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REFOLINON 3MG/ML SOLUTION FOR INJECTION

Active substance: CALCIUM FOLINATE

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090177e1843b3b6c\Final\Final On: 21-May-2013 12:50

PATIENT INFORMATION LEAFLET

Refolinon

®

3 mg/ml Solution for Injection
calcium folinate

Read all of this leaflet carefully before you start taking this medicine.
• 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. Do not pass it on to others. It
may harm them, even if their symptoms are the same as yours.
• If any of the side effects gets serious, or if you notice any side effects not
listed in this leaflet, please tell your doctor or pharmacist.
In this leaflet:
1. What Refolinon is and what it is used for
2. Before you are given Refolinon
3. How Refolinon is given to you
4. Possible side effects
5. How to store Refolinon
6. Further information
1. What Refolinon is and what it is used for
Refolinon contains calcium folinate which is chemically related to a vitamin
called folic acid. Refolinon increases the levels of folic acid in your body.
Methotrexate (a medicine used to treat cancer) can lower your body’s levels
of folic acid. Refolinon is used to reverse this and help to maintain folic acid
levels. This is known as ‘calcium folinate rescue’.
You should ask your doctor if you are unsure why you are being given
Refolinon.
2. Before you are given Refolinon
Do not take Refolinon:
• If you are allergic (hypersensitive) to calcium folinate or any of the other
ingredients of Refolinon.
• If you suffer from pernicious anaemia or any anaemia’s where vitamin B12
is deficient.
• If you are pregnant or breast-feeding your doctor will advise if you should
be given Refolinon.

Take special care with Refolinon
Refolinon Injection should only be given to you by intramuscular or
intravenous injection and not by any other routes of administration.
Talk to your doctor or pharmacist before using Refolinon.
• If you currently have, or have had any anaemias that needed treatment.
• If you are taking any other cytotoxic medicines (hydroxycarbamide,
cytarabine, mecaptopurine, thioguanine) as these can lead to
macrocytosis (enlarged red blood cells)
• If you have epilepsy and are taking phenobarbital, phenytoine, primidone,
and succinimides
• If you are taking methotrexate a medicine used in the treatment of cancer
• If you are on a controlled sodium diet
Taking other medicines
Some medicines can affect the way Refolinon works, or Refolinon itself can
reduce the effectiveness of other medicines taken at the same time.
• Refolinon can completely reduce or neutralise the effects of
cotrimoxazole, pyrimethamine when they are used together.
• Refolinon can reduce the effectiveness of drugs used to treat epilepsy
(phenobarbital, phenytoin or primidone) and lead to more frequent
seizures (fits).
• Refolinon may increase the side effects of fluorouracil (used to treat
cancer).
• The effectiveness of Refolinon can be reduced by chloramphenicol (an
antibiotic).
Please tell your doctor or pharmacist if you are taking or have recently taken
any other medicines, including medicines obtained without a prescription.
Pregnancy and Breast-feeding
If you are pregnant, or breast-feeding, think you may be pregnant or are
planning to have a baby, ask your doctor or pharmacist for advice before
taking this medicine.
Driving and using machines
Refolinon is not expected to affect your ability to drive or use machines.
Important information about some of the ingredients of Refolinon
This medicinal product contains less than 1 mmol sodium (23mg) per 30 mg
dose (10ml ) i.e. essentially ‘sodium –free.’
3. How Refolinon is given to you
Your medicine will be given to you by injection under the supervision of a
doctor.

The usual doses in adults and children are as follows:
Treatment of adverse drug reactions and intoxication induced by
folic acid antagonists:
Trimetrexate toxicity: Prevention: Calcium folinate should be administered
every day during treatment with trimetrexate and for 72 hours after the last
dose of trimetrexate.
Overdosage with trimetrexate: Calcium folinate should be administered for
up to 3 days every 6 hours.
Trimethoprim toxicity: After stopping trimethoprim, 3-10 mg/day calcium
folinate until recovery of a normal blood count.
Pyrimethamine toxicity: In case of high dose pyrimethamine or prolonged
treatment with low doses, calcium folinate 5 to 50 mg/day should be
simultaneously administered, based on the results of the peripheral blood
counts.
Refolinon for Calcium folinate rescue:
The dose of medicine given to you will depend on your medical condition,
the dose of methotrexate you have been given and the elimination of
methotrexate from your body.
To reduce the harmful effects of methotrexate the first dose of calcium
folinate is 15 mg given 12 to 24 hours after methotrexate treatment starts.
This is then followed by 15 mg every 6 hours for the next 72 hours.
The level of methotrexate left in your body will be measured 48 hours after
treatment with methotrexate has started. The dose of calcium folinate given
to you may need to be adjusted.
You will be closely monitored during the treatment. If you have any further
questions on this product, ask your doctor or pharmacist.
4. Possible side effects
Like all medicines, Refolinon can cause side effects, although not everybody
gets them.
Tell your doctor immediately if you experience any of the following
symptoms after taking this medicine. Although they are very rare, these
symptoms can be serious.
• An allergic reaction symptoms may include: rash or itching (especially
affecting the whole body), swelling of face, lips or tongue, which may
cause wheezing, difficulty in breathing and swallowing.

