Cyanocobalamin

NASCOBAL is indicated for: Vitamin B 12 maintenance therapy in adult patients with pernicious anemia who are in remission following intramuscular vitamin B 12 therapy and who have no nervous system involvement Treatment of adult patients with dietary, drug-induced, or malabsorption-related vitamin B 12 deficiency not due to pernicious anemia Prevention of vitamin B 12 deficiency in adult patients with vitamin B 12 requirements in excess of normal Limitations of Use NASCOBAL should not be used for the vitamin B 12 absorption test (Schilling test). In patients with correctible or temporary causes of vitamin B 12 deficiency, the benefit of continued long-term use of NASCOBAL following adequate correction of vitamin B 12 deficiency and underlying disease has not been established. The effectiveness of NASCOBAL in patients with active symptoms of nasal congestion, allergic rhinitis or upper respiratory infection has not been determined. Treatment with NASCOBAL should be deferred until symptoms have subsided. NASCOBAL is a vitamin B 12 indicated for: Vitamin B12 maintenance therapy in adult patients with pernicious anemia who are in remission following intramuscular vitamin B12 therapy and who have no nervous system involvement (1) Treatment of adult patients with dietary, drug-induced, or malabsorption-related vitamin B12 deficiency not due to pernicious anemia (1) Prevention of vitamin B12 deficiency in adult patients with vitamin B12 requirements in excess of normal (1) Limitations of Use: Should not be used for the vitamin B12 absorption test (Schilling test). (1) In patients with correctible or temporary causes of vitamin B12 deficiency the benefit of continued long-term use following correction of vitamin B 12 deficiency and underlying disease has not been established. (1) In patients with active symptoms of nasal congestion, allergic rhinitis or upper respiratory infection effectiveness has not been established. (1)

Nasal spray: 500 mcg/0.1 mL (per actuation), packaged in a single-use device containing 0.125 mL of solution Nasal spray: 500 mcg cyanocobalamin/0.1 mL (per actuation) (3)

NASCOBAL is contraindicated in patients with hypersensitivity to cobalt and/or vitamin B 12 or any of its excipients [see Warnings and Precautions (5.2) ] . Anaphylactic shock and death have been reported after parenteral vitamin B12 administration in sensitive patients.

• Hypersensitivity to cobalt, vitamin B 12 or any excipients (4)

• Severe Optic Atrophy in Patients with Leber’s Disease : Patients with early Leber’s disease who were treated with vitamin B 12 suffered severe and swift optic atrophy. NASCOBAL is not recommended for use in these patients.(5.1)
• Anaphylactic Reactions: Anaphylactic shock and death have been reported after parenteral vitamin B 12 administration. If patients are to start NASCOBAL before having tolerated cyanocobalamin parenterally, consider administering an intradermal test dose of parenteral vitamin B 12 to patients suspected of cyanocobalamin hypersensitivity. (2.1,5.2)
• Masking of Folate Deficiency with Vitamin B 12 Use: Doses of vitamin B 12 exceeding 10 mcg daily may produce hematologic response in patients with folate deficient megaloblastic anemia and may therefore mask a previously unrecognized folate deficiency. Assess both vitamin B 12 and folate levels prior to initiating therapy with NASCOBAL or with folic acid. (5.3)
• Hypokalemia and Thrombocytosis Due to Intense Treatment of Megaloblastic Anemia: Hypokalemia and sudden death may occur in severe megaloblastic anemia that is treated intensely with vitamin B 12 . Monitor serum potassium levels and platelet count during therapy. (5.4)
• Unmasking of Polycythemia Vera: Vitamin B 12 deficiency may suppress the signs of polycythemia vera. Treatment with NASCOBAL may unmask this condition. Patients exhibiting clinical or hematologic response consistent with polycythemia vera should be referred for further evaluation. (5.5)

5.1 Severe Optic Atrophy in Patients with Leber’s Disease Patients with early Leber’s disease (hereditary optic nerve atrophy) who were treated with vitamin B 12 suffered severe and swift optic atrophy. Cyanocobalamin products, including NASCOBAL, is not recommended for use in patients with Leber’s optic atrophy. For patients with Leber’s disease requiring vitamin B 12 , consider alternative therapy (e.g., hydroxocobalamin) for B 12 supplementation.

