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CALCIUM FOLINATE 10 MG/ML SOLUTION FOR INJECTION

Active substance(s): CALCIUM FOLINATE

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TEVA UK Ref:

231-30-84025-N LEA CALCIUM FOLINATE 10mg/ml SOL FOR INJ TEVAH Dimensions Changed:
No
Length:
268 mm
Width:
520 mm
Depth:
N/A
Foil Width:
N/A

Colours Used:

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4.1

4.2

26 May 2016
BLACK

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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.
Each ml 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.
Excipients with known effect: Each ml of solution for injection contains 0.14 mmol (3.22 mg) sodium.
For the full list of excipients see 6.1
PHARMACEUTICAL FORM
Solution for injection
Calcium Folinate 10mg/ml Solution for Injection is a clear, yellow, particle-free solution.
CLINICAL PARTICULARS
Therapeutic indications
Calcium folinate is indicated:
- 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.

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
- Hypersensitivity to the active substance, or to any of the excipients listed in section 6.1.
-

4.4

Posology and method of administration
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.
Posology
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.
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.
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.
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.
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:
Residual methotrexate blood level 48 hours
after the start of the methotrexate
administration
≥0.5µmol/l
≥1.0µmol/l
≥2.0µmol/l

3

Template

PRESCRIBER INFORMATION LEAFLET
1

Version:

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

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 children:
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.
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
4.5
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.
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.
The number of repeat cycles used is at the discretion of the clinician.
4.6
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.

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.
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.
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 Interaction with other medicinal products and other forms of interaction).
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.
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
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 5-fluorouracil.
Calcium folinate must not be mixed with 5-fluorouracil in the same i.v 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.
Calcium folinate/methotrexate
For specific details on reduction of methotrexate toxicity refer to the SmPC 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 SmPC 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.
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 toxicity decreases.
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.
Each ml of solution contains 0.14 mmol (3.22 mg) sodium. This should be taken into account in patients on a
controlled sodium diet.
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.
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).
Fertility, 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
should be weighed against possible hazards to the foetus. Should treatment with methotrexate or other

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

Package leaflet: Information
for the user

Calcium folinate

Calcium Folinate
10 mg/ml, solution for injection

Read all of this leaflet carefully before you start using this medicine because it contains
important information for you.

What is in this leaflet

What Calcium Folinate is and what it is used for
What you need to know before you use Calcium Folinate
How to use Calcium Folinate
Possible side effects
How to store Calcium Folinate
Contents of the pack and other information

What Calcium Folinate is and what it is used for

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist..
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm
them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible
side effects not listed in this leaflet. See section 4.

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

1

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
treatment of certain forms of colon cancer (metastatic colorectal carcinoma). This therapy
should only be applied when supervised by a doctor with experience in the use of cancer
chemotherapeutics. Finally Calcium Folinate is also used to prevent or treat a folate
deficiency, only when it is impossible to administer folic acid tablets.

What you need to know before you use Calcium Folinate

Use
- to diminish the harmfulness and effect of certain medicines (like methotrexate) in children
and adults.
- in combination with the medicine 5-fluorouracil, for the treatment of certain forms of
cancer.

2

Do not use Calcium Folinate:
• if you are allergic (hypersensitive) to calcium folinate or any of the other ingredients of
this medicine(listed in section 6).
• if you suffer from anaemia caused by a lack of vitamin B12 (for example pernicious
anaemia).

Warnings and precautions
Talk to your doctor or pharmacist before using 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 to use Calcium Folinate”).
- 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 “Other medicines and Calcium Folinate” 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.

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

Other medicines and Calcium Folinate
Tell your doctor of pharmacist if you are taking/using, have recently taken/used or might
take/use any other medicines.

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.

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
concomitant use of the solution for injection and:
- 5-fluorouracil (a medicine against certain forms of cancer). The effect and side effects of
5-fluorouracil are increased. Calcium Folinate and 5-fluorouracil are often given in
combination intentionally. However, also the undesirable side effects are enhanced.
- folic acid antagonists like cotrimoxazole, pyrimethamine or methotrexate. The effect of
the folic acid antagonist may either be reduced or completely neutralised. Calcium
Folinate and methotrexate are often given in combination intentionally.
- phenobarbital, primidone, phenytoin and succinimides (medicines against epilepsy). The
effect of these medicines may be diminished, which can cause epileptic seizures.

