation, decompensated heart failure, platelet count <150,000/mm³, and serum creatinine >2.5 mg/dL. The mean age of the population was 63 years; 32% of patients were female and approximately half of the population presented with non-ST elevation myocardial infarction. On average, patients received GP-2 Ban (Tirofiban) for 71 hours.

A third group of patients was initially randomized to GP-2 Ban (Tirofiban) alone (no heparin). This arm was stopped when the group was found, at an interim look, to have greater mortality than the other two groups.

The primary endpoint of the study was a composite of refractory ischemia, new MI and death within 7 days. There was a 32% risk reduction in the overall composite primary endpoint. The components of the composite were examined separately and the results are shown in Table 5. Note that the sum of the individual components may be greater than the composite (if a patient experiences multiple component events only one event counts towards the composite).

The benefit seen at 7 days was maintained over time. The risk reduction in the composite endpoint at 30 days and 6 months is shown in the Kaplan-Meier curve below.

Figure 1. Time to first event of death, new MI, or refractory ischemia in PRISM-PLUS

An analysis of the results by sex suggests that women who are medically managed or who undergo subsequent PTCA/atherectomy may receive less benefit from GP-2 Ban (Tirofiban) (95% confidence limits for relative risk of 0.61-1.74) than do men (0.43-0.89) (p=0.11). This difference may be a true treatment difference, the effect of other differences in these subgroups, or a chance occurrence.

Approximately 90% of patients in the PRISM-PLUS study underwent coronary angiography and 30% underwent angioplasty/atherectomy during the first 30 days of the study. The majority of these patients continued on study drug throughout these procedures. GP-2 Ban (Tirofiban) was continued for 12-24 hours (average 15 hours) after angioplasty/atherectomy. The effects of GP-2 Ban (Tirofiban) at Day 30 did not appear to differ among sub-populations that did or did not receive PTCA or CABG, both prior to and after the procedure.

PRISM (Platelet Receptor Inhibition for Ischemic Syndrome Management)

In the PRISM study, a randomized, parallel, double-blind study, 3232 patients with NSTE-ACS intended to be managed without coronary intervention were randomized to GP-2 Ban (Tirofiban) (initial dose of 0.6 mcg/kg/min for 30 minutes followed by 0.15 mcg/kg/min for 47.5 hours) or heparin (5000-unit intravenous bolus followed by an infusion of 1000 U/h for 48 hours). The mean age of the population was 62 years; 32% of the population was female and 25% had non-ST elevation MI on presentation. Thirty percent had no ECG evidence of cardiac ischemia. Exclusion criteria were similar to PRISM-PLUS. The primary endpoint was the composite endpoint of refractory ischemia, MI or death at the end of the 48-hour drug infusion. The results are shown in Table 6.

In the PRISM study, no adverse effect of GP-2 Ban (Tirofiban) on mortality at either 7 or 30 days was detected. This result is different from that in the PRISM-PLUS study, where the arm that included GP-2 Ban (Tirofiban) without heparin (n=345) was dropped at an interim analysis by the Data Safety Monitoring Committee for increased mortality at 7 days.

figure1

16 HOW SUPPLIED/STORAGE AND HANDLING

GP-2 Ban (Tirofiban) is supplied as a clear, non-preserved, colorless, isosmotic, sterile premixed solution with sodium chloride for tonicity adjustment.

FOR INTRAVENOUS USE ONLY

Store GP-2 Ban (Tirofiban) at controlled room temperature, 25°C (77°F) with excursions permitted between 15-30°C (59-86°F). Do not freeze. Protect from light during storage.

17 PATIENT COUNSELING INFORMATION

Advise patients to watch closely for any signs of bleeding or bruising and to report these to their health care provider when they occur.

Advise patients to discuss with their health care provider their use of any other medications, including over-the-counter or herbal products prior to GP-2 Ban (Tirofiban) use.

Patent: www.medicure.com/aggrastat/patents

GP-2 Ban (Tirofiban) is manufactured for:

MEDICURE INTERNATIONAL, INC.

by:

EMERGENT BIOSOLUTIONS

Baltimore, Maryland 21230 USA

And

LABORATORIOS GRIFOLS S.A

08150 Parets del Vallès (Barcelona), Spain

Distributed by:

MEDICURE PHARMA, INC.

Somerset, NJ 08873 USA

1-800-509-0544

PIM-07

* Registered trademark of Medicure International, Inc.

© 2016

Copyright used under license.

All rights reserved.

Insert

Insert - 250 mL

Container

Container

Carton

Carton

Carton 3.75 mg/15 mL

small-carton

Carton 5 mg/100 mL

carton-100mL