5.2 Anaphylactic Reactions Anaphylactic shock and death have been reported after parenteral vitamin B 12 administration. If patients are to start NASCOBAL before having tolerated cyanocobalamin parenterally, consider administering an intradermal test dose of parenteral vitamin B 12 to patients suspected of cyanocobalamin hypersensitivity [see Dosage and Administration (2.1) ] .

5.3 Masking of Folate Deficiency with Vitamin B12 Use Doses of vitamin B 12 exceeding 10 mcg daily may produce hematologic response in patients with folate deficient megaloblastic anemia and may therefore mask a previously unrecognized folate deficiency. Vitamin B 12 is not a substitute for folic acid [see Dosage and Administration (2.4) ] . Assess both vitamin B 12 and folate levels prior to initiating therapy with vitamin B 12, including NASCOBAL, or with folic acid [see Dosage and Administration (2.1) ] .

5.4 Hypokalemia and Thrombocytosis Due to Intense Treatment of Megaloblastic Anemia Hypokalemia and sudden death may occur in severe megaloblastic anemia that is treated intensely with vitamin B 12 . Hypokalemia and thrombocytosis can occur upon conversion of severe megaloblastic anemia to normal erythropoiesis with vitamin B 12 therapy. Therefore, serum potassium levels and platelet count should be monitored carefully during therapy [see Dosage and Administration (2.3) ] .

5.5 Unmasking of Polycythemia Vera Vitamin B 12 deficiency may suppress the signs of polycythemia vera. Treatment with vitamin B 12 may unmask this condition. Patients exhibiting clinical or hematologic response consistent with polycythemia vera should be referred for further evaluation.

The following serious adverse reactions are described elsewhere in the labeling: Severe Optic Atrophy in Patients with Leber’s Disease [see Warnings and Precautions (5.1) ] . Anaphylactic Reactions [see Warnings and Precautions (5.2) ] . Hypokalemia and Thrombocytosis Due to Intense Treatment of Megaloblastic Anemia [see Warnings and Precautions (5.4) ] . The most common adverse reactions (≥ 4%) were infection, headache, glossitis, paresthesia, asthenia, nausea and rhinitis (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Endo at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reactions described in Table 1 below are based on data from an eight week cross over trial in which vitamin B12 deficient patients in hematologic remission received one vitamin B12 intramuscular injection (N=25) and then received once weekly intranasal administration of another nasal cyanocobalamin formulation (N=24) for 4 weeks. Table 1. Adverse Reactions Following Intranasal or Intramuscular Administration of Cyanocobalamin In Vitamin B12 Deficient Patients in Hematologic Remission Adverse Reaction Number of Patients (%) Another Cyanocobalamin Nasal Formulation, 500 mcg (n=24) Intramuscular Cyanocobalamin*, 100 mcg (n=25) Infection a 3 (13) 3 (12) Headache 1 (4) 5 (20) Asthenia 1 (4) 4 (16) Nausea 1 (4) 1 (4) Glossitis 1 (4) 0 (0) Paresthesia 1 (4) 1 (4) Rhinitis 1 (4) 2 (8) a Sore throat, common cold * The data are not an adequate basis for comparison of rates between the study drug and the active control

Chloramphenicol may decrease the efficacy of NASCOBAL when used for treatment of anemia. If NASCOBAL is used for the treatment of anemia concomitantly with chloramphenicol, monitor for reduced efficacy and if needed, consider an alternative therapy

See Patient Counseling Information.

8.1 Pregnancy Risk Summary The limited available data on NASCOBAL in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. However, vitamin B12 is an essential vitamin and requirements are increased during pregnancy. Animal reproduction studies have not been conducted with vitamin B 12 . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation Risk Summary Vitamin B 12 is present in the milk of lactating women in concentrations which approximate the mother’s vitamin B 12 blood level. Vitamin B 12 does not appear to pose more than a minimal risk to breastfeeding children.

8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients.

8.5 Geriatric Use Clinical studies of NASCOBAL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Vitamin B 12 can be converted to coenzyme B 12 in tissues, and as such is essential for conversion of methylmalonate to succinate and synthesis of methionine from homocysteine, a reaction which also requires folate. In the absence of coenzyme B 12 , tetrahydrofolate cannot be regenerated from its inactive storage form, 5-methyltetrahydrofolate, and a functional folate deficiency occurs. Vitamin B 12 also may be involved in maintaining sulfhydryl (SH) groups in the reduced form required by many SH-activated enzyme systems. Through these reactions, vitamin B 12 is associated with fat and carbohydrate metabolism and protein synthesis.