Pregnancy and breast-feeding
If you are pregnant of breast-feeding, think you may be pregnant or are planning to have a
baby, ask your doctor or pharmacist for advice before using this medicine.
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 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.

Driving and using machines
There is no evidence that Calcium Folinate has an effect on the ability to drive or use
machines.

How to use Calcium Folinate

Calcium Folinate contains Sodium. This medicinal product contains 0.14 mmol (or 3.22 mg)
sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

3

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your
doctor or pharmacist if you are not sure.

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
for you.

The recommended dose is

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 (at the latest 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.

231-30-84025-N LEA CALCIUM FOLINATE 10mg/ml SOL FOR INJ TEVAH
26 May 2016
BLACK

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.
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.
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).
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 SmPC.
6
PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium chloride
Sodium hydroxide
Hydrochloric acid
Water for injections
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.
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.
Foscarnet
Foscarnet 24mg/ml with calcium folinate 20mg/ml: formation of a cloudy yellow solution reported.
6.3 Shelf life
Shelf-life as packed for sale
2 years
Shelf-life after first opening the container: For single dose use only. Any unused solution should be discarded
immediately after initial use.
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.
6.4 Special precautions for storage
Store in a refrigerator (2 °C – 8°C). Keep the vial in the outer carton.
For storage conditions after dilution of the medicinal product, see section 6.3.
6.5 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.
6.6 Special precautions for disposal and other handling
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 any unused medicinal product or waste material should be disposed of in
accordance with the local requirements
7
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
84025-N
To be completed upon approval

6-29116170/D

84025-N
PL 00289/0851

This leaflet was last revised: May 2016

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation holder and company responsible for manufacture: Teva UK Ltd.
Brampton Road, Hampden park, Eastbourne, East Sussex, BN22 9AG, United Kingdom.

Package size: 1 vial per carton.

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.

Immune system:
Very rare, including isolated reports:
Allergic reactions, including a sudden feeling of illness, feeling of fear, chills, itching, paleness
or redness, sweating, uncommon breathlessness, fast heart beat and shock (anaphylactic or
anaphylactoid reaction) and skin rash with intense itching (urticaria).

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

What Calcium Folinate looks like and contents of the pack

Very common side effects may affect more than 1 in 10 people
Common side effects may affect up to 1 in 10 people
Uncommon side effects may affect up to 1 in 100 people
Rare side effects may affect up to 1 in 1,000 people
Very rare side effects may affect up to 1 in 10,000 people.

The following side effects may occur:

- The active substance is: calcium folinate corresponding to 50 mg (5 ml), 100 mg (10 ml),
200 mg (20 ml), 300 mg (30 ml), and 500 mg (50 ml) of folinic acid, respectively.
- The other ingredients are: sodium chloride, sodium hydroxide, hydrochloric acid, water
for injections.

What Calcium Folinate contains

Tell your doctor immediately if you notice any of the following symptoms:
- Diarrhoea
- Mucositis
Above mentioned reactions can be serious side effects. Your doctor can decide to
discontinue the treatment.

Contents of the pack and other information

6

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.
Like all medicines, this medicine can cause side effects, although not everybody gets them.

Possible side effects

How to store Calcium Folinate

5

Pharmaceutical form and content

6-29116170/D

If you forget to use Calcium Folinate
When a dose is forgotten and Calcium Folinate is given in combination with methotrexate, the Keep this medicine out of the sight and reach of children.
toxic effects of methotrexate can occur (see Patient Information Leaflet of methotrexate).
Do not use this medicine after the expiry date which is stated on the package after Exp..
Consult your doctor when you have any doubt.
The expiry date refers to the last day of that month.
If you stop using Calcium Folinate
Store in a refrigerator (2 °C-8 °C) in the original package.
When Calcium Folinate is given in combination with methotrexate and treatment is stopped Do not throw away any medicines via wastewater or household waste. Ask your pharmacist
abruptly, the side effects of methotrexate, which were counteracted before by Calcium
how to throw away medicines you no longer use.. These measures will help protect the
Folinate, can appear. Therefore it is not advised to stop Calcium Folinate abruptly.
environment.
Always consult your doctor in case of any doubts

If you use more Calcium Folinate than you should
If more Calcium Folinate is given than recommended, the doctor will treat you as 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. If Calcium
Folinate is given in combination with methotrexate, too much Calcium Folinate can diminish
the effect of methotrexate.

