Megazid

Ceftazidime:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• Compatibility and stability
• How supplied
• References
• Rl-1116
• Megazid (Ceftazidime) reviews

INDICATIONS AND USAGE

Megazid (Ceftazidime) (ceftazidime for injection, USP) is indicated for the treatment of patients with infections caused by susceptible strains of the designated organisms in the following diseases:

• Lower Respiratory Tract Infections, including pneumonia, caused by Pseudomonas aeruginosa and other Pseudomonas spp.; Haemophilus influenzae, including ampicillin-resistant strains; Klebsiella spp.; Enterobacter spp.; Proteus mirabilis; Escherichia coli; Serratia spp.; Citrobacter spp.; Streptococcus pneumoniae ; and Staphylococcus aureus (methicillin-susceptible strains).
• Skin and Skin-Structure Infections caused by Pseudomonas aeruginosa ; Klebsiella spp.; Escherichia coli; Proteus spp., including Proteus mirabilis and indole-positive Proteus; Enterobacter spp.; Serratia spp.; Staphylococcus aureus (methicillin-susceptible strains); and Streptococcus pyogenes (group A beta-hemolytic streptococci).
• Urinary Tract Infections, both complicated and uncomplicated, caused by Pseudomonas aeruginosa; Enterobacter spp.; Proteus spp., including Proteus mirabilis and indole-positive Proteus; Klebsiella spp.; and Escherichia coli.
• Bacterial Septicemia caused by Pseudomonas aeruginosa, Klebsiella spp., Haemophilus influenzae, Escherichia coli, Serratia spp., Streptococcus pneumoniae, and Staphylococcus aureus (methicillin-susceptible strains).
• Bone and Joint Infections caused by Pseudomonas aeruginosa, Klebsiella spp., Enterobacter spp., and Staphylococcus aureus (methicillin-susceptible strains).
• Gynecologic Infections, including endometritis, pelvic cellulitis, and other infections of the female genital tract caused by Escherichia coli.
• Intra-abdominal Infections, including peritonitis caused by Escherichia coli, Klebsiella spp., and Staphylococcus aureus (methicillin-susceptible strains) and polymicrobial infections caused by aerobic and anaerobic organisms and Bacteroides spp. (many strains of Bacteroides fragilis are resistant).
• Central Nervous System Infections, including meningitis, caused by Haemophilus influenzae and Neisseria meningitidis. Megazid (Ceftazidime) has also been used successfully in a limited number of cases of meningitis due to Pseudomonas aeruginosa and Streptococcus pneumoniae.

Megazid (Ceftazidime) (ceftazidime for injection, USP) may be used alone in cases of confirmed or suspected sepsis. Megazid (Ceftazidime) has been used successfully in clinical trials as empiric therapy in cases where various concomitant therapies with other antibiotics have been used.

Megazid (Ceftazidime) may also be used concomitantly with other antibiotics, such as aminoglycosides, vancomycin, and clindamycin; in severe and life-threatening infections; and in the immunocompromised patient. When such concomitant treatment is appropriate, prescribing information in the labeling for the other antibiotics should be followed. The dose depends on the severity of the infection and the patient’s condition.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Megazid (Ceftazidime) (ceftazidime) and other antibacterial drugs, Megazid (Ceftazidime) (ceftazidime) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

CONTRAINDICATIONS

Megazid (Ceftazidime) is contraindicated in patients who have shown hypersensitivity to Megazid (Ceftazidime) or the cephalosporin group of antibiotics.

WARNINGS

BEFORE THERAPY WITH Megazid (Ceftazidime) IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO Megazid (Ceftazidime), CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-HYPERSENSITIVITY AMONG BETA-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO Megazid (Ceftazidime) OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, IV FLUIDS, IV ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Megazid (Ceftazidime), and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Elevated levels of Megazid (Ceftazidime) in patients with renal insufficiency can lead to seizures, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia (see PRECAUTIONS ).

PRECAUTIONS

General

High and prolonged serum Megazid concentrations can occur from usual dosages in patients with transient or persistent reduction of urinary output because of renal insufficiency.

The total daily dosage should be reduced when Megazid (Ceftazidime) is administered to patients with renal insufficiency (see DOSAGE AND ADMINISTRATION ). Elevated levels of Megazid (Ceftazidime) in these patients can lead to seizures, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia. Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organisms.

