CYANOCOBALAMINE

ADVERSE REACTIONS Generalized: Anaphylactic shock and death have been reported with administration of parenteral vitamin B 12 (see WARNINGS). Cardiovascular: Pulmonary edema and congestive heart failure early in treatment; peripheral vascular thrombosis. Hematological: Polycythemia vera Gastrointestinal: Mild transient diarrhea Dermatological: Itching; transitory exanthema Miscellaneous: Feeling of swelling of entire body To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1 877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CONTRAINDICATIONS Sensitivity to cobalt and/or vitamin B 12 is a contraindication.

DESCRIPTION Cyanocobalamin Injection, USP is a sterile solution of cyanocobalamin for intramuscular or subcutaneous injection. Each mL contains 1,000 mcg cyanocobalamin, Sodium Chloride 0.9%. Benzyl Alcohol 1.5% is present as a preservative. Sodium acetate and Glacial acetic acid are present as buffers. Hydrochloric acid and/or sodium hydroxide may have been added during manufacture to adjust the pH (range 4.5 to 7.0). Cyanocobalamin appears as dark red crystals or as an amorphous or crystalline red powder or purplish crystalline powder. Sparingly soluble in water and soluble in alcohol, practically insoluble in acetone, in chloroform and in either. It is stable to autoclaving for short periods at 121°C. The vitamin B12coenzymes are very unstable in light. The chemical name is 5,6-dimethyl-benzimidazolyl cyanocobamide; the molecular formula is C63H88CoN14O14P. The cobalt content is 4.34%. The molecular weight is 1355.4. The structural formula is represented below. Formula1.jpg

DOSAGE AND ADMINISTRATION Avoid using the intravenous route. Use of this product intravenously will result in almost all of the vitamin being lost in the urine. Pernicious Anemia: Parenteral vitamin B 12 is the recommended treatment and will be required for the remainder of the patient's life. The oral form is not dependable. A dose of 100 mcg daily for 6 or 7 days should be administered by intramuscular or deep subcutaneous injection. If there is clinical improvement and if a reticulocyte response is observed, the same amount may be given on alternate days for seven doses, then every 3 to 4 days for another 2 to 3 weeks. By this time hematologic values should have become normal. This regimen should be followed by 100 mcg monthly for life. Folic acid should be administered concomitantly if needed. Patients with Normal Intestinal Absorption: Where the oral route is not deemed adequate, initial treatment similar to that for patients with pernicious anemia may be indicated depending on the severity of the deficiency. Chronic treatment should be with an oral B 12 preparation. If other vitamin deficiencies are present, they should be treated. Schilling Test: The flushing dose is 1,000 mcg. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

INDICATIONS AND USAGE Cyanocobalamin is indicated for vitamin B 12 deficiencies due to malabsorption which may be associated with the following conditions: •Addisonian (pernicious) anemia •Gastrointestinal pathology, dysfunction, or surgery, including gluten enteropathy or sprue, small bowel bacteria overgrowth, total or partial gastrectomy •Fish tapeworm infestation •Malignancy of pancreas or bowel •Folic acid deficiency It may be possible to treat the underlying disease by surgical correction of anatomic lesions leading to small bowel bacterial overgrowth, expulsion of fish tapeworm, discontinuation of drugs leading to vitamin malabsorption (see Drug Interactions), use of a gluten-free diet in nontropical sprue, or administration of antibiotics in tropical sprue. Such measures remove the need for long-term administration of cyanocobalamin. Requirements of vitamin B 12 in excess of normal (due to pregnancy, thyrotoxicosis, hemolytic anemia, hemorrhage, malignancy, hepatic and renal disease) can usually be met with oral supplementation. Cyanocobalamin Injection, USP is also suitable for the vitamin B 12 absorption test (Schilling test).