Harmful effects of pyrimethamine (a medicine that is used for the treatment of malaria and
for an infection called toxoplasmosis, caused by a parasite):
If you receive a high dose of pyrimethamine or if pyrimethamine is taken for a long period,
you will receive 5-50 mg Calcium Folinate per day simultaneously.

Harmful effects of trimethoprim (an antibiotic used to treat certain infections):
After stopping treatment with trimethoprim, you will receive 3-10 mg Calcium Folinate daily.
Your doctor will decide on the duration of this treatment.

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.

To counteract the harmful effects of trimetrexate, trimethoprim, and pyrimethamine:

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 “Warning and precautions” and “Other medicines and Calcium Folinate ” in section
2. “What you need to know before you use Calcium Folinate”).
Gastrointestinal tract:
Rare:
Gastrointestinal disturbances after administration of high doses of Calcium Folinate.
Other
Uncommon
Fever
When given in combination with the medicine 5-fluorouracil the following side effects
may also occur:
Gastrointestinal tract
Very common
Diarrhoea (possibly severe and leading to drying out), vomiting and nausea
Other
Very common
Inflammation of the lining of the intestine and mouth (life-threatening conditions have occurred)
Reduction in the number of blood cells (including life-threatening conditions)
Common
Redness and swelling of the palms of the hands or soles of the feet which may cause the
skin to peel (hand-foot syndrome)
Not known
Elevated ammonia level in the blood
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. You can also report side effects directly via the Yellow Card
Scheme at: www.mhra.gov.uk/yellowcard
By reporting side effects you can help provide more information on the safety of this
medicine.

3

Template

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.
Breast-feeding
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
Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Rare (≥1/10,000 to <1/1,000)
Very rare (<1/10,000) including isolated reports
not known (cannot be estimated from the available data)
Both therapeutic indications:
Immune system disorders
Very rare, including incidental reports (<0.01%):
Allergic reactions, including anaphylactoid reactions and urticaria.
Psychiatric disorders
Rare
Insomnia, agitation and depression after high doses.
Gastrointestinal disorders
Rare
Gastrointestinal disorders after high doses.
Neurological disorders
Rare
Increase in the frequency of attacks in epileptics (see also section 4.5 Interaction with other medicinal products
and other forms of interaction).
General disorders and administration site conditions
Uncommon
Fever has been reported 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 toxicities:
Monthly regimen:
Gastrointestinal disorders
Very common
Vomiting and nausea
General disorders and administration site conditions
Very common
(Severe) mucosal toxicity
No enhancement of other 5-fluorouracil induced toxicities (e.g. neurotoxicity).
Weekly regimen:
Gastrointestinal disorders
Very common
Diarrhoea with higher grades of toxicity, and dehydration, resulting in hospital admission for treatment and
even death.
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.
4.9 Overdose
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 followed.
5
PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment ATC code: V03AF03.
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 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
Absorption
Following intramuscular administration of the aqueous solution, systemic availability is comparable to an
intravenous administration. However, lower peak serum levels (Cmax) are achieved.
Metabolism
Calcium folinate is a racemate where the L-form (L-5-formyl-tetrahydrofolate, L-5-formyl-THF), is the active
enantiomer.

• 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.

