Package leaflet: Information for the user

CITOFOLIN 15 mg tablets

Calcium folinate
Please read this leaflet carefully before using this medicine because it contains
important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
If you experience any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist. See section 4.

Contents of this leaflet

What CITOFOLIN is and what it is used for
What you need to know before taking CITOFOLIN
How to take CITOFOLIN
Possible side effects
How to store CITOFOLIN
Contents of the pack and other information

1. What CITOFOLIN is and what it is used for

CITOFOLIN contains the active substance calcium folinate.
The general therapeutic indication for CITOFOLIN is the treatment of folate deficiency states.
CITOFOLIN is therefore indicated in all forms of anemia due to folate deficiency caused by increased demand, reduced utilization, and/or inadequate dietary intake of folates.
In addition, calcium folinate is useful as an antidote to treat excessive doses of folic acid antagonists and to counteract the adverse effects induced by antineoplastic medicinal products such as aminopterin or methotrexate.

2. What you should know before taking CITOFOLIN

Do not take CITOFOLIN

if you are allergic to calcium folinate or to any of the other ingredients of this medicine (listed in section 6).
if you have a type of anaemia caused by vitamin B12 deficiency. CITOFOLIN must not be used for this type of anaemia because it may cause an apparent improvement in the condition, masking the progression of damage to the central nervous system.

Warnings and precautions
Talk to your doctor or pharmacist before taking CITOFOLIN if you think any of the following
conditions apply to you:

you are undergoing cancer treatment with any of the following medicines: hydroxycarbamide, cytarabine, mercaptopurine, thioguanine. These medicines may cause the formation in the blood of red blood cells larger than normal
(a condition known as "macrocytosis"). This condition must not be treated with
CITOFOLIN;
you have epilepsy and are being treated with any of the following medicines: phenobarbital, phenytoin, primidone, succinimides. Taking these together with CITOFOLIN may increase the frequency of epileptic seizures. Your doctor will monitor you frequently and may adjust the dose of your anti-epileptic medicine during and after treatment with CITOFOLIN (see section Interactions with other medicines and CITOFOLIN);
you are being treated for cancer with medicines belonging to the class of fluoropyrimidines, especially if the cancer has spread to the central nervous system. Treatment with CITOFOLIN together with these medicines may, although rarely, cause seizures and syncope (see section Interactions with other medicines and CITOFOLIN);
you have been treated with excessive doses of anticancer medicines that block the detoxifying action of folic acid. CITOFOLIN should be administered within 1 hour after administration of the anticancer medicine, as this medicine becomes ineffective after 4 hours.

CITOFOLIN must not be administered for the treatment of pernicious anaemia or other
megaloblastic anaemias due to vitamin B12 deficiency unless given in combination with vitamin B12; otherwise, haematological symptoms may improve while neurological manifestations continue to progress. Therapy should therefore be carried out under haematological monitoring.
Administration of CITOFOLIN must be performed carefully in order to avoid the risk of allergic reactions and adverse effects.

Interactions with other medicines
Tell your doctor if you are taking, have recently taken, or might take any other
medicines. CITOFOLIN may reduce the effectiveness of the following medicines:

medicines such as methotrexate, co-trimoxazole and pyrimethamine. Calcium folinate, the active substance in CITOFOLIN, may reduce the effectiveness of these medicines, even completely neutralizing them;
medicines for the treatment of epilepsy such as phenobarbital, primidone, phenytoin, succinimides. Calcium folinate may decrease the effectiveness of these medicines, resulting in an increased frequency of epileptic seizures.
CITOFOLIN may increase certain adverse effects caused by treatment with medicines belonging to the class of fluoropyrimidines (see section Warnings and precautions).

Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding,
ask your doctor for advice before taking this medicine.

Driving and using machines
It is not known whether CITOFOLIN affects the ability to drive or use machinery. If in doubt,
consult your doctor.

CITOFOLIN 15 mg tablets contain lactose.
If your doctor has diagnosed you with an intolerance to certain sugars, contact him or her before taking
this medicine.

3. How to take CITOFOLIN

Use in the treatment of anemias due to folate deficiency: the recommended dose of CITOFOLIN
for oral use may be indicated as one tablet (equivalent to 15 mg of folinic acid) daily or on alternate
days, according to medical prescription. Dosages to be used will be determined by the physician based on
the hematological profile. Treatment with CITOFOLIN should be continued until complete
remission of the clinical signs of folate deficiency and normalization of the hematological profile.
Use of calcium folinate within specific antineoplastic chemotherapy protocols involving
high-dose methotrexate: based on recent evidence, calcium folinate is used in a sequential regimen as
an antidote ("rescue" with calcium folinate) to improve the therapeutic index of methotrexate at high doses.
This approach has allowed better control of the tumor disease without significant increases in toxicity.
The therapeutic protocol includes the use of calcium folinate:

by parenteral route, in the initial phase corresponding to competitive antidotal action;
by oral route, in the subsequent phase where the biochemical-metabolic component predominates.

