Cyanocobalamin

Mechanism of Action

Vitamin B12 is essential for growth, cell reproduction, hematopoiesis, and nucleoprotein and myelin synthesis. Rapidly dividing cells (e.g., epithelial cells, bone marrow, myeloid cells) have the greatest requirement for vitamin B12. In tissues, vitamin B12 is essential for the conversion of methylmalonate to succinate and for the synthesis of methionine from homocysteine. In the absence of vitamin B12, tetrahydrofolate cannot be regenerated from 5-methyl tetrahydrofolate, and functional folate deficiency occurs. Vitamin B12 also may be involved in sulfhydryl-activated enzyme systems associated with fat and carbohydrate metabolism and protein synthesis.

Pharmacodynamics

In 24 vitamin B12 deficient patients who were stabilized on intramuscular (IM) vitamin B12 therapy, once daily intranasal dosing with CaloMist Nasal Spray for 8 weeks resulted in serum vitamin B12 concentrations that were within the target range (>200 ng/L) and slightly higher than those seen 2 to 4 weeks after administration of IM vitamin B12 (see Figure 1 - average mean increase from Visit 1 to Visits 3-6 = 45 ng/L). Twenty-three of these 24 patients received 50 mcg of CaloMist Nasal Spray daily for the duration of the trial; the remaining patient required doubling of the CaloMist Nasal Spray dose from 50 mcg to 100 mcg daily during the last week of the study because of declining vitamin B12 concentrations. One of the 25 patients dosed with CaloMist Nasal Spray was excluded from the efficacy analyses because a diagnosis of vitamin B12 deficiency could not be confirmed.

Figure 1 : Mean Vitamin B12 Serum Levels Over 8 Weeks of Intranasal (IN) Vitamin B12 Dosing in 24 Subjects Stabilized on Intramuscular (IM) Vitamin B12

Notes:

- Weeks -2 to -4 correspond to 2 to 4 weeks post last IM injection
- CaloMist Nasal Spray was initiated at Week 0.
- Figure shows mean vitamin B12 serum levels with 95% confidence intervals.

Pharmacokinetics Distribution

In the blood, vitamin BI2 is bound to transcobalamin II (a specific B-globulin carrier protein) and is distributed to tissues and stored primarily in the liver and bone marrow.

Elimination

About 3-8 mcg of vitamin B12 is secreted into the gastrointestinal tract daily via the bile. In subjects with sufficient intrinsic factor, all but about 1 mcg is reabsorbed. When vitamin B12 is administered in doses that saturate the binding capacity of plasma proteins and the liver, the unbound vitamin B12 is rapidly eliminated in the urine. Retention of vitamin B12 in the body is dose-dependent.

Cyanocobalamin is a synthetic form of vitamin B12 with equivalent vitamin B12 activity. The chemical name is 5,6-dimethyl-benzimidazolyl cyanocobamide. The cobalt content is 4.35%. The molecular formula is C63H88CoN14O14P, which corresponds to a molecular weight of 1355.38 and the following structural formula:

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 B12 coenzymes are very unstable in light.

Nascobal® Nasal Spray is a solution of Cyanocobalamin, USP (vitamin B12) for administration as a spray to the nasal mucosa. Each bottle of Nascobal (cyanocobalamin) Nasal Spray contains 2.3 mL of a 500 mcg / 0.1 mL solution of cyanocobalamin with sodium citrate, citric acid, glycerin and benzalkonium chloride in purified water. The spray solution has a pH between 4.5 and 5.5. The spray pump unit must be fully primed (see DOSAGE AND ADMINISTRATION) prior to initial use. After initial priming, each spray delivers an average of 500 mcg of cyanocobalamin and the 2.3 mL of spray solution contained in the bottle will deliver 8 doses of Nascobal (cyanocobalamin) Nasal Spray. The unit must be re-primed before each dose. (see DOSAGE AND ADMINISTRATION).

General Pharmacology And Mechanism Of Action

Vitamin B12 is essential to growth, cell reproduction, hematopoiesis, and nucleoprotein and myelin synthesis. Cells characterized by rapid division (e.g., epithelial cells, bone marrow, myeloid cells) appear to have the greatest requirement for vitamin B12. Vitamin

B12 can be converted to coenzyme B12 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 B12, tetrahydrofolate cannot be regenerated from its inactive storage form, 5- methyltetrahydrofolate, and a functional folate deficiency occurs. Vitamin B12 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. Vitamin B12 deficiency results in megaloblastic anemia, GI lesions, and neurologic damage that begins with an inability to produce myelin and is followed by gradual degeneration of the axon and nerve head.