WARNINGS Patients with early Leber's disease (hereditary optic nerve atrophy) who were treated with cyanocobalamin suffered severe and swift optic atrophy. Hypokalemia and sudden death may occur in severe megaloblastic anemia which is treated intensely. Anaphylactic shock and death have been reported after parenteral vitamin B 12 administration. An intradermal test dose is recommended before Cyanocobalamin Injection, USP is administered to patients suspected of being sensitive to this drug. This product contains Benzyl Alcohol. Benzyl Alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

OVERDOSAGE No overdosage has been reported with this drug.

CLINICAL PHARMACOLOGY Vitamin B 12 is essential to growth, cell reproduction, hematopoiesis, and nucleoprotein and myelin synthesis. Cyanocobalamin is quantitatively and rapidly absorbed from intramuscular and subcutaneous sites of injection; the plasma level of the compound reaches its peak within 1 hour after intramuscular injection. Absorbed vitamin B 12 is transported via specific B 12 binding proteins, transcobalamin I and II to the various tissues. The liver is the main organ for vitamin B 12 storage. Within 48 hours after injection of 100 or 1,000 mcg of vitamin B 12 , 50 to 98% of the injected dose may appear in the urine. The major portion is excreted within the first eight hours. Intravenous administration results in even more rapid excretion with little opportunity for liver storage. Gastrointestinal absorption of vitamin B 12 depends on the presence of sufficient intrinsic factor and calcium ions. Intrinsic factor deficiency causes pernicious anemia, which may be associated with subacute combined degeneration of the spinal cord. Prompt parenteral administration of vitamin B 12 prevents progression of neurologic damage. The average diet supplies about 5 to 15 mcg/day of vitamin B 12 in a protein-bound form that is available for absorption after normal digestion. Vitamin B 12 is not present in foods of plant origin, but is abundant in foods of animal origin. In people with normal absorption, deficiencies have been reported only in strict vegetarians who consume no products of animal origin (including no milk products or eggs). Vitamin B 12 is bound to intrinsic factor during transit through the stomach; separation occurs in the terminal ileum in the presence of calcium, and vitamin B 12 enters the mucosal cell for absorption. It is then transported by the transcobalamin binding proteins. A small amount (approximately 1% of the total amount ingested) is absorbed by simple diffusion, but this mechanism is adequate only with very large doses. Oral absorption is considered too undependable to rely on in patients with pernicious anemia or other conditions resulting in malabsorption of vitamin B 12 . Cyanocobalamin is the most widely used form of vitamin B 12, and has hematopoietic activity apparently identical to that of the antianemia factor in purified liver extract. Hydroxycobalamin is equally as effective as cyanocobalamin, and they share the cobalamin molecular structure.

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CYANOCOBALAMINE cyanocobalamine injection CYANOCOBALAMIN CYANOCOBALAMIN SODIUM CHLORIDE BENZYL ALCOHOL SODIUM ACETATE ACETIC ACID HYDROCHLORIC ACID SODIUM HYDROXIDE WATER

ANDA204829

CYANOCOBALAMINE

cyanocobalamine injection

0404-9995

HUMAN PRESCRIPTION DRUG

INTRAMUSCULAR,SUBCUTANEOUS

Sample Package Label Label1.jpg

How Supplied Cyanocobalamin Injection, USP 1,000 mcg/mL is supplied as follows: 10 mL Multiple Dose Vial, NDC 67457-399-10 Box of 1 vial. 10 mL Multiple Dose Vial, NDC 67457-399-25 Box of 25 vials. 30 mL Multiple Dose Vial, NDC 67457-400-31 Box of 1 vial. 30 mL Multiple Dose Vial, NDC 67457-400-05 Box of 5 vials. Store at 20o to 25oC (68o to 77oF). [See USP Controlled Room Temperature.] PROTECT FROM LIGHT. Product repackaged by: Henry Schein, Inc., Bastian, VA 24314 From Original Manufacturer/Distributor's NDC and Unit of Sale To Henry Schein Repackaged Product NDC and Unit of Sale Total Strength/Total Volume (Concentration) per unit NDC 67457-399-25 Box of 25 vials NDC 0404-9840-10 1 10 mL Multiple Dose Vial in a bag (Vial bears NDC 67457-399-10) 1,000 mcg/mL NDC 67457-400-05 Box of 5 vials NDC 0404-9995-30 1 30 mL Multiple Dose Vial in a bag (Vial bears NDC 67457-400-31) 1,000 mcg/mL Manufactured for: Mylan Institutional LLC Rockford, IL 61130 U.S.A. Manufactured by: Mylan Laboratories Limited Bangalore, India Code No.: KR/DRUGS/KTK/28/384/2009 1028190 MAY 2016