As with other antibiotics, prolonged use of Megazid (Ceftazidime) (ceftazidime for injection, USP) may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient’s condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Inducible type I beta-lactamase resistance has been noted with some organisms (e.g., Enterobacter spp., Pseudomonas spp., and Serratia spp.). As with other extended-spectrum beta-lactam antibiotics, resistance can develop during therapy, leading to clinical failure in some cases. When treating infections caused by these organisms, periodic susceptibility testing should be performed when clinically appropriate. If patients fail to respond to monotherapy, an aminoglycoside or similar agent should be considered.

Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal and hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated.

Megazid (Ceftazidime) should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

Distal necrosis can occur after inadvertent intra-arterial administration of Megazid (Ceftazidime).

Prescribing Megazid (Ceftazidime) (ceftazidime) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Information for Patients

Patients should be counseled that antibacterial drugs, including Megazid (Ceftazidime) (ceftazidime), should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Megazid (Ceftazidime) (ceftazidime) is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Megazid (Ceftazidime) (ceftazidime) or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Drug Interactions

Nephrotoxicity has been reported following concomitant administration of cephalosporins with aminoglycoside antibiotics or potent diuretics such as furosemide. Renal function should be carefully monitored, especially if higher dosages of the aminoglycosides are to be administered or if therapy is prolonged, because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity and ototoxicity were not noted when Megazid was given alone in clinical trials.

Chloramphenicol has been shown to be antagonistic to beta-lactam antibiotics, including Megazid (Ceftazidime), based on in vitro studies and time kill curves with enteric gram-negative bacilli. Due to the possibility of antagonism in vivo, particularly when bactericidal activity is desired, this drug combination should be avoided.

In common with other antibiotics, Megazid (Ceftazidime) may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.

Drug/Laboratory Test Interactions

The administration of Megazid (Ceftazidime) may result in a false-positive reaction for glucose in the urine when using CLINITEST^® tablets, Benedict's solution, or Fehling's solution.

It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as CLINISTIX^®) be used.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. However, a mouse micronucleus test and an Ames test were both negative for mutagenic effects.

Pregnancy

Teratogenic Effects

Pregnancy Category B. Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Megazid. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Megazid (Ceftazidime) is excreted in human milk in low concentrations. Caution should be exercised when Megazid (Ceftazidime) is administered to a nursing woman.

Pediatric Use

.

Geriatric Use

Of the 2,221 subjects who received Megazid (Ceftazidime) in 11 clinical studies, 824 (37%) were 65 and older while 391 (18%) were 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater susceptibility of some older individuals to drug effects cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION ).

ADVERSE REACTIONS

Megazid (Ceftazidime) is generally well tolerated. The incidence of adverse reactions associated with the administration of Megazid (Ceftazidime) was low in clinical trials. The most common were local reactions following IV injection and allergic and gastrointestinal reactions. Other adverse reactions were encountered infrequently. No disulfiram-like reactions were reported.

The following adverse effects from clinical trials were considered to be either related to Megazid (Ceftazidime) therapy or were of uncertain etiology:

Local Effects, reported in fewer than 2% of patients, were phlebitis and inflammation at the site of injection (1 in 69 patients).

Hypersensitivity Reactions, reported in 2% of patients, were pruritus, rash, and fever. Immediate reactions, generally manifested by rash and/or pruritus, occurred in 1 in 285 patients. Toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme have also been reported with cephalosporin antibiotics, including Megazid (Ceftazidime). Angioedema and anaphylaxis (bronchospasm and/or hypotension) have been reported very rarely.

Gastrointestinal Symptoms, reported in fewer than 2% of patients, were diarrhea (1 in 78), nausea (1 in 156), vomiting (1 in 500), and abdominal pain (1 in 416). The onset of pseudomembranous colitis symptoms may occur during or after treatment (see WARNINGS ).

Central Nervous System Reactions (fewer than 1%) included headache, dizziness, and paresthesia. Seizures have been reported with several cephalosporins, including Megazid (Ceftazidime). In addition, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported in renally impaired patients treated with unadjusted dosing regimens of Megazid (Ceftazidime) (see PRECAUTIONS: General ).

Less Frequent Adverse Events (fewer than 1%) were candidiasis (including oral thrush) and vaginitis.

Hematologic

Rare cases of hemolytic anemia have been reported.