You will find more about REFOLINON on
the back of this leaflet

PHYSICIAN LEAFLET

Refolinon

®

3 mg/ml Solution for Injection
calcium folinate

Quantitative and Qualitative Composition
Each ampoule of 2 ml or 10 ml solution contains 3 mg/ml of folinic acid
provided as calcium folinate. Each ampoule also contains water for
injections, sodium chloride, sodium hydroxide and hydrochloric acid (to
adjust the pH), sodium content of 0.192mmol/ampoule and 0.96mmol/
ampoule respectively.
For excipients, see section 6.1.
Uses:
• 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”.
Warning: Calcium folinate should not be given simultaneously with a folic
acid antagonist, for the purpose of reducing or preventing clinical toxicity, as
the therapeutic effect of the antagonist may be nullified.
Posology & Method of Administration:
For intravenous and intramuscular administration only. In the case of
intravenous administration, no more than 160 mg of calcium folinate should
be injected per minute due to the calcium content of the solution.
For intravenous infusion, calcium folinate may be diluted with 0.9% sodium
chloride solution or 5% glucose solution before use. Refer also to sections
6.3 and 6.6.
Calcium folinate rescue in methotrexate therapy:
Since the calcium folinate rescue dosage regimen depends heavily on
the posology and method of the intermediate- or high-dose methotrexate
administration, the methotrexate protocol will dictate the dosage regimen
of calcium folinate rescue. Therefore, it is best to refer to the applied
intermediate or high dose methotrexate protocol for posology and method
of administration of calcium 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 25-50 mg should
be given parenterally due to saturable enteral absorption of calcium folinate.
Calcium folinate rescue is necessary when methotrexate is given at doses
exceeding 500 mg/m² body surface and should be considered with doses
of 100 mg – 500 mg/m² body surface.
Dosage and duration of calcium folinate rescue primarily depend on the type
and dosage of methotrexate therapy, the occurrence of toxicity symptoms,
and the individual excretion capacity for methotrexate. As a rule, the first
dose of calcium folinate is 15 mg (6-12 mg/m²) to be given 12-24 hours
(24 hours at the latest) after the beginning of methotrexate infusion. The
same dose is given every 6 hours throughout a period of 72 hours. After
several parenteral doses treatment can be switched over to the oral form.
In addition to calcium folinate administration, measures to ensure the
prompt excretion of methotrexate (maintenance of high urine output and
alkalinisation of urine) are integral parts of the calcium folinate rescue
treatment. Renal function should be monitored through daily measurements
of serum creatinine.
Forty-eight hours after the start of the methotrexate infusion, the residual
methotrexate-level should be measured. If the residual methotrexate-level is
>0.5 μmol/l, calcium folinate dosages should be adapted according to the
following table:
Additional calcium folinate to be
Residual methotrexate blood level
administered every 6 hours
48 hours after the start of the
for 48 hours or until levels of
methotrexate administration:
methotrexate are lower than
0.05 µmol/l:
≥0.5 µmol/l
15 mg/m2
≥1.0 µmol/l
100 mg/m2
≥2.0 µmol/l
200 mg/m2
Antidote to the folic acid antagonists trimetrexate, trimethoprime, 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 by the
intravenous route at a dose of 20 mg/m² for 5 to 10 minutes every 6 hours
for a total daily dose of 80 mg/m². Daily doses of calcium folinate should be
adjusted depending on the haematological toxicity of trimetrexate.

Overdosage (possibly occurring with trimetrexate doses above
90 mg/m2 without concomitant administration of calcium folinate):
after stopping trimetrexate, calcium folinate 40 mg/m² IV every 6 hours
for 3 days.
Trimethoprime toxicity:
After stopping trimethoprime, 3-10 mg/day calcium folinate until recovery of
a normal blood count.
Pyrimethamine toxicity:
In case of high dose pyrimethamine or prolonged treatment with low doses,
calcium folinate 5 to 50 mg/day should be simultaneously administered,
based on the results of the peripheral blood counts.
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 during pregnancy
and lactation, see section 4.6, Pregnancy and Lactation and the summaries
of product characteristics for methotrexate containing medicinal products.
Special Warnings & 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 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, phenytoine, 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 Interactions).

