Get your patient on Cyanocobalamin - Cyanocobalamin spray, Metered (Cyanocobalamin)

Prior to treatment, obtain hematocrit, reticulocyte count, vitamin B12, 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 B12 prior to use of Cyanocobalamin Nasal Spray [see Warnings and Precautions (5.2) ] .

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.

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 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.

• Cyanocobalamin Nasal Spray should be administered with other therapy(ies) in:
• Patients with concurrent folate and vitamin B12 deficiency: Administer folic acid in addition to Cyanocobalamin Nasal Spray
• Patients with concurrent iron and vitamin B12 deficiency:  Administer iron in addition to Cyanocobalamin Nasal Spray
• Patients with correctible causes of vitamin B12 deficiency: Consider measures to treat the underlying condition associated with vitamin B12 deficiency in addition to treatment with Cyanocobalamin Nasal Spray

Risk Summary

The limited available data on Cyanocobalamin Nasal Spray 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 B12.

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.

Risk Summary

Vitamin B12 is present in the milk of lactating women in concentrations which approximate the mother's vitamin B12 blood level. Vitamin B12 does not appear to pose more than a minimal risk to breastfeeding children.

Safety and effectiveness have not been established in pediatric patients.

Clinical studies of Cyanocobalamin Nasal Spray 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.

Patients with early Leber's disease (hereditary optic nerve atrophy) who were treated with vitamin B12 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 B12, consider alternative therapy (e.g., hydroxocobalamin) for B12 supplementation.

Anaphylactic shock and death have been reported after parenteral vitamin B12 administration. If patients are to start Cyanocobalamin Nasal Spray before having tolerated cyanocobalamin parenterally, consider administering an intradermal test dose of parenteral vitamin B12 to patients suspected of cyanocobalamin hypersensitivity [see Dosage and Administration (2.1) ] .

Doses of vitamin B12 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 B12 is not a substitute for folic acid [see Dosage and Administration (2.4) ] . Assess both vitamin B12 and folate levels prior to initiating therapy with vitamin B12, including Cyanocobalamin Nasal Spray, or with folic acid [see Dosage and Administration (2.1) ] .

Hypokalemia and sudden death may occur in severe megaloblastic anemia that is treated intensely with vitamin B12. Hypokalemia and thrombocytosis can occur upon conversion of severe megaloblastic anemia to normal erythropoiesis with vitamin B12 therapy. Therefore, serum potassium levels and platelet count should be monitored carefully during therapy [see Dosage and Administration (2.3) ] .

Vitamin B12 deficiency may suppress the signs of polycythemia vera. Treatment with vitamin B12 may unmask this condition. Patients exhibiting clinical or hematologic response consistent with polycythemia vera should be referred for further evaluation.

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.

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 B12 is associated with fat and carbohydrate metabolism and protein synthesis.

Parenteral (intramuscular) administration of vitamin B ₁₂ completely reverses the megaloblastic anemia and GI symptoms of vitamin B ₁₂ deficiency; the degree of improvement in neurologic symptoms depends on the duration and severity of the lesions, although progression of the lesions is immediately arrested. In pernicious anemia patients, once weekly intranasal dosing with 500 mcg B12 gel resulted in a consistent increase in pre-dose serum B12 levels during one month of treatment (p < 0.003) above that seen one month after 100 mcg intramuscular dose (Figure 2).

Figure 2. Vitamin B12 Serum Trough Levels After Intramuscular Solution (IM) of 100 mcg and Nasal Gel (IN) Administration of 500 mcg Cyanocobalamin After Weekly Doses.

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.

A three way crossover study in 25 fasting healthy subjects was conducted to compare the bioavailability of the B12 nasal spray to the B12 nasal gel and to evaluate the relative bioavailability of the nasal formulations as compared to the intramuscular injection. The peak concentrations after administration of intranasal spray were reached in 1.25 +/

1.9 hours. The mean peak plasma concentration (Cmax) of B12, obtained after baseline correction, following administration of intranasal spray were 748 +/-549 pg/mL.

The bioavailability of the B12 nasal spray was found to be 10% less than the B12 nasal gel.

Distribution

In the blood, B12 is bound to transcobalamin II, a specific B-globulin carrier protein, and is distributed and stored primarily in the liver and bone marrow.

Elimination

About 3-8 mcg of B12 is secreted into the GI tract daily via the bile and undergoes some enterohepatic recycling; in normal subjects with sufficient intrinsic factor, all but about 1 mcg is reabsorbed. When B12 is administered in doses which saturate the binding capacity of plasma proteins and the liver, the unbound B12 is rapidly eliminated in the urine. Retention of B12 in the body is dose-dependent. About 80-90% of an intramuscular dose up to 50 mcg is retained in the body; this percentage drops to 55% for a 100 mcg dose, and decreases to 15% when a 1000 mcg dose is given.

Long-term studies in animals to evaluate carcinogenic potential have not been done.