DBL Leucovorin Ca

DBL Leucovorin Ca

calcium folinate

Manufacturer:

Pfizer

Distributor:

Zuellig Pharma

Marketer:

DKSH
Full Prescribing Info
Contents
Leucovorin calcium.
Description
The following DBL Leucovorin Calcium Injection presentations: 3 mg/mL, 15 mg/2 mL, 50 mg/5 mL and 300 mg/30 mL contain calcium folinate equivalent to 3 mg, 15 mg, 50 mg and 300 mg folinic acid respectively.
DBL Leucovorin Calcium Tablets contain calcium folinate equivalent to 15 mg folinic acid.
DBL Leucovorin Calcium Injection is a sterile solution of folinic acid (as calcium salt) in water for injections. Sodium chloride is included for isotonicity. Sodium hydroxide or hydrochloric acid is used to adjust pH. Neither the ampoules (3 mg/mL and 15 mg/2 mL) nor the vial presentations (50 mg/5 mL and 300 mg/30 mL) contain a bactericide.
Chemical formula: C20H21CaN707.
M.W. = 511.5 (Anhydrous).
Action
Pharmacology: Pharmacological actions: Folinic acid is the formyl derivative of tetrahydrofolic acid which is a metabolite and active form of folic acid. It is effective in the treatment of megaloblastic anaemia caused by folic acid deÞ ciency and is a potent antidote for both the haematopoietic and reticuloendothelial toxic effects of folic acid antagonists, e.g. methotrexate, pyrimethamine, trimethoprim. In some cancers, folinic acid enters and 'rescues' normal cells, in preference to tumor cells, from the toxic effects of folic acid antagonists, due to a difference in membrane transport mechanism. This principle is applied in high-dose methotrexate therapy with 'folinic acid rescue'.
Pharmacokinetics: Peak plasma levels of folinic acid are reached, on average 40 minutes and 1.7 hours after intramuscular and oral administration, respectively. The bioavailability of an oral dose is almost the same as an equivalent intramuscular dose.
Calcium folinate is rapidly and extensively converted to 5-methyl tetrahydrofolate (an active metabolite) in vivo, with less extensive conversion resulting from parenteral, as opposed to oral administration.
Tetrahydrofolic acid and its derivatives are distributed to all body tissues, being concentrated in the liver and found in moderate amounts in the CSF. Following a 15 mg dose given either orally or intramuscularly, peak serum folate concentrations of 0.268 micrograms/mL and 0.241 micrograms/mL were detected. Folinic acid is eliminated mainly as 10-formyl tetrahydrofolate and 5,10-methyl tetra-hydrofolate. The metabolites are mainly excreted via the urine (80-90%), with elimination being logarithmic in doses exceeding 1 mg.
Indications/Uses
Leucovorin Calcium has shown good results in the treatment of certain megaloblastic anaemias resulting from folic acid deficiency. This mainly occurs in infants, during pregnancy, in malabsorption syndromes, liver diseases, sprue and malnutrition. It is not more effective than folic acid for these conditions.
Leucovorin Calcium has also shown good results in reducing the toxicity and circumventing the effect of folic acid antagonists, if therapeutically desired.
Dosage/Direction for Use
Leucovorin Calcium may be given orally, or parenterally by intramuscular injection, intravenous injection or intravenous infusion. Leucovorin Calcium should not be administered intrathecally.
For Hospital Use Only.
DBL Leucovorin Calcium Injection contains no antimicrobial agent. This product is for single use in one patient only.
When required for intravenous infusion, leucovorin calcium may be diluted in 1 litre of 5% w/v glucose in water for injections or normal saline. Such solutions are stable for 24 hours when stored between 2 to 8°C. However, to avoid microbial contamination hazards, infusion should be commenced as soon as practicable after preparation of the solution. Infusion should be completed within 24 hours and any residue discarded.
Oral doses should be taken on an empty stomach or in the fasting state since studies of bioavailability of oral tablets have been done with fasting patients only.
In the treatment of accidental overdosage of folic acid antagonists, e.g. methotrexate, leucovorin calcium should be administered as promptly as possible. As the time interval between antifolate administration and leucovorin calcium rescue increases, leucovorin calcium's effectiveness in counteracting toxicity diminishes.
Monitoring of serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin calcium. Delayed methotrexate excretion may be caused by a third space fluid accumulation (ie ascites, pleural effusion), renal insufficiency or inadequate hydration. Under such circumstances, higher doses of leucovorin calcium or prolonged administration may be indicated. Because absorption is saturable, oral administration of doses greater than 25 mg is not recommended. Doses higher than those recommended for oral use must be given intravenously.
Laboratory tests. Patients being treated with leucovorin calcium following methotrexate therapy, including inadvertent overdose, or patients with impaired methotrexate elimination, should have serum creatinine and methotrexate levels determined at intervals of 24 hours. Leucovorin Calcium dosage should be adjusted on the basis of laboratory test results.
Leucovorin rescue after methotrexate therapy. The recommendations for leucovorin calcium rescue are based on a methotrexate dose of 12 to 15 g/m2 administered by intravenous infusion over four hours (see product information for methotrexate). Leucovorin Calcium rescue at a dose of 15 mg (approximately 10 mg/m2) every six hours for ten doses starts 24 hours after the beginning of the methotrexate infusion. In the presence of gastrointestinal toxicity, nausea or vomiting, calcium folinate should be administered parenterally. Serum creatinine and methotrexate levels should be determined at least once daily. Leucovorin Calcium administration, hydration and urinary alkalinisation (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). The leucovorin calcium dose should be adjusted or leucovorin rescue extended based on the following guidelines.

