Western Medicine Calcium Folinate Injection BP 100mg (Lyophilized
powder for I.V. injection after reconstitution)
Each vial of Calcium Folinate Injection contains:
Calfonate folinate 5mg 25mg 100mg
Natrium Citricum 15mg 75mg 300mg
Water for Injection qs. qs qs qs
What Calfonate Injection BP is used for
Calfonate Injection BP contains folinate. It belongs to a group of
vitamins used as an antidote to the harmful effects of methotrexate
therapy. Folinate acts in the same way as folic acid which may be
low in these patients.
Calfonate Injection BP may be used for the management of other
conditions that are not mentioned above. Your doctor will be able
to tell you about the specifice condiction for which you have been
prescribed Calfonate Injection BP.
[2.Qualitative and quantitative composition]
Each vial of 10 ml solution contains 10 mg/ml of folinic acid
provided as calcium folinate.
For excipients, see 6.1.
[3. Pharmaceutical form]
[4. Clinical particulars]
4.1 Therapeutic indications
Calcium folinate is indicated
a) to diminish the toxicity and counteract the action of folic acid
antagonists such as methotrexate in cytotoxic therapy and overdose
in adults and children. In cytotoxic therapy, this procedure is
commonly known as “Calcium Folinate Rescue”;
b) in combination with 5-fluorouracil in cytotoxic therapy.
4.2 Posology and method of administration
For intravenous and intramuscular administration only. In the case
of intravenous administration, no more than 160 mg of calcium
folinate should be injected per minute due to the calcium content
of the solution.
For intravenous infusion, calcium folinate may be diluted with 0.9%
sodium chloride solution or 5% glucose solution before use. Refer
also to sections 6.3 and 6.6.
Calcium folinate rescue in methotrexate therapy:
Since the calcium folinate rescue dosage regimen depends heavily on
the posology and method of the intermediate- or high-dose
methotrexate administration, the methotrexate protocol will dictate
the dosage regimen of calcium folinate rescue. Therefore, it is
best to refer to the applied intermediate or high dose methotrexate
protocol for posology and method of administration of calcium
The following guidelines may serve as an illustration of regimens
used in adults, elderly and children:
Calcium folinate rescue has to be performed by parenteral
administration in patients with malabsorption syndromes or other
gastrointestinal disorders where enteral absorption is not assured.
Dosages above 25-50 mg should be given parenterally due to
saturable enteral absorption of calcium folinate.
Calcium folinate rescue is necessary when methotrexate is given at
doses exceeding 500 mg/m2 body surface and should be considered
with doses of 100 mg – 500 mg/m2 body surface.
Dosage and duration of calcium folinate rescue primarily depend on
the type and dosage of methotrexate therapy, the occurrence of
toxicity symptoms, and the individual excretion capacity for
methotrexate. As a rule, the first dose of calcium folinate is 15
mg (6-12 mg/m2) to be given 12-24 hours (24 hours at the latest)
after the beginning of methotrexate infusion. The same dose is
given every 6 hours throughout a period of 72 hours. After several
parenteral doses treatment can be switched over to the oral form.
In addition to calcium folinate administration, measures to ensure
the prompt excretion of methotrexate (maintenance of high urine
output and alkalinisation of urine) are integral parts of the
calcium folinate rescue treatment. Renal function should be
monitored through daily measurements of serum creatinine.
Forty-eight hours after the start of the methotrexate infusion, the
residual methotrexate-level should be measured. If the residual
methotrexate-level is >0.5 µmol/l, calcium folinate dosages
should be adapted according to the following table:
|Residual methotrexate blood level 48 hours after the start of the
methotrexate administration:||Additional calcium folinate to be administered every 6 hours for 48
hours or until levels of methotrexate are lower than 0.05 µmol/l:|
|> 0.5 µmol/l||15 mg/m2|
|> 1.0 µmol/l||100 mg/m2|
|> 2.0 µmol/l||200 mg/m2|
In combination with 5-fluorouracil in cytotoxic therapy:
Different regimens and different dosages are used, without any
dosage having been proven to be the optimal one.
The following regimens have been used in adults and elderly in the
treatment of advanced or metastatic colorectal cancer and are given
as examples. There are no data on the use of these combinations in
Bimonthly regimen: Calcium folinate 200 mg/m2 by intravenous infusion over two
hours, followed by bolus 400 mg/m2 of 5-FU and 22-hour infusion of
5-FU (600 mg/m2) for 2 consecutive days, every 2 weeks on days 1
Weekly regimen: Calcium folinate 20 mg/m2 by bolus i.v. injection or 200 to 500
mg/m2 as i.v. infusion over a period of 2 hours plus 500 mg/m2
5-fluorouracil as i.v. bolus injection in the middle or at the end
of the calcium folinate infusion.
