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CALCIUM FOLINATE 10 MG/ML SOLUTION FOR INJECTION

Active substance(s): CALCIUM FOLINATE

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TEVA UK Ref:

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PRESCRIBER INFORMATION LEAFLET
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NAME OF THE MEDICINAL PRODUCT
Calcium Folinate 10mg/ml Solution for Injection
QUALITATIVE AND QUANTITATIVE COMPOSITION
Calcium Folinate 10mg/ml Solution for Injection contains Calcium Folinate, the formyl derivate of
tetrahydrofolic acid in the form of the calcium salt.
1ml of Calcium Folinate 10mg/ml Solution for Injection contains 10.8mg of calcium folinate, equivalent to
10.0mg of folinic acid
5ml solution for injection contains 54mg calcium folinate, equivalent to 50mg folinic acid.
10ml solution for injection contains 108mg calcium folinate, equivalent to 100mg folinic acid.
20ml solution for injection contains 216mg calcium folinate, equivalent to 200mg folinic acid.
30ml solution for injection contains 324mg calcium folinate, equivalent to 300mg folinic acid.
50ml solution for injection contains 540mg calcium folinate, equivalent to 500mg folinic acid.
For a full list of excipients see 6.1

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PHARMACEUTICAL FORM
Solution for injection
Calcium Folinate 10mg/ml Solution for Injection is a clear, yellow, particle-free solution.

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4.1

CLINICAL PARTICULARS
Therapeutic indications
Calcium folinate is indicated:
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4.2

Version:

231-30-84025-M LEA CALCIUM FOLINATE 10mg/ml SOL FOR INJ

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9 June 2015

Overdosage (possibly occurring with trimetrexate doses above 90mg/m2 without concomitant
administration of calcium folinate): after stopping trimetrexate, calcium folinate 40mg/m2 IV every
6 hours for 3 days.

Trimethoprim toxicity:
- After stopping trimethoprim, 3-10mg/day calcium folinate until recovery of a normal blood count.
Pyrimethamine toxicity:
- In cases of high dose pyrimethamine or prolonged treatment with low doses, calcium folinate 5 to
50mg/day should be simultaneously administered, based on the results of the peripheral blood counts.
4.3

Contraindications
- Known hypersensitivity to calcium folinate, or to any of the excipients.
-

Pernicious anaemia or other anaemias due to vitamin B12 deficiency.

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 medicinal products.
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.
General
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.

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"
In combination with 5-fluorouracil in cytotoxic therapy.

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.

Posology and method of administration
For intravenous and intramuscular administration only. In the case of intravenous administration, no more
than 160mg 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.

In epileptic patients treated with phenobarbital, phenytoin, primidone, and succinimides there is a risk of
increasing the frequency of seizures due to a decrease in 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 Interaction with other medicinal products and other forms of interaction).

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 folinate.

Calcium folinate/5-fluorouracil
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.

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 - 50mg should be given parenterally due to saturable enteral absorption of calcium folinate.

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.

Calcium folinate rescue is necessary when methotrexate is given at doses exceeding 500mg/m2 body surface
and should be considered with doses of 100mg - 500mg/m2 body surface.

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 illness are particularly prone to these toxicities. Therefore, particular care should be taken when
treating these patients.

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 15mg (6 - 12mg/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.

In elderly patients and patients who have undergone preliminary radiotherapy, it is recommended to begin
with a reduced dosage of 5-fluorouracil.

Forty-eight hours after the start of the methotrexate infusion, the residual methotrexate-level should be
measured. If the residual methotrexate-level is >0.5μmol/l, calcium folinate dosages should be adapted
according to the following table:

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.

Residual methotrexate blood level 48 hours
after the start of the methotrexate
administration
≥0.5μmol/l
≥1.0μmol/l
≥2.0μmol/l

Calcium folinate must not be mixed with 5-fluorouracil in the same IV injection or infusion.

Calcium folinate/methotrexate
For specific details on reduction of methotrexate toxicity refer to the SPC for methotrexate.

Additional calcium folinate to be administered
every 6 hours for 48 hours or until levels of
methotrexate are lower than 0.05μmol/l:
15mg/m2
100mg/m2
200mg/m2

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 pre-existing - 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.

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.

Excessive calcium folinate doses must be avoided since this may impair the antitumour activity of
methotrexate, especially in CNS tumours where calcium folinate accumulates after repeated courses.