Laboratory Test Changes noted during clinical trials with Megazid (Ceftazidime) (ceftazidime for injection, USP) were transient and included: eosinophilia (1 in 13), positive Coombs test without hemolysis (1 in 23), thrombocytosis (1 in 45), and slight elevations in one or more of the hepatic enzymes, aspartate aminotransferase (AST, SGOT) (1 in 16), alanine aminotransferase (ALT, SGPT) (1 in 15), LDH (1 in 18), GGT (1 in 19), and alkaline phosphatase (1 in 23). As with some other cephalosporins, transient elevations of blood urea, blood urea nitrogen, and/or serum creatinine were observed occasionally. Transient leukopenia, neutropenia, agranulocytosis, thrombocytopenia, and lymphocytosis were seen very rarely.

Postmarketing Experience with Megazid (Ceftazidime) (ceftazidime for injection, USP) Products

In addition to the adverse events reported during clinical trials, the following events have been observed during clinical practice in patients treated with Megazid (Ceftazidime) and were reported spontaneously. For some of these events, data are insufficient to allow an estimate of incidence or to establish causation.

General

Anaphylaxis; allergic reactions, which, in rare instances, were severe (e.g., cardiopulmonary arrest); urticaria; pain at injection site.

Hepatobiliary Tract

Hyperbilirubinemia, jaundice.

Renal and Genitourinary

Renal impairment.

Cephalosporin-Class Adverse Reactions

In addition to the adverse reactions listed above that have been observed in patients treated with Megazid (Ceftazidime), the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics:

Adverse Reactions

Colitis, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemorrhage.

Altered Laboratory Tests

Prolonged prothrombin time, false-positive test for urinary glucose, pancytopenia.

OVERDOSAGE

Megazid (Ceftazidime) overdosage has occurred in patients with renal failure. Reactions have included seizure activity, encephalopathy, asterixis, neuromuscular excitability, and coma. Patients who receive an acute overdosage should be carefully observed and given supportive treatment. In the presence of renal insufficiency, hemodialysis or peritoneal dialysis may aid in the removal of Megazid (Ceftazidime) from the body.

DOSAGE AND ADMINISTRATION

NOTE: The Pharmacy Bulk Package is intended for preparing IV admixtures only. Dosage recommendations for intramuscular or intravenous injection and intraperitoneal use are for informational purposes only.

Dosage: The usual adult dosage is 1 gram administered intravenously every 8 to 12 hours. The dosage and route should be determined by the susceptibility of the causative organisms, the severity of infection, and the condition and renal function of the patient.

The guidelines for dosage of Megazid (Ceftazidime) (ceftazidime for injection, USP) are listed in Table 5. The following dosage schedule is recommended.

Impaired Hepatic Function

No adjustment in dosage is required for patients with hepatic dysfunction.

Impaired Renal Function

Megazid (Ceftazidime) is excreted by the kidneys, almost exclusively by glomerular filtration. Therefore, in patients with impaired renal function (glomerular filtration rate [GFR] <50 mL/min), it is recommended that the dosage of Megazid (Ceftazidime) be reduced to compensate for its slower excretion. In patients with suspected renal insufficiency, an initial loading dose of 1 gram of Megazid (Ceftazidime) may be given. An estimate of GFR should be made to determine the appropriate maintenance dosage. The recommended dosage is presented in Table 6.

When only serum creatinine is available, the following formula (Cockcroft’s equation)⁴ may be used to estimate creatinine clearance. The serum creatinine should represent a steady state of renal function:

[Weight (kg) x (140 - age)]

Males: Creatinine clearance (mL/min) = ––––––––––––––––––––––––––

[72 x serum creatinine (mg/dL)]

Females: 0.85 x male value

In patients with severe infections who would normally receive 6 grams of Megazid (Ceftazidime) daily were it not for renal insufficiency, the unit dose given in the table above may be increased by 50% or the dosing frequency may be increased appropriately. Further dosing should be determined by therapeutic monitoring, severity of the infection, and susceptibility of the causative organism.

In pediatric patients as for adults, the creatinine clearance should be adjusted for body surface area or lean body mass, and the dosing frequency should be reduced in cases of renal insufficiency.

In patients undergoing hemodialysis, a loading dose of 1 gram is recommended, followed by 1 gram after each hemodialysis period.

Megazid (Ceftazidime) (ceftazidime for injection, USP) can also be used in patients undergoing intra-peritoneal dialysis and continuous ambulatory peritoneal dialysis. In such patients, a loading dose of 1 gram of Megazid (Ceftazidime) may be given, followed by 500 mg every 24 hours. In addition to IV use, Megazid (Ceftazidime) can be incorporated in the dialysis fluid at a concentration of 250 mg for 2 L of dialysis fluid.