PRECAUTIONS General Precautions: Vitamin B 12 deficiency that is allowed to progress for longer than 3 months may produce permanent degenerative lesions of the spinal cord. Doses of folic acid greater than 0.1 mg per day may result in hematologic remission in patients with vitamin B 1 2 deficiency. Neurologic manifestations will not be prevented with folic acid, and if not treated with vitamin B 12 , irreversible damage will result. Doses of cyanocobalamin exceeding 10 mcg daily may produce hematologic response in patients with folate deficiency. Indiscriminate administration may mask the true diagnosis. Information for Patients: Patients with pernicious anemia should be informed that they will require monthly injections of vitamin B 12 for the remainder of their lives. Failure to do so will result in return of the anemia and in development of incapacitating and irreversible damage to the nerves of the spinal cord. Also, patients should be warned about the danger of taking folic acid in place of vitamin B 12 , because the former may prevent anemia but allow progression of subacute combined degeneration. A vegetarian diet which contains no animal products (including milk products or eggs) does not supply any vitamin B 12 . Patients following such a diet should be advised to take oral vitamin B 12 regularly. The need for vitamin B 12 is increased by pregnancy and lactation. Deficiency has been recognized in infants of vegetarian mothers who were breast fed, even though the mothers had no symptoms of deficiency at the time. Laboratory Tests: During the initial treatment of patients with pernicious anemia, serum potassium must be observed closely the first 48 hours and potassium replaced if necessary. Hematocrit, reticulocyte count, vitamin B 12 , folate and iron levels should be obtained prior to treatment. Hematocrit and reticulocyte counts should be repeated daily from the fifth to seventh days of therapy and then frequently until the hematocrit is normal. If folate levels are low, folic acid should also be administered. If reticulocytes have not increased after treatment or if reticulocyte counts do not continue at least twice normal as long as the hematocrit is less than 35%, diagnosis or treatment should be reevaluated. Repeat determinations of iron and folic acid may reveal a complicating illness that might inhibit the response of the marrow. Patients with pernicious anemia have about 3 times the incidence of carcinoma of the stomach as the general population, so appropriate tests for this condition should be carried out when indicated. Drug/Laboratory Test Interactions: Persons taking most antibiotics, methotrexate and pyrimethamine invalidate folic acid and vitamin B 12 diagnostic blood assays. Colchicine para-aminosalicylic acid and heavy alcohol intake for longer than 2 weeks may produce malabsorption of vitamin B 12 . Carcinogenesis, Mutagenesis, Impairment of Fertility: Long term studies in animals to evaluate carcinogenic potential have not been done. There is no evidence from long-term use in patients with pernicious anemia that cyanocobalamin is carcinogenic. Pernicious anemia is associated with an increased incidence of carcinoma of the stomach, but this is believed to be related to the underlying pathology and not to treatment with cyanocobalamin. Pregnancy: Teratogenic Effects. Pregnancy Category C: Adequate and well-controlled studies have not been done in pregnant women. However, vitamin B 12 is an essential vitamin and requirements are increased during pregnancy. Amounts of vitamin B 12 that are recommended by the Food and Nutrition Board, National Academy of Science-National Research Council for pregnant women (4 mcg daily) should be consumed during pregnancy. Nursing Mothers: Vitamin B 12 is known to be excreted in human milk. Amounts of vitamin B 12 that are recommended by the Food and Nutrition Board, National Academy of Science National Research Council for lactating women (4 mcg daily) should be consumed during lactation. Pediatric Use: Intake in children should be in the amount (0.5 to 3 mcg daily) recommended by the Food and Nutrition Board, National Academy of Science-National Research Council.