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 children:

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.

Bimonthly regimen: calcium folinate 200mg/m2 by intravenous infusion over 2 hours, followed by bolus
400mg/m2 of 5-FU and 22-hour infusion of 5-FU (600mg/m2) for two consecutive days, every 2 weeks on
days 1 and 2.

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 toxicity decreases.

Weekly regimen: calcium folinate 20mg/m2 by bolus i.v. injection or 200 to 500mg/m2 as i.v. infusion over a
period of 2 hours plus 500mg/m2 5-fluorouracil as i.v. bolus injection in the middle or at the end of the
calcium folinate infusion.
Monthly regimen: calcium folinate 20mg/m2 by bolus i.v. injection or 200 to 500mg/m2 as i.v. infusion over a
period of 2 hours immediately followed by 425 or 370mg/m2 5-fluorouracil as i.v. bolus injection during five
consecutive days.

The possibility that the patient is taking other medications that interact with methotrexate (e.g. medications
that may interfere with methotrexate elimination or binding to serum albumin) should always be considered
when laboratory abnormalities or clinical toxicities are observed.
4.5

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
required.

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).

The number of repeat cycles used is at the discretion of the clinician.
Antidote to the folic acid antagonists, trimetrexate, trimethoprim, and pyrimethamine:
Trimetrexate toxicity:
- 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 20mg/m2 for 5 to 10 minutes every 6 hours for a total daily dose of
80mg/m2, or by oral route with four doses of 20mg/m2 administered at equal time intervals. Daily doses
of calcium folinate should be adjusted depending on the haematological toxicity of trimetrexate.

Interaction with other medicinal products and other forms of interaction
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 neutralised.

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
Pregnancy
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

Please cut here to separate the Prescriber and Patient Information Leaflets, thank you.

PACKAGE LEAFLET: INFORMATION
FOR THE USER

CALCIUM FOLINATE
10 mg/ml SOLUTION FOR

Inform your doctor if one of these warnings applies to you, or has applied in the past.

Taking other medicines
The following remarks might also apply to medicinal products you have taken/were given
some time ago or will take/be given in the near future.

Please note that the name of the medicines mentioned below might be familiar to you
under a different name, e.g. the brand name. In this paragraph only the name of the active
substance is used and not the brand name. Therefore, you should check the package and
patient information leaflet for the active substance of the medicines you already take or
have taken in the recent past.

Please tell your doctor or nurse if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.

Pregnancy and breast-feeding
The effects of Calcium Folinate on the unborn child are unknown. Calcium Folinate may
only be administered during pregnancy when clearly needed. This will be decided by your
doctor.
This advice is also applicable when you Calcium Folinate is administered in combination with
methotrexate. The administration of Calcium Folinate in combination with 5-fluorouracil
during pregnancy is not allowed because of the harmful effects of 5-fluorouracil.
It is not known whether Calcium Folinate is excreted in breast milk. Calcium Folinate should
only be administered to breast-feeding mothers when clearly needed. This will be decided
by your doctor. In combination with 5-fluorouracil, the administration of Calcium Folinate
during breastfeeding is not advised because of the harmful effects of 5-fluorouracil.

Ask your doctor or nurse for advice before taking any medicine.

INJECTION
Sometimes (medicinal) products that are given/taken concomitantly can influence each
other’s effect and/or side effect. This is called an interaction. An interaction can occur during
Calcium folinate
concomitant use of the solution for injection and:
Read all of this leaflet carefully before this medicine is given to you.
• 5-fluorouracil (a medicine against certain forms of cancer). The effect and side effects of
• Keep this leaflet. You may need to read it again.
5-fluorouracil are increased. Calcium Folinate and 5-fluorouracil are often given in
• If you have any further questions, ask your doctor or nurse.
combination intentionally. However, also the undesirable side effects are enhanced.
• This medicine has been prescribed for you. Do not pass it on to others. It may harm them,
• folic acid antagonists like cotrimoxazole, pyrimethamine or methotrexate. The effect of
even if their symptoms are the same as yours.
the folic acid antagonist may either be reduced or completely neutralised. Calcium
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any
Folinate and methotrexate are often given in combination intentionally.
possible side effects not listed in this leaflet. See section 4.
• phenobarbital, primidone, phenytoin and succinimides (medicines against epilepsy). The
effect of these medicines may be diminished, which can cause epileptic seizures.