Version:

Colours Used:

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Dimensions Changed:
No
Length:
268 mm
Width:
520 mm
Depth:
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Foil Width:
N/A

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

TEVA UK Ref:

TEVA UK Ref:

231-30-60057-A LEA CALCIUM FOLINATE 10mg/ml INJ TEVAH Dim’s Changed?:
Length:
Width:
Depth:
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No
420 mm
300 mm
N/A
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Version:

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Colours Used:

11 August 2016
BLACK
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93.131.319-A
Calcium Folinate
10 mg/ml Solution For Injection
PRESCRIBER INFORMATION LEAFLET
1
NAME OF THE MEDICINAL PRODUCT
Calcium Folinate 10mg/ml Solution for Injection
2
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.
Each ml 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.
Excipients with known effect: Each ml of solution for injection contains 0.14 mmol (3.22 mg) sodium.
For the full list of excipients see 6.1
3
PHARMACEUTICAL FORM
Solution for injection
Calcium Folinate 10mg/ml Solution for Injection is a clear, yellow, particle-free solution.
4
CLINICAL PARTICULARS
4.1 Therapeutic indications
Calcium folinate is indicated:
- 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.
4.2 Posology and method of administration
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.
Posology
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.
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.
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.
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.
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:
Residual methotrexate blood level 48 hours
after the start of the methotrexate
administration
≥0.5µmol/l
≥1.0µmol/l
≥2.0µmol/l

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

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 children:
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.
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.
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.
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.
- 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
- Hypersensitivity to the active substance, or to any of the excipients listed in section 6.1.
- 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.
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 Interaction with other medicinal products and other forms of interaction).
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.
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 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
5-fluorouracil.
Calcium folinate must not be mixed with 5-fluorouracil in the same i.v 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.
Calcium folinate/methotrexate
For specific details on reduction of methotrexate toxicity refer to the SmPC 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 SmPC 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.
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 toxicity decreases.
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.
Each ml of solution contains 0.14 mmol (3.22 mg) sodium. This should be taken into account in patients on a controlled sodium diet.
4.5 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.
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 Fertility, 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 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.
Breast-feeding
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
Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Rare (≥1/10,000 to <1/1,000)
Very rare (<1/10,000) including isolated reports
not known (cannot be estimated from the available data)

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 injection
Calcium folinate

What is in this leaflet

Read all of this leaflet carefully before you start using this
medicine because it contains important information for you.
• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or
pharmacist.
• This medicine has been prescribed for you only. Do not
pass it on to others. It may harm them, even if their
signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or
pharmacist. This includes any possible side effects not
listed in this leaflet. See section 4.

What Calcium Folinate is and what it is
used for

1. What Calcium Folinate is and what it is used for
2. What you need to know before you use Calcium
Folinate
How to use Calcium Folinate
Possible side effects
How to store Calcium Folinate
Contents of the pack and other information

3.
4.
5.
6.

1

What you need to know before you use
Calcium Folinate

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 treatment of certain forms
of colon cancer (metastatic colorectal carcinoma). This
therapy should only be applied when supervised by a
doctor with experience in the use of cancer
chemotherapeutics. Finally Calcium Folinate is also used to
prevent or treat a folate deficiency, only when it is
impossible to administer folic acid tablets.
Use
- to diminish the harmfulness and effect of certain
medicines (like methotrexate) in children and adults.
- in combination with the medicine 5-fluorouracil, for the
treatment of certain forms of cancer.

2

Do not use Calcium Folinate:
- if you are allergic (hypersensitive) to calcium folinate or
any of the other ingredients of this medicine (listed in
section 6).
- if you suffer from anaemia caused by a lack of vitamin
B12 (for example pernicious anaemia).
Warnings and precautions
Talk to your doctor or pharmacist before using 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
to use Calcium Folinate”).
- 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 “Other
medicines and Calcium Folinate” 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.
Inform your doctor if one of these warnings applies to you,
or has applied in the past.

Other medicines and Calcium Folinate
Tell your doctor or pharmacist if you are taking/using, have
recently taken/used or might take/use any other medicines.
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.
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 concomitant use of the solution for injection and:
- 5-fluorouracil (a medicine against certain forms of
cancer). The effect and side effects of 5- fluorouracil are
increased. Calcium Folinate and 5-fluorouracil are often
given in combination intentionally. However, also the
undesirable side effects are enhanced.
- folic acid antagonists like cotrimoxazole, pyrimethamine
or methotrexate. The effect of the folic acid antagonist
may either be reduced or completely neutralised. Calcium
Folinate and methotrexate are often given in
combination intentionally.
- phenobarbital, primidone, phenytoin and succinimides
(medicines against epilepsy). The effect of these medicines
may be diminished, which can cause epileptic seizures.

