Monograph: |
Calcium folinate
A white , yellowish-white, or yellow, odourless, amorphous or
cryatalline powder. Practically insoluble in alcohol and in
acetone. A 2.5% solution has a pH of 6.8 to 8.0. Store in
airtight containers. Protect from light.
Calcium folinate and fluorouracil. with or without 5% glu-
cose, were incompatible when mixed in various ratios and
stored in polyvinyl chloride containers at various tempera-
tures.
Adverse Effects
Occasional hypersensitivity reactions have been re-
ported; pyrexia has occured rarely after injections.
PRECAUTIONS:
Folic acid in doses above 0.1 mg daily may obscure pernicious anemia in that hematologic remission can occur while neurological manifestations remain progressive.
Folinic acid should not be administered simultane-
ously with a folic acid antagonist such as methotrex-
ate as this may nullify the effect of the antagonist.
Folinic acid enhances the toxicity, as well as the an-
tineoplastic action, of fluorouracil, especially on the
gastro-intestinal tract.
Pharrnacokinetics
Calcium folinate is well absorbed after oral and in-
tramuscular administration and, unlike folic acid,
is rapidly converted to biologically active
folates. Folate is concentrated in the liver and CSF
although distribution occurs to all body tissues.
Folates are mainly excreted in the urine, with small
amounts in the faeces.
Uses and Administration
Folinic acid is the 5-formyl derivative of tetrahydro-
folic acid, the active form of folic acid. Folinic acid
is used principally as an antidote to folic acid
antagonists, such as methotrexate (p.548), which
block the conversion of folic acid to tetrahydrofolate
by binding the enzyme dihydrofolate reductase. It
does not block the antimicrobial action of folate an-
tagonists such as trimethoprim or pyrimethamine,
but may reduce their haematological toxicities.
Folinic acid, as calcium folinate. can be adminis-
tered by mouth, by intramuscular injection, or by in-
travenous injection or infusion. Doses of calcium
folinate are given in terms of folinic acid.
In cases of inadvertent overdosage of a folic acid an-
tagonist, folinic acid should be administered as soon
as possible and preferably within the first hour.
Doses equal to or greater than the dose of meth-
otrexate have been recommended. Alternatively it
has been stated that where large overdoses of meth-
otrexate have been given, calcium folinate may be
given by intravenous infusion in a dose equivalent to
75 mg of folinic acid within 12 hours, followed by
12 mg intramuscularly every 6 hours for 4 doses. In
less severe overdosage 6 to 12 mg of folinic acid in-
tramuscularly every 6 hours for 4 doses may be ad-
equate. Although vincristine is not a folic acid
antagonist, folinic acid has also been proposed for
some manifestations of vincristine toxicity overdos-
age.
Folinic acid is used in conjunction with high-dose
methotrexate antineoplastic therapy to reduce the
toxicity of the methotrexate ('folinic acid rescue';
'calcium leucovorin rescue'). Folinic acid is given
after an appropriate interval, usually of up to 24
hours, has elapsed for methotrexate to exert its anti-
neoplastic effect and the objective is to maintain
plasma concentrations of reduced folates at a level
equivalent to or greater than the plasma-methotrex-
ate concentration. Dosage must therefore be adapted
according to the methotrexate regimen, and the pa-
tient's ability to clear the antineoplastic. In general.
doses of up to 120 mg have been given over 12 to 24
hours, by intramuscular injection or intravenous in-
jection or infusion, followed by 12 to 15 mg intra-
muscularly. or 15 mg by mouth, every 6 hours for
the next 48 hours. With doses of methotrexate below
100 mg. folinic acid 15 mg by mouth every 6 hours
for 48 to 72 hours may suffice.
Folinic acid is also used to enhance the cytotoxic ef-
fect of fluorouracil in advanced colorectal cancer
(see p.536) although conclusive survival benefits
have not yet been shown. One suggested regimen is
folinic acid 200 mg per sq.m body-surface by slow
intravenous injection over at least 3 to 5 minutes fol-
lowed by fluorouracil at an initial dose of 370 mg
per 1 intravenously: the treatment is given daily for
5 consecutive days and may be repeated at intervals
of 21 to 28 days. Lower doses of folinic acid (20 mg
per nr by intravenous injection followed by fluoro-
uracil 425 mg per nr) have also been used.
Folinic acid. like folic acid, is effective in the treat-
ment of folate-deficient megaloblastic anaemia (see
p.703). Doses of 15 mg daily by mouth have been
suggested. If given intramuscularly a dose of up to
I mg daily has been recommended on the grounds
that higher doses have not been proven to be any
more effective. It is unsuitable for megaloblastic
anaemia secondary to vitamin-B12 deficiencies.
Calcium levofolinate. the active laevo-isomer, is
used similarly to calcium folinate. in doses half
those recommended for the racemic form. Calcium
mefolinate is also used.
HIV Infection and AIDS. Calcium folinate has been used
to reduce the toxicity of pyrimethamine and trimethoprim in
patients with HIV infection. However, adjunctive administra-
tion of oral calcium folinate to patients with AIDS receiving
co-trimoxazole for the treatment of Pneumocystis carimi
pneumonia (PCP). was associated with a higher rate of thera-
peutic failure and a decrease in survival and did not reduce the
frequency of dose-limiting co-trimoxazole toxicity.' Calcium
folinate did not reduce the toxicity of co-trimoxazole being
used for the primary prophylaxis of PCP.
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