Biological Therapies Cyanocobalamin 1 mg in 1 mL Injection

MIMS Revision Date: 01 January 2019

1 Name of Medicine

Cyanocobalamin.

2 Qualitative and Quantitative Composition

Biological Therapies Cyanocobalamin 1 mg in 1 mL Injection vial contains a minimum of 1 mL of solution and has cyanocobalamin 1 mg as an active ingredient. Each 1 mL contains cyanocobalamin 1 mg, sodium chloride 9 mg, hydrochloric acid for pH adjustment and water for injections.

3 Pharmaceutical Form

Biological Therapies Cyanocobalamin 1 mg in 1 mL Injection is a clear red coloured solution for injection supplied in amber glass vials. The pH of the solution is 3.8-5.5.

4 Clinical Particulars

4.1 Therapeutic Indications

Pernicious anaemia as a result of in situ B₁₂ deficiency.

4.2 Dose and Method of Administration

Warnings. A sensitivity history should be obtained from the patient prior to administration of vitamin B₁₂. An intradermal test dose is recommended before vitamin B₁₂ is administered to patients who may be sensitive to cobalamins.
Anaphylactic shock and death have been reported after parenteral vitamin B₁₂ administration. Should anaphylactic shock occur, immediately stop administration of the product and administer the appropriate dose of adrenaline 1:1000 (1 mg/1 mL) intramuscularly. This may be repeated at five minute intervals, if clinically indicated. Additionally, intravenous administration of corticosteroids and antihistamines may be considered.
Diagnosis of vitamin B₁₂ deficiency should be confirmed by laboratory investigation before institution of vitamin B₁₂ therapy. Do not use vitamin B₁₂ until diagnosis is fully established, as it may mask symptoms of subacute degeneration of the spinal cord, or of the true diagnosis of pernicious anaemia.
Hematocrit, reticulocyte count, vitamin B₁₂, folate and iron levels should be obtained prior to treatment.
If folate levels are low, folic acid should also be administered.
Patients with pernicious anemia should be informed that they will require monthly injections of vitamin B₁₂ 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.
If the solution is cloudy or contains visually detectable particles, please contact the Quality Assurance Manager at Biological Therapies.
Single use only. Biological Therapies Cyanocobalamin 1 mg in 1 mL Injection contains no antimicrobial agent. Use in one patient on one occasion only and discard any residue.
It is recommended to administer Biological Therapies Cyanocobalamin 1 mg in 1 mL Injection by slow intramuscular (deep intragluteal) injection or as determined by the physician.
For patient comfort, warm solution to body temperature before administration.
For short periods, daily doses of 5 mg in adults and 1 mg in neonates have been given for other disorders.
Patient monitoring. During the initial treatment of patients with pernicious anemia, serum potassium must be observed closely during the first 48 hours and potassium replaced if necessary.
Hematocrit and reticulocyte counts should be repeated daily from the fifth to seventh days of therapy and then frequently until the hematocrit is normal.
If reticulocytes have not increased after treatment or if reticulocyte counts do not continue at least twice normal while the hematocrit is less than 35%, diagnosis or treatment should be re-evaluated. Repeat determinations of iron and folic acid may reveal a complicating illness that might inhibit the response of the marrow.
Regular blood tests to determine vitamin B₁₂ levels are advisable during treatment.

4.3 Contraindications

Known hypersensitivity to B₁₂, or pre-existing hypervitaminosis. Known sensitivity to cyanocobalamin or any other ingredient in the preparation. Known sensitivity to cobalt.
Cyanocobalamin should not, if possible, be given to patients or used to treat megaloblastic anaemia of pregnancy without first confirming the diagnosis (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

