CYANOCOBALAMIN: 4,061 Adverse Event Reports & Safety Profile

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.

Cyanocobalamin Nasal Spray 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.

Cyanocobalamin Nasal

Spray is a solution of cyanocobalamin, USP (vitamin B 12 ) for administration as a spray to the nasal mucosa. Each unit dose device of Cyanocobalamin 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. chemical structure image

AND USAGE Cyanocobalamin Nasal Spray 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
• Cyanocobalamin Nasal Spray 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 Cyanocobalamin Nasal Spray following adequate correction of vitamin B 12 deficiency and underlying disease has not been established.
• The effectiveness of Cyanocobalamin Nasal Spray in patients with active symptoms of nasal congestion, allergic rhinitis or upper respiratory infection has not been determined. Treatment with Cyanocobalamin Nasal Spray should be deferred until symptoms have subsided.

Cyanocobalamin Nasal

Spray is a vitamin B 12 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 ( 1 )
• Treatment of adult patients with dietary, drug-induced, or malabsorption-related vitamin B 12 deficiency not due to pernicious anemia ( 1 )
• Prevention of vitamin B 12 deficiency in adult patients with vitamin B 12 requirements in excess of normal ( 1 ) Limitations of Use:
• Should not be used for the vitamin B 12 absorption test (Schilling test). ( 1 )
• In patients with correctible or temporary causes of vitamin B 12 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 )

AND ADMINISTRATION

• 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 B 12 levels periodically. Obtain a serum B 12 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 B 12 decline after one month of treatment, 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). ( 2.3 )
• See Full Prescribing Information to see what other therapies should be administered with Cyanocobalamin Nasal Spray. ( 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . Consider the potential for concomitant drugs to interfere with vitamin B 12 and folate diagnostic blood assays <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span> . In patients with suspected cobalamin hypersensitivity, consider administering an intradermal test dose of parenteral vitamin B 12 prior to use of Cyanocobalamin Nasal Spray <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> .

2.2 Recommended Dosage The recommended initial dose of Cyanocobalamin Nasal Spray is one spray (500 mcg) administered in ONE nostril once weekly.

Administer Cyanocobalamin Nasal

Spray 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 Cyanocobalamin Nasal Spray 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3)]</span>.

Dosage

Modifications If serum levels of B 12 decline after one month of treatment with Cyanocobalamin Nasal Spray, 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 Cyanocobalamin Nasal Spray. 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 Cyanocobalamin Nasal Spray with Other Therapy Cyanocobalamin Nasal Spray should be administered with other therapy(ies) in: - Patients with concurrent folate and vitamin B 12 deficiency: Administer folic acid in addition to Cyanocobalamin Nasal Spray - Patients with concurrent iron and vitamin B 12 deficiency: Administer iron in addition to Cyanocobalamin Nasal Spray - 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 Cyanocobalamin Nasal Spray

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

REACTIONS 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

AND PRECAUTIONS

• 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.

Cyanocobalamin Nasal

Spray 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 Cyanocobalamin Nasal Spray 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 Cyanocobalamin Nasal Spray 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 Cyanocobalamin Nasal Spray 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 Cyanocobalamin Nasal Spray, 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 Cyanocobalamin Nasal Spray before having tolerated cyanocobalamin parenterally, consider administering an intradermal test dose of parenteral vitamin B 12 to patients suspected of cyanocobalamin hypersensitivity <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> .

5.3 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. Vitamin B 12 is not a substitute for folic acid <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . Assess both vitamin B 12 and folate levels prior to initiating therapy with vitamin B 12 , including Cyanocobalamin Nasal Spray, or with folic acid <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> .

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

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.

PRECAUTIONS General Vitamin B 12 deficiency that is allowed to progress for longer than three months may produce permanent degenerative lesions of the spinal cord. Doses of folic acid greater than 0.1 mg/day may result in hematologic remission in patients with Vitamin B 12 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 instructed 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 5th to 7th 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 three 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 two weeks may produce malabsorption of Vitamin B 12 . Carcinogenesis, Mutagenesis 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 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.

General

Vitamin B 12 deficiency that is allowed to progress for longer than three months may produce permanent degenerative lesions of the spinal cord. Doses of folic acid greater than 0.1 mg/day may result in hematologic remission in patients with Vitamin B 12 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 instructed 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 5th to 7th 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 three 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 two weeks may produce malabsorption of Vitamin B 12 .

Carcinogenesis, Mutagenesis 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 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.

INTERACTIONS Chloramphenicol may decrease the efficacy of Cyanocobalamin Nasal Spray when used for treatment of anemia.

If Cyanocobalamin Nasal

Spray is used for the treatment of anemia concomitantly with chloramphenicol, monitor for reduced efficacy and if needed, consider an alternative therapy.