IN THIS LEAFLET:

WHAT CALCIUM FOLINATE IS AND WHAT IT IS USED FOR

What Calcium Folinate is and what it is used for
Before you receive Calcium Folinate
How Calcium Folinate is given
Possible side effects
How to store Calcium Folinate
Further information

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1.
2.
3.
4.
5.
6.

Calcium Folinate is an antidote. Antidotes prevent the damage caused by other substances.
Calcium Folinate is administered as an injection or infusion by your doctor.
Calcium Folinate is used to help prevent the side effects of treatment or overdose with the
medicine methotrexate, when used in high doses. Calcium Folinate is being administered a
few hours after methotrexate, to allow methotrexate to have its effect first.
Calcium Folinate is also used in combination with the medicine 5-fluorouracil for the

3

In general the dosage regimen is as follows:
After one cycle of moderate- to high-dose methotrexate
Adults, elderly patients and children:
As a rule, the first dose of Calcium Folinate is 15 mg (6-12 mg/per square metre of your
body surface area) to be given 12-24 hours (maximum 24 hours) after starting the
methotrexate infusion. Over a period of 72 hours, the same dose is repeated every 6 hours.
After administration of a few injections or infusions, it is possible to switch to tablets.

In combination with 5-fluorouracil for the treatment of certain forms of colon cancer
(metastatic colorectal carcinoma):
Adults and elderly patients
• Bimonthly regimen: on two consecutive days, every two weeks: 200 mg of Calcium
Folinate per square metre of your body surface area as an infusion over a period of two
hours, followed by an injection of 400 mg of 5-fluorouracil per square metre of your body
surface area and 600 mg of 5-fluorouracil per square metre of your body surface area as
an infusion over a period of 22 hours.
• Weekly regimen: 20 mg of Calcium Folinate per square metre of your body surface area
as a single injection, or 200 to 500 mg of Calcium Folinate per square metre of your body
surface area as an infusion over a period of two hours plus 500 mg of 5-fluorouracil per
square metre of your body surface area as an intravenous injection in the middle or at the
end of the Calcium Folinate infusion.
• Monthly regimen: once a month during five consecutive days: 20 mg of Calcium Folinate
per square metre of your body surface area as a single injection, or 200 to 500 mg of
Calcium Folinate per square metre of your body surface area as an infusion over a period
of two hours, immediately followed by 425 or 370 mg of 5-fluorouracil per square metre
of your body surface area as a single injection.

treatment of certain forms of colon cancer (metastatic colorectal carcinoma). This therapy
Driving and using machines
should only be applied when supervised by a doctor with experience in the use of cancer
There is no evidence that Calcium Folinate has an effect on the ability to drive or use
chemotherapeutics. Finally Calcium Folinate is also used to prevent or treat a folate
machines.
deficiency, only when it is impossible to administer folic acid tablets.
Important information about some of the ingredients of Calcium Folinate
Use
This
medicinal
product contains 0.14 mmol (or 3.3 mg) sodium per ml. This should be taken
• to diminish the harmfulness and effect of certain medicines (like methotrexate) in children into consideration by patients on a controlled sodium diet.
and adults.
• in combination with the medicine 5-fluorouracil, for the treatment of certain forms of
HOW CALCIUM FOLINATE IS USED
cancer.
The dosage can vary from patient to patient since the dose will be calculated by your body
surface area (based on your height and weight).Your doctor will decide what dosage is best
BEFORE YOU RECEIVE CALCIUM FOLINATE
for you.

2

Do not use Calcium Folinate if you:
• are allergic (hypersensitive) to calcium folinate or any of the other ingredients of this
medicine
• suffer from anaemia caused by a lack of vitamin B12 (for example pernicious anaemia).

