NASCOBAL

Cyanocobalamin is a synthetic form of vitamin B 12 . The chemical name is 5,6-dimethyl-benzimidazolyl cyanocobamide. The cobalt content is 4.35%. The molecular formula is C 63 H 88 CoN 14 O 14 P, which corresponds to a molecular weight of 1355.38 and the following structural formula: Figure 1. Nascobal Chemical Structure Cyanocobalamin occurs as dark red crystals or orthorhombic needles or crystalline red powder. It is very hygroscopic in the anhydrous form, and sparingly to moderately soluble in water (1:80). Its pharmacologic activity is destroyed by heavy metals (iron) and strong oxidizing or reducing agents (vitamin C), but not by autoclaving for short periods of time (15-20 minutes) at 121°C. The vitamin B 12 coenzymes are very unstable in light. NASCOBAL (cyanocobalamin) nasal spray is a solution of cyanocobalamin, USP (vitamin B 12 ) for administration as a spray to the nasal mucosa. Each single-use device of NASCOBAL NASAL SPRAY contains 0.125 mL of a 500 mcg/0.1 mL solution of cyanocobalamin with, benzalkonium chloride in purified water, citric acid, glycerin and sodium citrate. The spray solution has a pH between 4.5 and 5.5. Each spray delivers an average of 500 mcg of cyanocobalamin per actuation. Image-1

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)

Prior to treatment, obtain hematocrit, reticulocyte count, vitamin B 12 , folate, and iron levels. (2.1) The recommended initial dose is one spray (500 mcg) in one nostril once weekly. (2.2) Administer at least one hour before or one hour after ingestion of hot foods or liquids. (2.2) Monitor serum B12 levels periodically.Obtain a serum B12 level and peripheral blood count one month after treatment initiation, then subsequently at intervals of 3 to 6 months. (2.3) If serum levels of B12 decline after one month of treatment, consider increasing the dose. Assess serum B12 level one month after each dose adjustment.If serum B12 levels are persistently low, consider alternative therapy (e.g., intramuscular or subcutaneous vitamin B12 therapy). (2.3) See Full Prescibing Information to see what other therapies should be administered with NASCOBAL. (2.4) 2.1 Testing and Other Considerations Prior to Dosing Prior to treatment, obtain hematocrit, reticulocyte count, vitamin B 12 , folate, and iron levels [see Dosage and Administration (2.4) ] . Consider the potential for concomitant drugs to interfere with vitamin B 12 and folate diagnostic blood assays [see Drug Interactions (7) ] . In patients with suspected cobalamin hypersensitivity, consider administering an intradermal test dose of parenteral vitamin B 12 prior to use of NASCOBAL [see Warnings and Precautions (5.2) ] . 2.2 Recommended Dosage The recommended initial dose of NASCOBAL is one spray (500 mcg) administered in ONE nostril once weekly. Administer NASCOBAL at least one hour before or one hour after ingestion of hot foods or liquids since hot foods may cause nasal secretions and a resulting loss of medication. Defer use of NASCOBAL in patients with nasal congestion, allergic rhinitis, or upper respiratory infections until after symptoms have subsided. 2.3 Monitoring, Dosage Modifications, and Treatment Duration Monitoring for Response and Safety Monitor serum B 12 levels periodically during therapy to establish adequacy of therapy. Obtain a serum B 12 level and peripheral blood count one month after treatment initiation, then subsequently at intervals of 3 to 6 months [see Warnings and Precautions (5.3) ] . Dosage Modifications If serum levels of B 12 decline after one month of treatment with NASCOBAL, consider increasing the dose. Assess serum B 12 level one month after each dose adjustment. If serum B 12 levels are persistently low, consider alternative therapy (e.g., intramuscular or subcutaneous vitamin B 12 therapy). Treatment Duration In patients whose underlying cause of vitamin B 12 deficiency has been corrected and are deemed no longer at risk for vitamin B 12 deficiency, discontinue NASCOBAL. The safety and effectiveness of continued long-term use in these individuals has not been established. In patients with pernicious anemia, continue appropriate vitamin B 12 treatment indefinitely. 2.4 Administration of NASCOBAL with Other Therapy NASCOBAL should be administered with other therapy(ies) in: Patients with concurrent folate and vitamin B 12 deficiency:Administer folic acid in addition to NASCOBAL Patients with concurrent iron and vitamin B 12 deficiency:Administer iron in addition to NASCOBAL Patients with correctible causes of vitamin B 12 deficiency:Consider measures to treat the underlying condition associated with vitamin B 12 deficiency in addition to treatment with NASCOBAL

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)

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 Par Pharmaceutical, Inc. 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