Currently, however, standardized dosage regimens have not been precisely defined. Since
calcium folinate is an antagonist of methotrexate, their concomitant administration can only be performed
when a specific therapeutic protocol has been established for each individual case.
Antidote in case of methotrexate overdose: calcium folinate, the specific antidote of
methotrexate, can neutralize the toxic effects exerted by the antimetabolite methotrexate on the
hematopoietic system and on the mucous membranes of the digestive tract. In its role as an antidote,
calcium folinate is administered at different dosages depending on the desired effect.
In cases of accidental overdose, to achieve a competitive effect, intravenous infusion of calcium
folinate is recommended (up to 100 mg within the first 12 hours); to achieve a biochemical-metabolic
effect, calcium folinate is recommended by intramuscular or intravenous route or orally (15 mg every 6 hours for 4 doses).
In cases of adverse effects from conventional doses of methotrexate, calcium folinate is recommended
by intramuscular or intravenous route or orally (15 mg every 6 hours for 4 doses).
In cases of accidental administration, calcium folinate should be taken at doses equal to or higher than
those of methotrexate within the first hour, since administration at later times is less effective.
Calcium folinate administration must be performed carefully to avoid the risk of allergic reactions and
adverse effects.
If you take more CITOFOLIN than you should
If you take more CITOFOLIN than recommended, contact your doctor immediately.
To date, no toxic effects from overdose have been reported for CITOFOLIN, even with doses
much higher than the therapeutic ones.
However, excessive amounts of calcium folinate may negate the chemotherapeutic effects of
folic acid antagonists.

4. Possible side effects

Contact your doctor immediately if you experience the following side effects, as they may be
serious and your doctor may decide to discontinue treatment with CITOFOLIN:

Stevens-Johnson syndrome, a severe acute hypersensitivity reaction affecting the skin and mucous membranes in various parts of the body, with areas of necrosis and skin peeling. This reaction can sometimes be fatal;
Toxic Epidermal Necrolysis, a severe acute hypersensitivity reaction, with almost complete necrosis of the skin and mucous membranes. This reaction can be fatal;
Like all medicines, this medicine can cause side effects, although not everybody gets them.

Uncommon (affects up to 1 in 100 people):

fever

Rare (affects up to 1 in 1,000 people):

increased frequency of seizures in epileptic patients
sudden and transient loss of consciousness (syncope)
depression
agitation
gastrointestinal disorders
sleep difficulties (insomnia)

Very rare (affects up to 1 in 10,000 people):

Severe allergic reactions (anaphylactoid/anaphylactic reactions, including shock), which may present as sudden rash and itching (urticaria), swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing), and feeling faint. This is a serious side effect requiring urgent medical attention.

Side effects with unknown frequency (frequency cannot be estimated from the available data):

inflammation of the lip skin, manifesting as cracks, swelling and small ulcers starting from the corners or edges and spreading onto the lips (cheilitis);
kidney problems caused by calcium-ceftriaxone deposits. You may experience pain when urinating, or a reduced amount of urine produced.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at
http://www.agenziafarmaco.gov.it/content/come-segnalare-una-sospetta-reazione-avversa.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store CITOFOLIN

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 packaging after "Exp.".
The expiry date refers to the last day of that month. This date applies to the product in its original,
intact packaging and stored correctly.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What CITOFOLIN contains

The active substance is calcium folinate. The tablets contain 16.2 mg of anhydrous calcium folinate (equivalent to 15 mg of folinic acid).
The other components are: lactose monohydrate, talc, magnesium stearate, microcrystalline cellulose.

Description of the appearance of CITOFOLIN and package contents
Box containing a PVC/PP/Al blister pack with 10 tablets of 15 mg
Marketing Authorization Holder
SUBSTIPHARM 24 rue Erlanger, 75016 Paris - France
Marketing Authorization Holder's Representative in Italy
SUBSTIPHARM S.r.l. Via Felice Casati, 20 – 20124 Milano
Manufacturers
Patheon Italia S.p.A. - 20900 Monza
Alternatively
Doppel Farmaceutici S.r.l.
Via Volturno, 48
Quinto De’ Stampi 20089 Rozzano (MI)