Biological Therapies Folic Acid 15 mg in 1 mL Injection

MIMS Revision Date: 01 June 2019

1 Name of Medicine

Folic acid.

2 Qualitative and Quantitative Composition

Biological Therapies Folic Acid Injection contains folic acid adjusted to pH with sodium hydroxide in water for injections. Disodium edetate 2 mg/mL is used as a stabiliser. Each 1 mL solution contains 15 mg of folic acid as an active ingredient.
The total sodium content in undiluted Biological Therapies Folic Acid Injection 15 mg in 1 mL is approximately 2.4 mg/mL, the pH range 8 to 11.
Folic acid, (2S)-2-[[4-[[(2-amino-4-oxo-1,4-dihydropteridin-6-yl) methyl]amino] benzoyl]amino] pentanedioic acid, is prepared synthetically. Folates are complex organic compounds present in liver, yeast and natural sources.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Biological Therapies Folic Acid Injection is a yellow colour and is a clear solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Folate deficiency may exist that is unable to be corrected by oral intake and in these cases parenteral administration may be preferable. Oral intake may be insufficient in: malabsorption disorders, gastrointestinal pathologies, pregnancy and lactation, alcoholism, haemolytic anaemia, exfoliative dermatitis and chronic infection.
Specific indications may include:
1. Megaloblastic anaemia where the anaemia has been proven to be due to folate deficiency only.
2. Prevention of folic acid deficiency in pregnancy and lactation.

4.2 Dose and Method of Administration

Biological Therapies Folic Acid Injection is used for parenteral folic acid therapy, and may be administered, usually by intramuscular, or less commonly by intravenous or subcutaneous injection. Although Biological Therapies Folic Acid Injection can be given undiluted for intramuscular or subcutaneous use, it must be diluted before intravenous use. Biological Therapies Folic Acid Injection contains no antimicrobial agent. It is for single use in one patient only. Discard any residue.
A dilute solution of Biological Therapies Folic Acid Injection 15 mg in 1 mL for intravenous injection, containing 100 micrograms/mL, may be prepared by adding 1 mL (15 mg) of the injection to 149 mL of normal saline or 149 mL of 5% glucose.
For treatment of megaloblastic anaemia in adults, 1-5 mg per day is recommended. Adjust the dosage according to the severity of the anaemia and to the presence or absence of malabsorption syndromes. For the treatment of megaloblastic anaemia in pre-term infants less than 2 kg body weight, 100-200 micrograms daily, orally or intramuscularly, should be used. Treating megaloblastic anaemia in infants 5-12 months of age, satisfactory response has been obtained using 50 micrograms daily, orally or intramuscularly.
The usual therapeutic dose in paediatric practice for the treatment of megaloblastic anaemia due to folic acid deficiency is 1-5 mg daily. This supra-physiological dosage can produce a partial haematological response in primary B₁₂ deficiency and therefore must not be used until B₁₂ deficiency has been excluded.
For prophylaxis in pregnancy and lactation, 500 micrograms of folic acid/day prevented signs of folic acid deficiency in well-nourished pregnant women.

4.3 Contraindications

This drug is contra-indicated in patients who may be hypersensitive to it. Although rare, an anaphylactic reaction has been reported.
Folic acid should not be prescribed for megaloblastic anaemia due to vitamin B₁₂ deficiency.