Monthly regimen: Calcium folinate 20 mg/m2 by bolus i.v. injection or 200 to 500
mg/m2 as i.v. infusion over a period of 2 hours immediately
followed by 425 or 370 mg/m2 5-fluorouracil as i.v. bolus injection
during five consecutive days.
For the combination therapy with 5-fluorouracil, modification of
the 5-fluorouracil dosage and the treatment-free interval may be
necessary depending on patient condition, clinical response and
dose limiting toxicity as stated in the product information of
5-fluorouracil. A reduction of calcium folinate dosage is not
The number of repeat cycles used is at the discretion of the
Antidote to the folic acid antagonists trimetrexate, trimethoprim,
• Prevention: Calcium folinate should be administered every day
during treatment with trimetrexate and for 72 hours after the last
dose of trimetrexate. Calcium folinate can be administered either
by the intravenous route at a dose of 20 mg/m2for 5 to 10 minutes
every 6 hours for a total daily dose of 80 mg/m2, or by oral route
with four doses of 20 mg/m2administered at equal time intervals.
Daily doses of calcium folinate should be adjusted depending on the
haematological toxicity of trimetrexate.
• Overdosage (possibly occurring with trimetrexate doses above 90
mg/m2 without concomitant administration of calcium folinate):
after stopping trimetrexate, calcium folinate 40 mg/m2 IV every 6
hours for 3 days.
• After stopping trimethoprim, 3-10 mg/day calcium folinate until
recovery of a normal blood count.
• In case of high dose pyrimethamine or prolonged treatment with
low doses, calcium folinate 5 to 50 mg/day should be simultaneously
administered, based on the results of the peripheral blood counts.
• Known hypersensitivity to calcium folinate, or to any of the
• Pernicious anaemia or other anaemias due to vitamin B12
Regarding the use of calcium folinate with methotrexate or
5-fluorouracil during pregnancy and lactation, see section 4.6,
“Pregnancy and Lactation” and the summaries of product
characteristics for methotrexate- and 5-fluorouracil- containing
4.4 Special warnings and precautions for use
Calcium folinate should only be given by intramuscular or
intravenous injection and must not be administered intrathecally. When folinic acid has been administered intrathecally following
intrathecal overdose of methotrexate death has been reported.
Calcium folinate should be used with methotrexate or 5-fluorouracil
only under the direct supervision of a clinician experienced in the
use of cancer chemotherapeutic agents.
Calcium folinate treatment may mask pernicious anaemia and other
anaemias resulting from vitamin B12 deficiency.
Many cytotoxic medicinal products – direct or indirect DNA
synthesis inhibitors – lead to macrocytosis (hydroxycarbamide,
cytarabine, mecaptopurine, thioguanine). Such macrocytosis should
not be treated with folinic acid.
In epileptic patients treated with phenobarbital, phenytoin,
primidone, and succinimides there is a risk to increase the
frequency of seizures due to a decrease of plasma concentrations of
anti-epileptic drugs. Clinical monitoring, possibly monitoring of
the plasma concentrations and, if necessary, dose adaptation of the
anti-epileptic drug during calcium folinate administration and
after discontinuation is recommended (see also section 4.5
Calcium folinate may enhance the toxicity risk of 5-fluorouracil,
particularly in elderly or debilitated patients. The most common
manifestations are leucopenia, mucositis, stomatitis and/or
diarrhoea, which may be dose limiting. When calcium folinate and
5-fluorouracil are used in combination, the 5- fluorouracil dosage
has to be reduced more in cases of toxicity than when
5-fluorouracil is used alone.
Combined 5-fluorouracil/calcium folinate treatment should neither
be initiated nor maintained in patients with symptoms of
gastrointestinal toxicity, regardless of the severity, until all of
these symptoms have completely disappeared.
Because diarrhoea may be a sign of gastrointestinal toxicity,
patients presenting with diarrhoea must be carefully monitored
until the symptoms have disappeared completely, since a rapid
clinical deterioration leading to death can occur. If diarrhoea
and/or stomatitis occur, it is advisable to reduce the dose of 5-FU
until symptoms have fully disappeared. Especially the elderly and
patients with a low physical performance due to their illness are
prone to these toxicities. Therefore, particular care should be
taken when treating these patients.