Note: Generally Megazid (Ceftazidime) should be continued for 2 days after the signs and symptoms of infection have disappeared, but in complicated infections longer therapy may be required.

Administration

Pharmacy Bulk Package is for use in a pharmacy admixture service only. Refer to Table 7. See above NOTE concerning the proper use of Pharmacy Bulk Packages.

Intravenous Administration

The IV route is preferable for patients with bacterial septicemia, bacterial meningitis, peritonitis, or other severe or life-threatening infections, or for patients who may be poor risks because of lowered resistance resulting from such debilitating conditions as malnutrition, trauma, surgery, diabetes, heart failure, or malignancy, particularly if shock is present or pending.

Intermittent IV infusion with a Y-type administration set can be accomplished with compatible solutions. However, during infusion of a solution containing Megazid (Ceftazidime), it is desirable to discontinue the other solution.

All vials of Megazid (Ceftazidime) as supplied are under reduced pressure. When Megazid (Ceftazidime) is dissolved, carbon dioxide is released and a positive pressure develops.

Solutions of Megazid (Ceftazidime), like those of most beta-lactam antibiotics, should not be added to solutions of aminoglycoside antibiotics because of potential interaction.

However, if concurrent therapy with Megazid (Ceftazidime) and an aminoglycoside is indicated, each of these antibiotics can be administered separately to the same patient.

Directions for Use of Pharmacy Bulk Packages:

Reconstitute with Sterile Water for Injection according to Table 7.

Note: The Pharmacy Bulk Package is for use in a pharmacy admixture service only. Using aseptic technique, the closure should be penetrated only 1 time after reconstitution using a sterile dispensing set which allows measured dispensing of the contents. Use of a syringe and needle is not recommended as it may cause leakage. The withdrawal of container contents should be accomplished without delay. THE ENTIRE CONTENTS OF THE VIAL SHOULD BE DISPENSED WITHIN 4 HOURS OF INITIAL ENTRY.

A plastic bail attached to the Pharmacy Bulk Package provides a suitable hanging device while dispensing in the pharmacy.

Reconstitute with Sterile Water for Injection according to Table 7.

The vacuum may assist entry of the diluent. SHAKE WELL.

Insert a gas relief needle through the vial closure to relieve the internal pressure. Remove the gas relief needle before extracting any solution.

COMPATIBILITY AND STABILITY

IMPORTANT: The following chemical stability information in no way indicates that it would be acceptable practice to use this product well after the preparation time. Good professional practice suggests that compounded admixtures should be administered as soon after preparation as is feasible.

Intravenous: Megazid (Ceftazidime) (ceftazidime for injection, USP) when reconstituted as directed with Sterile Water for Injection, should be used within 4 hours. Solutions in Sterile Water for Injection in the original container or in 0.9% Sodium Chloride Injection in VIAFLEX^® small-volume containers that are frozen immediately after reconstitution are stable for 3 months when stored at -20°C. Do not force thaw by immersion in water baths or by microwave irradiation. Once thawed, solutions should not be refrozen. Thawed solutions may be stored for up to 24 hours at room temperature or for 7 days in a refrigerator. More concentrated solutions in Sterile Water for Injection in the original container that are frozen immediately after reconstitution are stable for 3 months when stored at -20°C. Once thawed, solutions should not be refrozen. Thawed solutions may be stored for up to 8 hours at room temperature or for 4 days in a refrigerator.

Megazid (Ceftazidime) (ceftazidime for injection, USP) is compatible with the more commonly used IV infusion fluids. Solutions at concentrations between 1 mg/mL and 40 mg/mL in 0.9% Sodium Chloride Injection; 1/6 M Sodium Lactate Injection; 5% Dextrose Injection; 5% Dextrose and 0.225% Sodium Chloride Injection; 5% Dextrose and 0.45% Sodium Chloride Injection; 5% Dextrose and 0.9% Sodium Chloride Injection; 10% Dextrose Injection; Ringer’s Injection, USP; Lactated Ringer’s Injection, USP 10% Invert Sugar in Water for Injection; and NORMOSOL^®-M in 5% Dextrose Injection may be stored for up to 24 hours at room temperature or for 7 days if refrigerated.

Megazid (Ceftazidime) is less stable in Sodium Bicarbonate Injection than in other IV fluids. It is not recommended as a diluent. Solutions of Megazid (Ceftazidime) in 5% Dextrose Injection and 0.9% Sodium Chloride Injection are stable for at least 6 hours at room temperature in plastic tubing, drip chambers and volume control devices of common IV infusion sets.