Cyanocobalamin is the most stable and widely used form of vitamin B12, and has hematopoietic activity apparently identical to that of the antianemia factor in purified liver extract. The information below, describing the clinical pharmacology of cyanocobalamin, has been derived from studies with injectable vitamin B12.

Vitamin B12 is quantitatively and rapidly absorbed from intramuscular and subcutaneous sites of injection. It is bound to plasma proteins and stored in the liver. Vitamin B12 is excreted in the bile and undergoes some enterohepatic recycling. Absorbed vitamin B12 is transported via specific B12 binding proteins, transcobalamin I and II, to the various tissues. The liver is the main organ for vitamin B12 storage.

Parenteral (intramuscular) administration of vitamin B12 completely reverses the megaloblastic anemia and GI symptoms of vitamin B12 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.

Gastrointestinal absorption of vitamin B12 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 B12 prevents progression of neurologic damage.

The average diet supplies about 4 to 15 mcg/day of vitamin B12 in a protein-bound form that is available for absorption after normal digestion. Vitamin B12 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 B12 is bound to intrinsic factor during transit through the stomach; separation occurs in the terminal ileum in the presence of calcium, and vitamin B12 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 B12.

Colchicine, para-aminosalicylic acid, and heavy alcohol intake for longer than 2 weeks may produce malabsorption of vitamin B12.

Pharmacokinetics

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 average peak concentration of B12 obtained after baseline correction following administration of intranasal spray was 757.96 +/- 532.17 pg/mL. The bioavailability of the nasal spray relative to the intramuscular injection was found to be 6.1%. The bioavailability of the B12 nasal spray was found to be 10% less than the B12 nasal gel. The 90% confidence intervals for the loge-transformed AUC(0-t) and Cmax was 71.71% - 114.19% and 71.6% - 118.66% respectively.

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).

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.

About 3-8 mcg of B12 is secreted into the GI tract daily via the bile; 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.

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

Patients with pernicious anemia should be instructed that they will require weekly intranasal administration of Nascobal (cyanocobalamin) Nasal Spray 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 B12, because the former may prevent anemia but allow progression of subacute combined degeneration of the spinal cord.

(Hot foods may cause nasal secretions and a resulting loss of medication; therefore, patients should be told to administer Nascobal (cyanocobalamin) Nasal Spray at least one hour before or one hour after ingestion of hot foods or liquids).

A vegetarian diet which contains no animal products (including milk products or eggs) does not supply any vitamin B12. Therefore, patients following such a diet should be advised to take Nascobal (cyanocobalamin) Nasal Spray weekly. The need for vitamin B12 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.

Because the nasal dosage forms of Vitamin B12 have a lower absorption than intramuscular dosage, nasal dosage forms are administered weekly, rather than the monthly intramuscular dosage. As shown in the Figure above, at the end of a month, weekly nasal administration results in significantly higher serum Vitamin B12 levels than after intramuscular administration. The patient should also understand the importance of returning for follow-up blood tests every 3 to 6 months to confirm adequacy of the therapy.

Careful instructions on the actuator assembly, removal of safety clip, priming of the actuator and nasal administration of Nascobal (cyanocobalamin) Nasal Spray should be given to the patient. Although instructions for patients are supplied with individual bottles, procedures for use should be demonstrated to each patient.

Storage Conditions

Protect from light. Keep covered in carton until ready to use. Store upright at controlled room temperature 15°C to 30°C (59°F to 86°F). Protect from freezing.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• antibiotics such as chloramphenicol (Chloromycetin, Mychel-S)
• colchicine (Colcrys)
• folic acid
• methotrexate (Rheumatrex, Trexall)
• para-aminosalicylic acid (Paser)
• pyrimethamine (Daraprim)

Your doctor may need to change the doses of your medications or monitor you carefully for side effects.

This is not a complete list of cyanocobalamin drug interactions. Ask your doctor or pharmacist for more information.

Cyanocobalamin is a man-made form of vitamin B12. Vitamin B12 is important for growth, cell reproduction, blood formation, and protein and tissue synthesis.

Cyanocobalamin is used to treat vitamin B12 deficiency in people with pernicious anemia and other conditions.

Cyanocobalamin may also be used for other purposes not listed in this medication guide.

• Celiac Disease
• Crohn's Disease

Read the Cyanocobalamin User Reviews »

© Cyanocobalamin Patient Information is supplied by Cerner Multum, Inc. and Cyanocobalamin Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

You should not use this medicine if you are allergic to cobalt, or if you have Leber's disease. Cyanocobalamin can lead to optic nerve damage (and possibly blindness) in people with Leber's disease.