4.4 Special Warnings and Precautions for Use

Folic acid treatment may correct the haematological features of vitamin B₁₂ deficiency without correcting the progressive neurological damage due to vitamin B₁₂ deficiency. Therefore vitamin B₁₂ deficiency needs to be excluded before treatment with folic acid alone.
Patients receiving diphenylhydantoin treatment should be monitored for possible loss of seizure control following large doses of folic acid. Folic acid does not correct folate deficiency due to dihydrofolate reductase inhibitors, such as methotrexate. Folinic acid should be used for this purpose. Caution is advised in patients who may have folate-dependent tumours.
Vitamin B₁₂ concentrations in blood may be reduced by large and continuous doses of folic acid.
Use in the elderly. No data available.
Paediatric use. No data available.
Effects on laboratory tests. No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate) - not necessarily inclusive (≥ major clinical significance).
Note. Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Analgesics, long-term use or anticonvulsants, hydantoin or carbamazepine or estrogens or oral contraceptives or phenobarbital or primidone. Requirements for folic acid may be increased in patients receiving these medications. Concurrent use with folic acid may decrease the effects of hydantoin anticonvulsants by antagonism of their central nervous system (CNS) effects; an increase in hydantoin dosage may be necessary for patients who receive folic acid supplementation.
Antacids, aluminum- or magnesium-containing (with orally administered folic acid). Prolonged use of aluminum- and/or magnesium containing antacids may decrease folic acid absorption by lowering the pH of the small intestine; patients should be advised to take antacids at least 2 hours after folic acid.
Antibiotics. May interfere with the microbiologic method of assay for serum and erythrocyte folic acid concentrations and cause falsely low results.
Cholestyramine (with orally administered folic acid). Concurrent use with folic acid may interfere with absorption of folic acid; folic acid supplementation taken at least 1 hour before or 4 to 6 hours after cholestyramine is recommended in patients receiving cholestyramine for prolonged periods.
Methotrexate or pyrimethamine or triamterene or trimethoprim. Act as folate antagonists by inhibiting dihydrofolate reductase; most significant with high doses and/or prolonged use; leucovorin calcium must be used instead of folic acid in patients receiving these medications.
Sulfonamides, including sulfasalazine (with orally administered folic acid). Inhibit absorption of folate; folic acid requirements may be increased in patients receiving sulfasalazine.
Zinc supplements (with orally administered folic acid). Some studies have found that folate may decrease the absorption of zinc, but not in the presence of excessive zinc; other studies have found no inhibition.
Absorption of folic acid is decreased in chronic alcoholics. This effect can be partially reversed by abstinence from alcohol.
Folic acid is incompatible with oxidising and reducing agents and with ions of heavy metals.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility. No data available.
Use in pregnancy. (Category A*)
Therapeutic indications include use as a prophylactic in pregnancy and supplementation of lactating women when they are folic acid deficient. Folic acid is excreted in breast milk.
*Australian categorization definition of Category A: "Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed."
Use in lactation. Folic acid is excreted in breast milk.

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)

Note. No side effects other than an allergic reaction have been reported with folic acid administration, even at doses of up to 10 times the recommended dietary allowances (RDA) for 1 month.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate) - not necessarily inclusive:
Those indicating need for medical attention - incidence rare. Allergic reaction, specifically bronchospasm (shortness of breath; troubled breathing; tightness of chest; wheezing), erythema (reddened skin), fever, general malaise (general weakness or discomfort), skin rash or itching.
Note. Side effects including abdominal bloating and gas, anorexia, confusion, depression, difficulty in concentrating, excitement, irritability, impaired judgment, nausea, trouble in sleeping, and unpleasant taste were reported in a study of patients taking 15 mg daily.
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

In a double blind randomised trial 15 mg of folic acid per day for one month produced no signs of toxicity in healthy volunteers.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action. Folic acid is reduced to a number of compounds including tetrahydrofolic acid in the body. In the reduced form it is a coenzyme acting as an acceptor of one-carbon units. It is required for the synthesis of purine and pyrimidine bases, for the metabolism of amino acids such as serine-glycine interconversion, methionine methyl group biosynthesis and the degradation of histidine. It is involved in the maturation of all rapidly proliferating tissues particularly those of bone marrow and the gastrointestinal tract. Folate deficiency leads to megaloblastic anaemia.
Clinical trials. No data available.

5.2 Pharmacokinetic Properties

Distribution. Protein binding is extensive (to plasma proteins). The principal storage site is the liver. Folic acid is distributed into breast milk.
Metabolism. Hepatic. Folic acid is converted (in the presence of ascorbic acid) in the liver and plasma to its metabolically active form (tetrahydrofolic acid) by dihydrofolate reductase.
Excretion. There is an enterohepatic circulation for folate; about 4 to 5 micrograms is excreted in the urine daily. Administration of larger doses of folic acid leads to proportionately more of the vitamin being excreted in the urine.

5.3 Preclinical Safety Data

Genotoxicity. No data available.
Carcinogenicity. No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each 1 mL solution contains the following excipient ingredients:
Disodium edetate: 2 mg;
Sodium hydroxide: qs to adjust pH;
Water for injections: qs to 1 mL.

6.2 Incompatibilities

Folic acid is incompatible with oxidising and reducing agents and with ions of heavy metals (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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 at 2°C to 8°C (Refrigerate. Do not freeze). Protect from light. Keep out of reach of children.

6.5 Nature and Contents of Container

Container type. Amber glass vial sealed with a rubber stopper and an aluminium seal with a flip-top insert.
Pack sizes. Biological Therapies Folic Acid 15 mg in 1 mL Injection is contained in a 2 mL amber glass vial and has three pack sizes:
10 x 1 mL vials per carton;
6 x 1 mL vials per carton;
1 x 1 mL vial per carton.
AUST R 106971.

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: C₁₉H₁₉N₇O₆, Molecular weight: 441.4.
Chemical structure.

CAS number. 59-30-3.

7 Medicine Schedule (Poisons Standard)

S4.

Date of First Approval

19 January 2006

Date of Revision

01 April 2019

Summary Table of Changes