Pregnancy and breast-feeding
If you are pregnant of breast-feeding, think you may be
pregnant or are planning to have a baby, ask your doctor or
pharmacist for advice before using this medicine.
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 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.

How to use Calcium Folinate

Ask your doctor or nurse for advice before taking any medicine.
Driving and using machines
There is no evidence that Calcium Folinate has an effect on
the ability to drive or use machines.
Calcium Folinate contains Sodium. This medicinal product
contains 0.14 mmol (or 3.22 mg) sodium per ml. To be taken
into consideration by patients on a controlled sodium diet.

3

Always use this medicine exactly as your doctor or
pharmacist has told you. Check with your doctor or
pharmacist if you are not sure.
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 for you.
The recommended dose is

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 (at the latest 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.

231-30-60057-A LEA CALCIUM FOLINATE 10mg/ml INJ TEVAH
BLACK

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.
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).
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 SmPC.
6
PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium chloride
Sodium hydroxide
Hydrochloric acid
Water for injections
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.
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.
Foscarnet
Foscarnet 24mg/ml with calcium folinate 20mg/ml: formation of a cloudy yellow solution reported.
6.3 Shelf life
Shelf-life as packed for sale
2 years
Shelf-life after first opening the vial: For single dose use only. Any unused solution should be discarded immediately after initial use.
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.
6.4 Special precautions for storage
Store in a refrigerator (2 °C - 8 °C). Keep the vial in the outer carton.
For storage conditions after dilution of the medicinal product, see section 6.3.
6.5 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.
6.6 Special precautions for disposal and other handling
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 any unused medicinal product or waste material should be disposed of in accordance with the local
requirements
7
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
28/07/2016

60057-A

60057-A

93.131.319-A

This leaflet was last revised: August 2016
PL 00289/0851

Immune system:
Very rare, including isolated reports:
Allergic reactions, including a sudden feeling of illness,
feeling of fear, chills, itching, paleness or redness, sweating,
uncommon breathlessness, fast heart beat and shock
(anaphylactic or anaphylactoid reaction) and skin rash with
intense itching (urticaria).

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation holder and company responsible
for manufacture: Teva UK Ltd. Brampton Road, Hampden
Park, Eastbourne, East Sussex, BN22 9AG, United Kingdom.

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.
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.
Package size: 1 vial per carton.

Like all medicines, this medicine can cause side effects,
although not everybody gets them.
Tell your doctor immediately if you notice any of the
following symptoms:
- Diarrhoea
- Mucositis
Above mentioned reactions can be serious side effects.
Your doctor can decide to discontinue the treatment.
The following side effects may occur:
Very common side effects may affect more than 1 in 10 people
Common side effects may affect up to 1 in 10 people
Uncommon side effects may affect up to 1 in 100 people
Rare side effects may affect up to 1 in 1,000 people
Very rare side effects may affect up to 1 in 10,000 people.

4

Possible side effects

What Calcium Folinate contains
- The active substance is: calcium folinate corresponding to
50 mg (5 ml), 100 mg (10 ml), 200 mg (20 ml), 300 mg
(30 ml), and 500 mg (50 ml) of folinic acid, respectively.
- The other ingredients are: sodium chloride, sodium
hydroxide, hydrochloric acid, water for injections.
If you have any further questions on the use of this medicine,
ask your doctor or pharmacist.

Pharmaceutical form and content
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.

93.131.319-A

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is
stated on the package after Exp. The expiry date refers to
the last day of that month.
Store in a refrigerator (2 °C-8 °C) in the original package.
Do not throw away any medicines via wastewater or
household waste. Ask your pharmacist how to throw away
any medicines you no longer use. These measures will help
protect the environment.
If you use more Calcium Folinate than you should
If more Calcium Folinate is given than recommended, the
doctor will treat you as 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. If Calcium Folinate is
given in combination with methotrexate, too much Calcium
Folinate can diminish the effect of methotrexate.