Take special care with Calcium Folinate
• if diarrhoea or mucositis occur during the use of Calcium Folinate in combination with the
medicine 5-fluorouracil (see also “Possible side effects”). Your doctor can decide to
decrease the 5-fluorouracil dose or stop the treatment. Elderly and weak patients are
more susceptible to these side effects
• if you are simultaneously being treated with methotrexate; Calcium Folinate should not
be administered together with methotrexate, because Calcium Folinate is able to
counteract the effects of methotrexate totally. Therefore, Calcium Folinate should always
be administered several hours after the treatment with methotrexate (see also section 3.
“How Calcium Folinate is used”).
• if you have been treated with radiotherapy before, and you receive Calcium Folinate in
combination with the medicine 5-fluorouracil; your doctor will reduce the dosage of
5-fluorouracil
• if you receive Calcium Folinate in combination with the medicine 5-fluorouracil and your
doctor notices that the amount of calcium in your blood has decreased; your doctor will
prescribe extra calcium
• if you take certain anti-epileptics; epileptic seizures may occur more frequently (see also
the paragraph “Taking other medicines” and the section “Possible side effects”)
• if you take/are given certain medicines for the treatment of cancer, like
hydroxycarbamide, cytarabine, mercaptopurine and thioguanine. These medicines may
cause a blood disorder (macrocytosis) that should not be treated with Calcium Folinate
• if your kidneys do not function well and Calcium Folinate is given in combination with
methotrexate; your doctor may decide to increase the Calcium Folinate dosage or to
prescribe longer use of it.

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.

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
Both therapeutic indications:
Immune system disorders
Very rare, including incidental reports (<0.01%):
Allergic reactions, including anaphylactoid reactions and urticaria.

Excretion
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.
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PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium chloride
Sodium hydroxide
Hydrochloric acid
Water for injections

Psychiatric disorders
Rare (0.01-0.1%):
Insomnia, agitation and depression after high doses.
Gastrointestinal disorders
Rare (0.01-0.1%):
Gastrointestinal disorders after high doses.
Neurological disorders
Rare (0.01-0.1%):
Increase in the frequency of attacks in epileptics (see also section 4.5 Interaction with other medicinal products
and other forms of interaction).

6.2 Incompatibilities
Calcium Folinate 10mg/ml Solution for Injection should not be mixed with any other drug, unless
compatibility has been satisfactorily demonstrated.
Incompatibilities have been reported between injectable forms of calcium folinate and injectable forms of
droperidol, fluorouracil, foscarnet and methotrexate.
Droperidol
1. Droperidol 1.25mg/0.5ml with calcium folinate 5mg/0.5ml, immediate precipitation in direct admixture in
syringe for 5 minutes at 25°C followed by 8 minutes of centrifugation.
2. Droperidol 2.5mg/0.5ml with calcium folinate 10mg/0.5ml, immediate precipitation when the drugs were
injected sequentially into a Y-site without flushing the Y-side arm between injections.

General disorders and administration site conditions
Uncommon (0.1-1%):
Fever has been observed after administration of 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 toxicities:

Fluorouracil
Calcium folinate must not be mixed in the same infusion as 5-fluorouracil because a precipitate may form.
Fluorouracil 50mg/ml with calcium folinate 20mg/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
containers.

Monthly regimen:
Gastrointestinal disorders
Very common (>10%):
Vomiting and nausea

Foscarnet
Foscarnet 24mg/ml with calcium folinate 20mg/ml: formation of a cloudy yellow solution reported.

Shelf-life after first opening the container: For single dose use only. Any unused solution should be discarded
immediately after initial use.

Overdose
There have been no reported sequelae in patients who have received significantly more calcium folinate than 6.4
the recommended dosage. However, excessive amounts of calcium folinate may nullify the chemotherapeutic
effect of folic acid antagonists.
6.5
Should overdosage of the combination of 5-fluorouracil and calcium folinate occur, the overdosage
instructions for 5-FU should be followed.

6.6

Calcium folinate is the sodium 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 reduced 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 fluorouracil (5-FU) to enhance its
cytotoxic activity. 5-FU inhibits thymidylate synthase (TS), a key enzyme involved in pyrimidine biosynthesis,
and 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 7
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.

MARKETING AUTHORISATION HOLDER
Teva UK Limited
Brampton Road
Hampden Park
Eastbourne
East Sussex
BN22 9AG

8

MARKETING AUTHORISATION NUMBER(S)
PL 00289/0851

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
28/04/2006 / 11/02/2008

10

DATE OF REVISION OF THE TEXT
04/06/2015

84025-M

84025-M
Nervous system:
Rare:
Sleeplessness, agitation and depression after administration of high doses. In combination with
certain anti-epileptics, the frequency of seizures is rarely increased (see also the paragraphs
“Take special care with Calcium Folinate” and “Taking other medicines” in section 2. “Before
Calcium Folinate is used”).