Click on icon to see table/diagram/image

Patients who experience delayed methotrexate elimination are likely to develop reversible renal failure. In addition to appropriate leucovorin calcium therapy, these patients require continuing hydration and urinary alkalinisation and close monitoring of fluid and electrolyte status until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved.
Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration which are significant but less severe than the abnormalities described above. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g. medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.
Note. The above dosage recommendations do not necessarily apply to experimental high dose methotrexate therapy. High dose methotrexate therapy should only be administered by qualified specialists and in hospitals where the necessary facilities are available. Recent published literature should be consulted for details at all times.
Impaired methotrexate elimination or inadvertent overdosage. Leucovorin Calcium rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion. Leucovorin Calcium 10 mg/m2 should be administered intravenously, intramuscular or orally every six hours until the serum methotrexate level is less than 10-8M. In the presence of gastrointestinal toxicity, nausea or vomiting, leucovorin calcium should be administered parenterally. Serum creatinine and methotrexate levels should be determined at intervals of 24 hours. If the 24 hour serum creatinine has increased 50% over baseline or if the 24 hour methotrexate level is greater than 5 x 10-6 M or the 48 hour level is greater than 9 x 10-7 M, the dose of leucovorin calcium should be increased to 100 mg/m2 intravenously every three hours until the methotrexate level is less than 10-8M.
Hydration (3 L/day) and urinary alkalinisation with sodium bicarbonate solution should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.
Treatment of megaloblastic anaemias. Parenteral administration. Up to 1 mg daily. There is no evidence that doses greater than 1 mg/day have greater efficacy than those of 1 mg; additionally, loss of folate in urine becomes roughly logarithmic as the amount administered exceeds 1 mg.
Oral administration. Daily doses of 5 to 15 mg.
Treatment of pyrimethamine overdosage. The dosage of pyrimethamine in treating toxoplasmosis is 10 to 20 times its dosage for malaria and approaches the toxic level. Since leucovorin calcium is not utilised by protozoa, it can be given simultaneously without impairing the effectiveness of therapy. The usual dosage is 3 to 9 mg/day by intramuscular injection for three days or until the platelet and leucocyte counts have reached safe levels.
Overdosage
Excessive amounts of leucovorin nullify the chemotherapeutic effect of folic acid antagonists.
In case of overdose, immediately contact the Poisons Information Centre for advice (In Australia, call 13 11 26, in New Zealand, call 0800 764 766).
Contraindications
Leucovorin Calcium is improper therapy for pernicious anaemia and other megaloblastic anaemias secondary to the lack of Vitamin B12. When treating these conditions with Leucovorin Calcium, haematological remission may occur, but neurological manifestations are likely to progress.
Special Precautions
Leucovorin Calcium should only be used with folic acid antagonists, e.g. methotrexate, or fluoropyrimidines, e.g. 5-fluorouracil, under the direct supervision of a clinician experienced in the use of cancer chemotherapeutic agents.
Parenteral administration is preferable to oral dosing if there is a possibility that the patient may vomit or not absorb Leucovorin Calcium.