How to store Calcium Folinate

5

Harmful effects of pyrimethamine (a medicine that is used
for the treatment of malaria and for an infection called
toxoplasmosis, caused by a parasite):
If you receive a high dose of pyrimethamine or if
pyrimethamine is taken for a long period, you will receive
5-50 mg Calcium Folinate per day simultaneously.

Reporting of side effects
If you get any side effects, talk to your doctor or
pharmacist. This includes any possible side effects not
listed in this leaflet. You can also report side effects directly
via the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard
By reporting side effects you can help provide more
information on the safety of this medicine.

Other
Very common
Inflammation of the lining of the intestine and mouth
(life-threatening conditions have occurred)
Reduction in the number of blood cells (including
life-threatening conditions)
Common
Redness and swelling of the palms of the hands or soles of
the feet which may cause the skin to peel (hand-foot
syndrome)
Not known
Elevated ammonia level in the blood

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.
Harmful effects of trimethoprim (an antibiotic used to treat
certain infections):
After stopping treatment with trimethoprim, you will
receive 3-10 mg Calcium Folinate daily. Your doctor will
decide on the duration of this treatment.

To counteract the harmful effects of trimetrexate,
trimethoprim, and pyrimethamine:

Other
Uncommon
Fever
When given in combination with the medicine
5-fluorouracil the following side effects may also occur:
Gastrointestinal tract
Very common
Diarrhoea (possibly severe and leading to drying out),
vomiting and nausea

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 “Warnings and precautions” and
“Other medicines and Calcium Folinate” in section 2.
“What you need to know before you use Calcium Folinate”).
Gastrointestinal tract:
Rare:
Gastrointestinal disturbances after administration of high
doses of Calcium Folinate.

11 August 2016

Template

Both therapeutic indications:
Immune system disorders
Very rare, including incidental reports (<0.01%):
Allergic reactions, including anaphylactoid/anaphylactic reactions and urticaria.
Psychiatric disorders
Rare
Insomnia, agitation and depression after high doses.
Gastrointestinal disorders
Rare
Gastrointestinal disorders after high doses.
Neurological disorders
Rare
Increase in the frequency of attacks in epileptics (see also section 4.5 Interaction with other medicinal products and other forms of
interaction).
General disorders and administration site conditions
Uncommon
Fever has been reported 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 toxicities:
Metabolism and nutrition disorder
Not known
Hyperammonaemia
Blood and lymphatic system disorders
Very common
Bone marrow failure, including fatal cases
General disorders and administration site conditions
Very common
Mucositis, including stomatitis and cheilitis. Fatalities have occurred as a result of mucositis.
Skin and subcutaneous tissue disorders
Common
Palmar-Plantar Erythrodysaesthesia
Monthly regimen:
Gastrointestinal disorders
Very common
Vomiting and nausea
General disorders and administration site conditions
Very common
(Severe) mucosal toxicity
No enhancement of other 5-fluorouracil induced toxicities (e.g. neurotoxicity).
Weekly regimen:
Gastrointestinal disorders
Very common
Diarrhoea with higher grades of toxicity, and dehydration, resulting in hospital admission for treatment and even death.
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.
4.9 Overdose
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
followed.
5
PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment ATC code: V03AF03.
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 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
Absorption
Following intramuscular administration of the aqueous solution, systemic availability is comparable to an intravenous administration.
However, lower peak serum levels (Cmax) are achieved.
Metabolism
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.
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.

• 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.

4

Colours Used:

Contents of the pack and other
information

No
420 mm
300 mm
N/A
N/A

6

Dim’s Changed?:
Length:
Width:
Depth:
Foil Width:

Version:

If you forget to use Calcium Folinate
When a dose is forgotten and Calcium Folinate is given in
combination with methotrexate, the toxic effects of
methotrexate can occur (see Patient Information Leaflet of
methotrexate). Consult your doctor when you have any doubt.
If you stop using Calcium Folinate
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 Folinate, can appear. Therefore it is not advised
to stop Calcium Folinate abruptly.
Always consult your doctor in case of any doubts

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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