4.4 Special Warnings and Precautions for Use

The therapeutic response to vitamin B₁₂ may be impaired by concurrent infection, uraemia, folic acid or iron deficiency or by drugs with bone marrow suppressing effects such as chloramphenicol.
Allergy. A sensitivity history should be obtained from the patient prior to administration of vitamin B₁₂. An intradermal test dose is recommended before vitamin B₁₂ is administered to patients who may be sensitive to cobalamins.
Anaphylactic shock and death have been reported after parenteral vitamin B₁₂ administration. Should anaphylactic shock occur, immediately stop administration of the product and administer the appropriate dose of adrenaline 1:1000 (1 mg/1 mL) intramuscularly. This may be repeated at five minute intervals, if clinically indicated. Additionally, intravenous administration of corticosteroids and antihistamines may be considered.
Hypokalaemia. Hypokalaemia and cardiac arrest have been reported when megaloblastic anaemia is treated intensively.
Serum potassium is to be carefully monitored during the initial phase of treatment in pernicious anaemia.
Degenerative lesions of the spinal cord. Vitamin B₁₂ deficiency that is allowed to progress for longer than 3 months may produce permanent degenerative lesions of the spinal cord.
Do not use vitamin B₁₂ until diagnosis is fully established, as it may mask symptoms of subacute degeneration of the spinal cord, or of the true diagnosis of pernicious anaemia.
Folic acid. Folic acid may potentiate the neurological complications of vitamin B₁₂ deficiency, so should not be administered to patients with pernicious anaemia (see Section 4.5 Interactions with Other Medicines and Other Forms of Interaction).
Doses of folic acid greater than 0.1 mg per day may result in hematologic remission in patients with vitamin B₁₂ deficiency.
Neurologic manifestations will not be prevented with folic acid, and if not treated with vitamin B₁₂, irreversible damage will result.
Folate deficiency. Doses in excess of 10 microgram daily may produce a haematological response in patients with folate deficiency: indiscriminate administration may mask the true diagnosis of folate deficiency.
Diet. A vegetarian diet which contains no animal products (including milk products or eggs) does not supply any vitamin B₁₂. Patients following such a diet, should be advised to take oral vitamin B₁₂ regularly.
Other warnings. Treatment with vitamin B₁₂ may unmask polycythaemia vera, because vitamin B₁₂ deficiency may suppress the symptoms of this condition.
Early Leber's disease (hereditary optic nerve neuropathy involving impaired cyanide detoxification). Severe optic nerve atrophy has occurred rapidly after administration of cyanocobalamin.
Use in the elderly. No data available.
Paediatric use. No data available.
Effects on laboratory tests. Most antibiotics, methotrexate and pyrimethamine invalidate folic acid and vitamin B₁₂ blood assays.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Colchicine para-aminosalicylic acid and heavy alcohol intake for longer than two weeks may produce malabsorption of vitamin B₁₂.
Serum concentrations of cyanocobalamin may be lowered by oral contraceptives.
Vitamin B₁₂ concentrations in the blood may be reduced following administration of large and continuous doses of folic acid. Folic acid administration may impair the therapeutic response to cyanocobalamin.
The therapeutic response to vitamin B₁₂ may be impaired by drugs with bone marrow suppressing effects such as chloramphenicol.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility. No data available.
Use in pregnancy. Exempt from classification in the Australian categorisation system for prescribing medicines in pregnancy.
The need for vitamin B₁₂ is increased by pregnancy and lactation.
Problems in humans have not been documented with intake of normal daily amounts. Vitamin B₁₂ crosses the placental barrier. There are no studies establishing the safety of this drug during pregnancy. It is not recommended for pregnancy unless the expected benefits outweigh any potential risk to the infant.
Megaloblastic anaemia occurring during pregnancy is usually due to folic acid deficiency rather than vitamin B₁₂ deficiency.
Cyanocobalamin should not be used for the treatment of megaloblastic anaemia of pregnancy caused by folic acid deficiency.
Use in lactation. Cyanocobalamin is distributed into breast milk. Therefore it is not recommended for breastfeeding mothers unless the expected benefits to the mother outweigh any potential risk to the infant.
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.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person’s ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Generalized. Anaphylactic shock and death have been reported with administration of parenteral vitamin B₁₂ (see Section 4.4 Special Warnings and Precautions for Use). Allergic hypersensitivity reactions have rarely occurred.
Cardiovascular. Pulmonary oedema and congestive heart failure early in treatment; peripheral vascular thrombosis. Cardiac arrest, low blood pressure.
Nervous system. Severe dizziness, drowsiness, muscular paralysis, vision problems, loss of consciousness.
Hematological. Polycythemia vera. Hypokalaemia.
Gastrointestinal. Mild transient diarrhea, prolonged abdominal pain, prolonged nausea or vomiting.
Dermatological. Itching; transitory exanthema.
Miscellaneous. Feeling of swelling of entire body bleeding.
Reporting suspected adverse effects. Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