In elderly patients and patients who have undergone preliminary
radiotherapy, it is recommended to begin with a reduced dosage of
Calcium folinate must not be mixed with 5-fluorouracil in the same
IV injection or infusion.
Calcium levels should be monitored in patients receiving combined
5-fluorouracil/calcium folinate treatment and calcium
supplementation should be provided if calcium levels are low.
For specific details on reduction of methotrexate toxicity refer to
the SPC of methotrexate.
Calcium folinate has no effect on non-haematological toxicities of
methotrexate such as the nephrotoxicity resulting from methotrexate
and/or metabolite precipitation in the kidney. Patients who
experience delayed early methotrexate elimination are likely to
develop reversible renal failure and all toxicities associated with
methotrexate (please refer to the SPC for methotrexate). The
presence of preexisting- or methotrexate-induced renal
insufficiency is potentially associated with delayed excretion of
methotrexate and may increase the need for higher doses or more
prolonged use of calcium folinate.
Excessive calcium folinate doses must be avoided since this might
impair the antitumour activity of methotrexate, especially in CNS
tumours where calcium folinate accumulates after repeated courses.
Resistance to methotrexate as a result of decreased membrane
transport implies also resistance to folinic acid rescue as both
medicinal products share the same transport system.
An accidental overdose with a folate antagonist, such as
methotrexate, should be treated as a medical emergency. As the time
interval between methotrexate administration and calcium folinate
rescue increases, calcium folinate effectiveness in counteracting
The possibility that the patient is taking other medications that
interact with methotrexate (eg, medications which may interfere
with methotrexate elimination or binding to serum albumin) should
always be considered when laboratory abnormalities or clinical
toxicities are observed.
4.5 Interaction with other medicinal products and other forms of
When calcium folinate is given in conjunction with a folic acid
antagonist (e.g. cotrimoxazole, pyrimethamine) the efficacy of the
folic acid antagonist may either be reduced or completely
Calcium folinate may diminish the effect of anti-epileptic
substances: phenobarbital, primidone, phenytoin and succinimides,
and may increase the frequency of seizures (a decrease of plasma
levels of enzymatic inductor anticonvulsant drugs may be observed
because the hepatic metabolism is increased as folates are one of
the cofactors) (see also sections 4.4 and 4.8).
Concomitant administration of calcium folinate with 5-fluorouracil
has been shown to enhance the efficacy and toxicity of
5-fluorouracil (see sections 4.2, 4.4 and 4.8).
4.6 Pregnancy and lactation
There are no adequate and well-controlled clinical studies
conducted in pregnant or breast-feeding women. No formal animal
reproductive toxicity studies with calcium folinate have been
conducted. There are no indications that folic acid induces harmful
effects if administered during pregnancy. During pregnancy,
methotrexate should only be administered on strict indications,
where the benefits of the drug to the mother should be weighed
against possible hazards to the foetus. Should treatment with
methotrexate or other folate antagonists take place despite
pregnancy or lactation, there are no limitations as to the use of
calcium folinate to diminish toxicity or counteract the effects.
5-fluorouracil use is generally contraindicated during pregnancy
and contraindicated during breastfeeding; this applies also to the
combined use of calcium folinate with 5-fluorouracil.
Please refer also to the summaries of product characteristics for
methotrexate-, other folate antagonists and 5-fluorouracil-
containing medicinal products.
It is not known whether calcium folinate is excreted into human
breast milk. Calcium folinate can be used during breast feeding
when considered necessary according to the therapeutic indications.
4.7 Effects on ability to drive and use machines
There is no evidence that calcium folinate has an effect on the
ability to drive or use machines.
4.8 Undesirable effects
Immune system disorders
Very rare (<0.01%): allergic reactions, including anaphylactoid
reactions and urticaria.
Rare (0.01-0.1%): insomnia, agitation and depression after high
Rare (0.01-0.1%): gastrointestinal disorders after high doses.
Rare (0.01-0.1%): increase in the frequency of attacks in
epileptics (see also section 4.5 Interactions...).
General disorders and administration site conditions
Uncommon (0.1-1%): fever has been observed after administration of
calcium folinate as solution for injection.
Combination therapy with 5-fluorouracil:
Generally, the safety profile depends on the applied regimen of
5-fluorouracil due to enhancement of the 5-fluorouracil induced
Very common (>10%): vomiting and nausea
General disorders and administration site conditions
Very common (>10%): (severe) mucosal toxicity.
No enhancement of other 5-fluorouracil induced toxicities (e.g.