Because of the calcium ion content of the Leucovorin Calcium injections, no more than 160 mg (16 mL) should be injected intravenously per minute.
Leucovorin Calcium may enhance the toxicity of fluorouracil. Deaths from severe enterocolitis, diarrhoea and dehydration have been reported in elderly patients receiving leucovorin calcium and fluorouracil. Concomitant granulocytopenia and fever were present in some, but not all, of the patients.
Seizures and/or syncope have been reported rarely in cancer patients receiving leucovorin calcium, usually in association with fluoropyrimidine administration, and most commonly in those with CNS metastases. Since three patients had recurrent neurological symptoms on rechallenge with leucovorin calcium, further treatment with leucovorin calcium is not recommended in these circumstances.
Simultaneous therapy with a folic acid antagonist and leucovorin calcium is not recommended because the effect of the folic acid antagonist is either reduced or completely inhibited.
Leucovorin Calcium has no effect on nonhaematological toxicities of methotrexate, such as the nephrotoxicity resulting from medicine and/or metabolite precipitation in the kidney.
Leucovorin Calcium is not suitable for the treatment if pernicious anaemias and other anaemias resulting from lack of vitamin B12. Haematological remissions may occur, while the neurological manifestations remain progressive.
Use in pregnancy (Category A): Category A: Drugs which have been taken by a large number of pregnant women and women of childbearing age without proven increase in frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.
Use in lactation: It is not known whether this medicine is excreted in human milk. Because many medicines are excreted in human milk, caution should be exercised when leucovorin calcium is administered to a breastfeeding mother.
Use In Pregnancy & Lactation
Use in pregnancy (Category A): Category A: Drugs which have been taken by a large number of pregnant women and women of childbearing age without proven increase in frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.
Use in lactation: It is not known whether this medicine is excreted in human milk. Because many medicines are excreted in human milk, caution should be exercised when leucovorin calcium is administered to a breastfeeding mother.
Adverse Reactions
Allergic sensitisation, including anaphylactoid reactions and urticaria, has been reported following both oral and parenteral administration of folic acid. Nausea and vomiting with very high doses of leucovorin calcium have been reported. Seizures and/or syncope have been reported rarely in cancer patients receiving leucovorin calcium, usually in association with fluoropyrimidine administration (see Precautions).
Drug Interactions
Folic acid in large amounts may counteract the antiepileptic effect of phenobarbitone, phenytoin and primidone and increase the frequency of seizures in susceptible children.
High oral, intravenous or intramuscular doses of leucovorin calcium may reduce the efficacy of intrathecally administered methotrexate.
Leucovorin Calcium may enhance the toxicity of fluorouracil.
Leucovorin calcium has been reported to be incompatible with droperidol and phosphonosulphate.
Storage
Store at 2 to 8°C. (Refrigerate. Do not freeze). Protect from light.
ATC Classification
V03AF03 - calcium folinate ; Belongs to the class of detoxifying agents used in antineoplastic treatment.
Presentation/Packing
Inj (vial) 50 mg/5 mL x 1's.
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