Megazid (Ceftazidime) at a concentration of 4 mg/mL has been found compatible for 24 hours at room temperature or for 7 days under refrigeration in 0.9% Sodium Chloride Injection or 5% Dextrose Injection when admixed with cefuroxime sodium (ZINACEF^®) 3 mg/mL, heparin 10 U/mL or 50 U/mL, or potassium chloride 10 mEq/L or 40 mEq/L.

Vancomycin solution exhibits a physical incompatibility when mixed with a number of drugs, including Megazid (Ceftazidime). The likelihood of precipitation with Megazid (Ceftazidime) is dependent on the concentrations of vancomycin and Megazid (Ceftazidime) present. It is therefore recommended, when both drugs are to be administered by intermittent IV infusion, that they be given separately, flushing the IV lines (with 1 of the compatible IV fluids) between the administration of these 2 agents.

Note: Parenteral drug products should be inspected visually for particulate matter before administration whenever solution and container permit.

As with other cephalosporins, Megazid (Ceftazidime) (ceftazidime for injection, USP) powder, as well as solutions, tend to darken depending on storage conditions; within the stated recommendations, however, product potency is not adversely affected.

HOW SUPPLIED

Megazid (Ceftazidime) in the dry state should be stored at 20° to 25°C (68° to 77°F) and protected from light. Megazid (Ceftazidime) (ceftazidime for injection, USP) is a dry, white to off-white powder supplied in vials as follows:

Pharmacy Bulk Package Bottles: equivalent to 6 grams of Megazid (Ceftazidime).

6 gram (tray of 10) NDC 0409-5086-11

Also available as:

Vials: equivalent to 1 gram and 2 grams of Megazid (Ceftazidime).

1 gram (tray of 25) NDC 0409-5082-16

2 gram (tray of 10) NDC 0409-5084-11

ADD-Vantage^® Vials: equivalent to 1 gram and 2 grams of Megazid (Ceftazidime).

1 gram: NDC 0409-5092-16

2 gram: NDC 0409-5093-11

REFERENCES

• Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
• Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fourth Informational Supplement, CLSI document M100-S24. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2014.
• Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
• Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eighth Edition. CLSI document M11-A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2012.
• Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41.

Revised: 5/2016

EN-4285

Manufactured by Sandoz GmbH for

Hospira Worldwide, Inc., Lake Forest, IL 60045, USA

Made in Kundl, Austria.

46184541

Hospira logo

RL-1116

Sodium Carbonate:

• 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
• Megazid (Sodium Carbonate) reviews

1 INDICATIONS AND USAGE

Megazid nitrite is indicated for sequential use with Megazid (Sodium Carbonate) 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

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

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

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

3 DOSAGE FORMS AND STRENGTHS

Megazid (Sodium Carbonate) Nitrite Injection consists of:

• One vial of Megazid (Sodium Carbonate) 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: Megazid 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 Megazid (Sodium Carbonate) 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. Megazid (Sodium Carbonate) 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 Megazid (Sodium Carbonate) 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 Megazid nitrite.

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

5.3 Anemia

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

5.4 Smoke Inhalation Injury

Megazid 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 Megazid (Sodium Carbonate) 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 Megazid 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 Megazid (Sodium Carbonate) nitrite.

5.7 Use with Other Drugs

Megazid (Sodium Carbonate) 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 Megazid (Sodium Carbonate) nitrite.

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

8 USE IN SPECIFIC POPULATIONS

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

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

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

Megazid (Sodium Carbonate) 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 Megazid (Sodium Carbonate) 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

Megazid (Sodium Carbonate) 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

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

Megazid (Sodium Carbonate) 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 Megazid (Sodium Carbonate) 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 Megazid (Sodium Carbonate) 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

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

Structure of Megazid (Sodium Carbonate) Nitrite

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

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

Megazid (Sodium Carbonate) Nitrite

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

Megazid (Sodium Carbonate) 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. Megazid (Sodium Carbonate) 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

Megazid (Sodium Carbonate) Nitrite

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

12.3 Pharmacokinetics

Megazid (Sodium Carbonate) Nitrite

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

Mutagenesis

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

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

14 CLINICAL STUDIES

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

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

17 PATIENT COUNSELING INFORMATION

Megazid 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

Megazid (Sodium Carbonate) 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

Megazid (Sodium Carbonate) 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