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation holder and company responsible for manufacture: TEVA UK
Limited, Eastbourne, BN22 9AG.
Immune system:
This leaflet was last revised: June 2015
Very rare, including isolated reports:
Allergic reactions, including a sudden feeling of illness, feeling of fear, chills, itching, paleness PL 00289/0851
or redness, sweating, uncommon breathlessness, fast heart beat and shock (anaphylactoid
reaction) and skin rash with intense itching (urticaria).

Package size: 1 vial per carton.

Very common side effects occur in more than 1 in people
Common side effects occur in more than 1 in 100, but less than 1 in 10 people
Uncommon side effects occur in more than 1 in 1,000, but less than 1 in 100 people
Rare side effects occur in more than 1 in 10,000, but less than 1 in 1,000 people
Very rare side effects occur in less than 1 in 10,000 people.

Calcium Folinate is packed in clear, colourless Type I glass vials with chlorobutyl rubber
stoppers, with aluminium crimping caps.
The vials contain 5 ml, 10 ml, 20 ml, 30 ml or 50 ml solution for injection.

6-29116170/C

The following side effects may occur:

What Calcium Folinate looks like and contents of the pack
Solution for injection.
Calcium Folinate 10 mg/ml, solution for injection is a clear, yellow, particle-free solution.

6

5

Other
Very common
Harmful effects of trimethoprim (an antibiotic used to treat certain infections):
Inflammation of the mucosa (mucositis).
After stopping treatment with trimethoprim, you will receive 3-10 mg Calcium Folinate daily.
Reporting of side effects
Your doctor will decide on the duration of this treatment.
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any
Harmful effects of pyrimethamine (a medicine that is used for the treatment of malaria and possible side effects not listed in this leaflet. You can also report side effects directly via the
for an infection called toxoplasmosis, caused by a parasite):
Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
If you receive a high dose of pyrimethamine or if pyrimethamine is taken for a long period,
By reporting side effects you can help provide more information on the safety of this
you will receive 5-50 mg Calcium Folinate per day simultaneously.
medicine.
If more Calcium Folinate is given than recommended
If more Calcium Folinate is given than recommended, the doctor will treat you as
HOW TO STORE CALCIUM FOLINATE
appropriate. If you suspect a serious overdose, talk to a doctor or pharmacist immediately. In
case of a high dose, the effects as described in the section “possible side effects” can occur. Store at 2-8°C (in a refrigerator) in the original package.
If you Calcium Folinate is given in combination with methotrexate, too much Calcium
Keep out of the reach and sight of children.
Folinate can diminish the effect of methotrexate.
Calcium Folinate should not be used after the expiry date which is stated on the package
If Calcium Folinate is forgotten
after “do not use after” or “exp”. The first 2 numbers relate to the month and the last
When a dose is forgotten and Calcium Folinate is given in combination with methotrexate,
numbers to the year. The expiry date refers to the last day of that month.
the toxic effects of methotrexate can occur (see Patient Information Leaflet of
Medicines should not be disposed of via wastewater or household waste. Ask your
methotrexate). Consult your doctor when you have any doubt.
pharmacist how to dispose of medicines no longer required. These measures will help to
If Calcium Folinate is stopped
protect the environment.
When Calcium Folinate is given in combination with methotrexate and treatment is stopped
abruptly, the side effects of methotrexate, which were counteracted before by Calcium
FURTHER INFORMATION
Folinate, can appear. Therefore it is not advised to stop Calcium Folinate abruptly.
Pharmaceutical form and content
Always consult your doctor in case of any doubts.

Gastrointestinal tract
Very common
Diarrhoea, vomiting and nausea

When given in combination with the medicine 5-fluorouracil the following side effects may
also occur:

Other
Uncommon
Fever

To counteract the harmful effects of trimetrexate, trimethoprim, and pyrimethamine:
Harmful effects of trimetrexate (a medicine used to treat certain forms of pneumonia,
especially in patients with AIDS):
To prevent toxicity caused by trimetrexate, you will receive Calcium Folinate every day
during treatment with trimetrexate, and until 72 hours after the last dose of trimetrexate.
Your doctor will administer Calcium Folinate by infusion for 5-10 minutes in a dose of 20 mg
per square metre of your body surface area. This will be repeated every 6 hours, resulting in
a total daily dose of 80 mg per square metre of your body surface area. Tablets are an
alternative to infusion. Four times a day you will receive a dosage of 20 mg per square metre
of your body surface area, equally divided over the day. Your doctor may decide to give you
another dose.
In case of overdosage of trimetrexate, your doctor will administer Calcium Folinate after
stopping trimetrexate. Calcium Folinate will be administered in a vein every 6 hours for 3
days, in a dosage of 40 mg per square metre of your body surface area.