To make sure cyanocobalamin is safe for you, tell your doctor if you have:

• any type of infection;

• iron or folic acid deficiency;

• kidney or liver disease; or

• if you are receiving any medication or treatment that affects bone marrow.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

Cyanocobalamin can pass into breast milk and may harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

WARNING: 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.

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 B12 administration. An intradermal test dose is recommended before Cyanocobalamin injection 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.

No overdosage has been reported with this drug.

Coenzyme for various metabolic functions, including fat and carbohydrate metabolism and protein synthesis, used in cell replication and hematopoiesis

Absorption

Oral: Variable from the terminal ileum; requires the presence of calcium and gastric “intrinsic factor” to transfer the compound across the intestinal mucosa

Distribution

Principally stored in the liver and bone marrow, also stored in the kidneys and adrenals

Metabolism

Converted in tissues to active coenzymes, methylcobalamin and deoxyadenosylcobalamin; undergoes some enterohepatic recycling

Excretion

Urine (50% to 98%, unchanged drug)

Megaloblastic anemia: IM:

Conversion of megaloblastic to normoblastic erythroid hyperplasia within bone marrow: 8 hours

Increased reticulocytes: 2 to 5 days

Complicated vitamin B12 deficiency: IM, SubQ: Resolution of:

Psychiatric sequelae: 24 hours

Thrombocytopenia: 10 days

Granulocytopenia: 2 weeks

Time to Peak

Serum: IM, SubQ: 30 minutes to 2 hours; Intranasal: 1.6 hours

Protein Binding

Transcobalamins

Methotrexate, pyrimethamine, and most antibiotics invalidate folic acid and vitamin B12 diagnostic blood assays

Frequency not defined.

Cardiovascular: Congestive heart failure, peripheral vascular disease, thrombosis (peripheral)

Central nervous system: Abnormal gait, anxiety, ataxia, dizziness, headache, hypoesthesia, nervousness, pain, paresthesia

Dermatologic: Pruritus, skin rash (transient), urticaria

Gastrointestinal: Diarrhea, dyspepsia, glossitis, nausea, sore throat, vomiting

Hematologic & Oncologic: Polycythemia vera

Hypersensitivity: Anaphylaxis (parenteral)

Infection: Infection

Neuromuscular & skeletal: Arthritis, back pain, myalgia, weakness

Respiratory: Dyspnea, pulmonary edema, rhinitis

Concerns related to adverse effects:

• CNS effects: Vitamin B12 deficiency for >3 months results in irreversible degenerative CNS lesions; neurologic manifestations will not be prevented with folic acid unless vitamin B12 is also given. Spinal cord degeneration might also occur when folic acid used as a substitute for vitamin B12 in anemia prevention.

• Hypokalemia: Treatment of severe vitamin B12 megaloblastic anemia may result in severe hypokalemia, sometimes fatal, due to intracellular potassium shift upon anemia resolution.

• Thrombocytosis: Treatment of severe vitamin B12 megaloblastic anemia may result in thrombocytosis.

Disease-related concerns:

• Leber’s disease: Use with caution in patients with Leber’s disease patients; B12 treatment may result in rapid optic atrophy.

• Pernicious anemia: Appropriate use: IM/SubQ routes are used to treat pernicious anemia; oral and intranasal administration are not indicated until hematologic remission and no signs of nervous system involvement.

• Polycythemia vera: Vitamin B12 deficiency masks signs of polycythemia vera; vitamin B12 administration may unmask this condition.

Dosage form specific issues:

• Aluminum: The parenteral product may contain aluminum; toxic aluminum concentrations may be seen with high doses, prolonged use, or renal dysfunction. Premature neonates are at higher risk due to immature renal function and aluminum intake from other parenteral sources. Parenteral aluminum exposure of >4 to 5 mcg/kg/day is associated with CNS and bone toxicity; tissue loading may occur at lower doses (Federal Register, 2002). See manufacturer’s labeling.

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

• Intranasal administration: Efficacy in patients with nasal pathology or with other concomitant intranasal therapy has not been determined. Use with caution.

Other warnings/precautions:

• IV administration: Avoid intravenous route; anaphylactic shock has occurred.

• Test dose: Intradermal test dose of vitamin B12 is recommended for any patient suspected of cyanocobalamin sensitivity prior to intranasal or injectable administration.

Vitamin B12, hemoglobin, hematocrit, erythrocyte and reticulocyte count, folate and iron levels should be obtained prior to treatment; vitamin B12 and peripheral blood counts should be monitored 1 month after beginning treatment, then every 3-6 months thereafter.

Megaloblastic anemia: In addition to normal hematological parameters, serum potassium and platelet counts should be monitored during therapy