Very common (>10%): diarrhoea with higher grades of toxicity,
and dehydration, resulting in hospital admission for treatment and
There have been no reported sequelae in patients who have received
significantly more calcium folinate than the recommended dosage.
However, excessive amounts of calcium folinate may nullify the
chemotherapeutic effect of folic acid antagonists.
Should overdosage of the combination of 5-fluorouracil and calcium
folinate occur, the overdosage instructions for 5-FU should be
[5. Pharmacological properties]
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Detoxifying agents for antineoplastic
treatment; ATC code: V03AF03
Calcium folinate is the calcium salt of 5-formyl tetrahydrofolic
acid. It is an active metabolite of folinic acid and an essential
coenzyme for nucleic acid synthesis in cytotoxic therapy.
Calcium folinate is frequently used to diminish the toxicity and
counteract the action of folate antagonists, such as methotrexate.
Calcium folinate and folate antagonists share the same membrane
transport carrier and compete for transport into cells, stimulating
folate antagonist efflux. It also protects cells from the effects
of folate antagonist by repletion of the reduce folate pool.
Calcium folinate serves as a pre-reduced source of H4 folate; it
can therefore bypass folate antagonist blockage and provide a
source for the various coenzyme forms of folic acid.
Calcium folinate is also frequently used in the biochemical
modulation of fluoropyridine (5-FU) to enhance its cytotoxic
activity. 5-FU inhibits thymidylate synthase (TS), a key enzyme
involved in pyrimidine biosynthesis, and calcium folinate enhances
TS inhibition by increasing the intracellular folate pool, thus
stabilising the 5FU-TS complex and increasing activity.
Finally intravenous calcium folinate can be administered for the
prevention and treatment of folate deficiency when it cannot be
prevented or corrected by the administration of folic acid by the
oral route. This may be the case during total parenteral nutrition
and severe malabsorption disorders. It is also indicated for the
treatment of megaloblastic anaemia due to folic acid deficiency,
when oral administration is not feasible.
5.2 Pharmacokinetic properties
Following intramuscular administration of the aqueous solution,
systemic availability is comparable to an intravenous
administration. However, lower peak serum levels (Cmax) are
Calcium folinate is a racemate where the L-form
(L-5-formyl-tetrahydrofolate, L-5-formyl-THF), is the active
enantiomer. The major metabolic product of folinic acid is
5-methyl-tetrahydrofolic acid (5-methyl-THF) which is predominantly
produced in the liver and intestinal mucosa.
The distribution volume of folinic acid is not known.
Peak serum levels of the parent substance
(D/L-5-formyl-tetrahydrofolic acid, folinic acid) are reached 10
minutes after i.v. administration.
AUC for L-5-formyl-THF and 5-methyl-THF were 28.4±3.5 mg.min/l and 129±112 mg.min/l after a dose of 25
mg. The inactive D-isomer is present in higher concentration than
The elimination half-life is 32 - 35 minutes for the active L-form
and 352 - 485 minutes for the inactive D-form, respectively.
The total terminal half-life of the active metabolites is about 6
hours (after intravenous and intramuscular administration).
80-90 % with the urine (5- and 10-formyl-tetrahydrofolates inactive
metabolites), 5-8 % with the faeces.
5.3 Preclinical safety data
There are no preclinical data considered relevant to clinical
safety beyond data included in other sections of the SPC.
[6. Pharmaceutical particulars]
6.1 List of excipients
Water for Injections
Incompatibilities have been reported between injectable forms of
calcium folinate and injectable forms of droperidol, fluorouracil,
foscarnet and methotrexate.
1. Droperidol 1.25 mg/0.5 ml with calcium folinate 5 mg/0.5 ml,
immediate precipitation in direct admixture in syringe for 5
minutes at 25° C followed by 8 minutes of centrifugation.
2. Droperidol 2.5 mg/0.5 ml with calcium folinate 10 mg/0.5 ml,
immediate precipitation when the drugs were injected sequentially
into a Y-site without flushing the Y-side arm between injections.
Calcium folinate must not be mixed in the same infusion as
5-fluorouracil because a precipitate may form. Fluorouracil 50
mg/ml with calcium folinate 20 mg/ml, with or without dextrose 5%
in water, has been shown to be incompatible when mixed in different
amounts and stored at 4°C, 23°C, or 32° C in polyvinyl chloride
Foscarnet 24 mg/ml with calcium folinate 20 mg/ml formation of a
cloudy yellow solution reported.
Keep out of the reach of children.
Store between 15°C to 30°C away from light.