Gastrointestinal tract:
Rare:
Gastrointestinal disturbances after administration of high doses of Calcium Folinate.

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.

Special precautions for disposal
Calcium Folinate 10mg/ml Solution for Injection is intended for single dose use only. Any unused solution
should be discarded immediately after initial use.
For intravenous infusion, calcium folinate may be diluted according to directions with the recommended
infusion fluids, 0.9% w/v Sodium Chloride Intravenous Infusion or 5% w/v Glucose Intravenous Infusion
before administration.
The administration of Calcium Folinate 10mg/ml Solution for Injection depends on the individual dosage
regime. See also section 4.2. In the case of intravenous administration, no more than 160mg of calcium
folinate should be injected per minute due to the calcium content of the solution.
Prior to administration, the sterile solution for injection should be visually inspected for clarity, particulate
matter, discolouration and the integrity of the container. The solution should only be used if it is clear and the
container is undamaged.
Any unused portion of the solution should be disposed of in accordance with the local requirements

Calcium Folinate is a solution for injection and contains calcium folinate corresponding to
10 mg of folinic acid per ml, which equals 50 mg folinic acid for the 5 ml vial, 100 mg for
the 10 ml vial, 200 mg for the 20 ml vial, 300 mg for the 30 ml vial, and 500 mg for the
50 ml vial.

Metabolism
Calcium folinate is a racemate where the L-form (L-5-formyl-tetrahydrofolate, L-5-formyl-THF), is the active
enantiomer.

If you have any further questions on the use of this product, ask your doctor or nurse.

5.2 Pharmacokinetic properties
Absorption
Following intramuscular administration of the aqueous solution, systemic availability is comparable to an
intravenous administration. However, lower peak serum levels (Cmax) are achieved.

Nature and contents of container
Clear, Type I glass vials with chlorobutyl rubber stoppers, Type I, with aluminium crimping caps. Vials
containing 5ml, 10ml, 20ml, 30ml and 50ml solution for injection.
Package size: 1 vial per carton
Not all pack sizes may be marketed.

• Diarrhoea
• Mucositis
Above mentioned reactions can be serious side effects. Your doctor can decide to
discontinue the treatment.

PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment; ATC code: V03AF03.

Special precautions for storage
Store at 2 – 8°C. Keep the vial in the outer carton.

6-29116170/C

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Shelf-life after dilution according to directions
When diluted according to directions with the recommended infusion fluids, 0.9% w/v Sodium Chloride
Intravenous Infusion or 5% w/v Glucose Intravenous Infusion, chemical and physical in-use stability of diluted
solution has been demonstrated for 72 hours at room temperature (below 25°C).
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use
storage times and conditions prior to use are the responsibility of the user and would normally not be longer
than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

What Calcium Folinate contains
• The active substance is: calcium folinate corresponding to 50 mg (5 ml), 100 mg (10 ml),
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
200 mg (20 ml), 300 mg (30 ml), and 500 mg (50 ml) of folinic acid, respectively.
please tell your doctor.
• The other ingredients are: sodium chloride, sodium hydroxide, hydrochloric acid, water
for injections.
Tell your doctor immediately if you notice any of the following symptoms:

Weekly regimen:
Gastrointestinal disorders
Very common (>10%):
Diarrhoea with higher grades of toxicity, and dehydration, resulting in hospital admission for treatment and
even death.

POSSIBLE SIDE EFFECTS

No enhancement of other 5-fluorouracil induced toxicities (e.g. neurotoxicity).

6.3 Shelf life
Shelf-life as packed for sale
2 years

4

General disorders and administration site conditions
Very common (>10%):
(Severe) mucosal toxicity

5
5.1

9 June 2015

Elimination
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).

Lactation
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

2

Distribution
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±3.5mg.min/l and 129±112mg.min/l after a dose of
25mg. The inactive D-isomer is present in higher concentration than L-5-formyl-tetrahydrofolate.

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.

4.9

Version:

231-30-84025-M LEA CALCIUM FOLINATE 10mg/ml SOL FOR INJ

Like all medicines, Calcium Folinate can cause side effects, although not everybody gets
them.

TEVA UK Ref:

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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