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Calcium folinate/methotrexate
For specific details on reduction of methotrexate toxicity refer to the SPC of
methotrexate.
Calcium folinate has no effect on non-haematological toxicities of
methotrexate such as the nephrotoxicity resulting from methotrexate and/
or metabolite precipitation in the kidney. Patients who experience delayed
early methotrexate elimination are likely to develop reversible renal failure
and all toxicities associated with methotrexate (please refer to the SPC for
methotrexate). The presence of preexisting- or methotrexate-induced renal
insufficiency is potentially associated with delayed excretion of methotrexate
and may increase the need for higher doses or more prolonged use of
calcium folinate.
Excessive calcium folinate doses must be avoided since this might impair
the antitumour activity of methotrexate, especially in CNS tumours where
calcium folinate accumulates after repeated courses.
Resistance to methotrexate as a result of decreased membrane transport
implies also resistance to folinic acid rescue as both medicinal products
share the same transport system.
An accidental overdose with a folate antagonist, such as methotrexate,
should be treated as a medical emergency. As the time interval between
methotrexate administration and calcium folinate rescue increases, calcium
folinate effectiveness in counteracting toxicity decreases.
The possibility that the patient is taking other medications that interact
with methotrexate (e.g, medications which may interfere with methotrexate
elimination or binding to serum albumin) should always be considered when
laboratory abnormalities or clinical toxicities are observed.
Refolinon solution for injection contains sodium 2.2 mg/ml. To be taken into
consideration by patients on a controlled sodium diet.
Interactions with other medicaments 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. Therefore it should not be
given in conjunction with a folic acid antagonist.
Calcium folinate may diminish the effect of anti-epileptic substances: phenobarbital, primidone, phenytoine 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.

Concurrent administration of chloramphenicol and folic acid in folatedeficient patients may result in antagonism of the haematopoietic
response to folic acid.
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.
Please refer to the SPC for methotrexate, other folate antagonists containing
medicinal products.
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.
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.
Undesirable Effects:
Immune system disorders
Very rare (<0.01%): allergic reactions, including anaphylactoid reactions and
urticaria.
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 Interactions).
General disorders and administration site conditions
Uncommon (0.1-1%): fever has been observed after administration of
calcium folinate as solution for injection.

Overdose
There have been no reported sequelae in patients who have received
significantly more calcium folinate then the recommended dosage. However,
excessive amounts of calcium folinate may nullify the chemotherapeutic
effect of folic acid antagonists.
Special precautions for storage
Store at 2°C - 8°C (in a refrigerator).
Store in original container to protect from light.
Special precautions for disposal and other handling
Prior to administration, calcium folinate should be inspected visually. The
solution for injection or infusion should be clear and yellowish solution. If
cloudy in appearance or particles are observed, the solution should be
discarded. Calcium folinate solution for injection or infusion is intended only
for single use. Any unused potion of the solution should be disposed of in
accordance with local requirements.
Package Quantities: Refolinon Injection - 10 x 2 ml ampoules, 5 x 10 ml
ampoules and 10 x 10 ml ampoules.
POM
PL 00057/1039
Product Licence Holder:
Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK.
Further information is available to the medical and allied professional on
request from:
Medical Information Department, Pfizer Limited, Walton Oaks, Dorking
Road, Tadworth, KT20 7NS - Tel: 01304 616161
Leaflet last revised to 05/2013

The following side effects are listed below by frequency:
Uncommon: may affect up to 1 in 100 people
• Fever after the injection
Rare: may affect up to 1 in 1000 people
• sleeplessness
• agitation
• depression
• disorders affecting the intestines after high doses of Refolinon.
• increased amount of epileptic attacks if you are epileptic due to Refolinon
interacting with your epilepsy medicines.
If any of the side effects gets serious, or if you notice any side effects not
listed in this leaflet, please tell your doctor or pharmacist.
5. How to store Refolinon
Keep out of the sight and reach of children.
Refolinon should not be used after the expiry date printed on the box and
on the ampoule after EXP. The expiry date refers to the last day of the
month.
Store your medicine in the fridge at 2°C-8°C, store in its original container to
protect from light.
Medicines should not be disposed of via wastewater or household waste.
Ask your pharmacist how to dispose of medicines no longer required. These
measures will help to protect the environment.
6. Further information
What Refolinon contains
The active substance in Refolinon Injection is folinic acid. Each ml of solution
contains 3 mg of folinic acid as the calcium salt (calcium folinate).
Other ingredients are: water for injections, sodium chloride, hydrochloric
acid and sodium hydroxide (to adjust pH), sodium content of 0.192mmol/
ampoule (2 ml) or 0.96mmol/ampoule (10 ml)
What Refolinon looks like and contents of the pack
Refolinon Injection is a sterile, clear, pale yellow liquid for injection.
The 2 ml ampoules are packed in a carton of 10 ampoules
The 10 ml ampoules are packed in cartons of 5 or 10 ampoules

Marketing Authorisation Holder
Pfizer Limited
Ramsgate Road
Sandwich, Kent
CT13 9NJ
Manufacturer
Orion Corporation
P O Box 65
02101 Espoo
Finland
Leaflet last revised to 05/2013
Ref: RE 8_0

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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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