No overdosage has been reported with this medicine.
For information on the management of overdose please contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action. Several chemically related forms of vitamin B₁₂, differing in slight modification of a side chain attached to the cobalamin nucleus have been isolated. Such variants of vitamin B₁₂ include cyanocobalamin, hydroxocobalamin, adenosylcobalamin and methylcobalamin.
Vitamin B₁₂ is essential for normal growth, haematopoiesis, production of all epithelial cells and maintenance of myelin throughout the nervous system. Whenever nucleic acid synthesis occurs and therefore whenever cell reproduction occurs, vitamin B₁₂ is required.
The amounts of vitamin B₁₂ needed to maintain normal blood forming functions are small and low doses are sufficient to correct the usual symptoms of vitamin B₁₂ deficiency.
Vitamin B₁₂ acts as an enzyme or co-enzyme in a number of metabolic processes and is transformed in the body to at least two compounds which possess enzymatic properties.
In humans there are two active forms of Vitamin B₁₂.
i) Co-enzyme B₁₂ (adenosylcobalamin) is required for conversion of propionate to succinate, thus involving vitamin B₁₂ in both fat and carbohydrate metabolism.
ii) Co-methylcobalamin acts in a transmethylation process converting homocysteine to methionine, thus involving vitamin B₁₂ in fat and protein metabolism.
In some cases of vitamin B₁₂ deficiency, severe neurological symptoms develop, as vitamin B₁₂ is necessary for the formation of protein structures required for the integrity of the nerve cell and myelin sheath.
Clinical trials. No data available.

5.2 Pharmacokinetic Properties

Absorption . Cyanocobalamin is quantitatively and rapidly absorbed from intramuscular and subcutaneous sites of injection; the plasma level of the compound reaches its peak within 1 hour after intramuscular injection. 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.
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 5 to 15 microgram/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.
Excretion. Within 48 hours after injection of 100 or 1000 microgram of cyanocobalamin, 50 to 98% of the injected dose may appear in the urine. The major portion is excreted within the first eight hours. Intravenous administration results in even more rapid excretion with little opportunity for liver storage.
Cyanocobalamin is the most widely used form of vitamin B₁₂, and has hematopoietic activity apparently identical to that of the antianemia factor in purified liver extract. Hydroxycobalamin is equally as effective as cyanocobalamin, and they share the cobalamin molecular structure.

5.3 Preclinical Safety Data

Genotoxicity. No data available.
Carcinogenicity. 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.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

Container type. Amber glass vial sealed with a rubber stopper and an aluminium seal with a tear-away centre.
Pack sizes. 1, 3, 10 or 20 vials per carton.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Molecular formula: C₆₃H₈₈CoN₁₄O₁₄P. Molecular weight: 1355.39.
Cyanocobalamin appears as dark red crystals or an amorphous or crystalline red powder. It is very hygroscopic in the anhydrous form, and sparingly soluble in water (1:80).
Chemical structure.

CAS number. 68-19-9.

7 Medicine Schedule (Poisons Standard)

Unscheduled.

Date of First Approval

08 October 1991

Date of Revision

22 October 2018

Summary Table of Changes