Lederfolin: detailed information

Package leaflet: Information for the user

LEDERFOLIN 7.5 mg tablets, 2.5 mg granules for oral solution, 25 mg powder for injectable solution for intravenous use

Calcium levo-folinate
Please read all of this leaflet carefully before taking 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 other people, 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 Lederfolin is and what it is used for
What you need to know before taking Lederfolin
How to take Lederfolin
Possible side effects
How to store Lederfolin
Contents of the pack and other information

1. What Lederfolin is and what it is used for

Lederfolin contains the active substance calcium levo-folinato, which belongs to a group of medicines called "antidotes for cytostatic therapy". Calcium levo-folinato is derived from folic acid and is essential for DNA synthesis, an organic substance containing all the genetic information required for cell function.
Lederfolin is used:

as an antidote against medicines that inhibit the action of folic acid and to counteract the side effects of two anticancer drugs: aminopterin and methotrexate.
to treat anaemias caused by folate deficiency.

2. What you need to know before taking Lederfolin

Do not take Lederfolin:

if you are allergic to calcium leucovorin or to any of the other ingredients of this medicine (listed in section 6); Lederfolin must not be used concomitantly with ceftriaxone (an antibiotic), even when separate infusion lines are used, as renal problems due to calcium-ceftriaxone deposits have been reported.

Warnings and precautions
Talk to your doctor or pharmacist before taking Lederfolin.
Use this medicine in combination with methotrexate (an antitumor medicine) only under the direct supervision of a physician experienced in the use of anticancer drugs.
This medicine must not be administered by injection into the lumbar region of the spinal column (intrathecal administration). Intrathecal administration of Lederfolin, performed to counteract an excessive intrathecal dose of methotrexate, may result in death.
Please consult your doctor before taking Lederfolin if you think any of the following conditions apply to you:

you are undergoing cancer treatment with any of the following medicines: hydroxyurea, cytarabine, mercaptopurine, thioguanine, methotrexate, 5-fluorouracil, or similar medicines;
you have epilepsy and are being treated with any of the following medicines: phenobarbital, phenytoin, primidone, or succinimides. Combination with Lederfolin may lead to an increased frequency of epileptic seizures.

Laboratory tests
If your condition requires treatment with Lederfolin in combination with methotrexate, your doctor will prescribe frequent blood and urine tests. During treatment, foods (e.g. cheese, egg yolk, white and red meat, fish; nuts, legumes, and cereals), beverages (e.g. fruit juices such as cranberry juice, yogurt), and medicines that may increase urinary acidity (e.g. those containing bicarbonate) should be avoided.

Other medicines and Lederfolin
Inform your doctor if you are taking, have recently taken, or might take any other medicine.
Inform your doctor if you are being treated with:

methotrexate (a medicine used to treat certain cancers, rheumatic diseases, and skin conditions);
co-trimoxazole, ceftriaxone, and chloramphenicol (antibiotics used to treat bacterial infections);
pyrimethamine (a medicine used for malaria);
phenobarbital, primidone, phenytoin, succinimides (medicines used to treat epilepsy);
5-fluorouracil (an anticancer medicine) and similar medicines. 5-fluorouracil must not be combined with Lederfolin in the same injection or intravenous infusion.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor before taking this medicine.

Pregnancy
Anemias during pregnancy due to increased folate requirements can be improved or normalized with Lederfolin. No harmful effects of folic acid administered during pregnancy are known.

Breastfeeding
Calcium leucovorin passes into breast milk. Your doctor will prescribe Lederfolin only if clearly necessary.

Driving and using machines
It is not known whether Lederfolin affects the ability to drive or use machinery.

Lederfolin 7.5 mg tablets contain lactose.
If your doctor has diagnosed you with an intolerance to certain sugars, contact him/her before taking this medicine.

Lederfolin 2.5 mg oral granules for solution contain sucrose.
If your doctor has diagnosed you with an intolerance to certain sugars, contact him/her before taking this medicine.

Lederfolin contains sodium
Lederfolin 7.5 mg tablets contain less than 1 mmol (23 mg) of sodium per tablet, i.e. essentially ‘sodium-free’.
Lederfolin 25 mg Powder for injectable solution for intravenous use contains less than 1 mmol (23 mg) of sodium per vial, i.e. essentially ‘sodium-free’.

3. How to take Lederfolin

Take this medicine exactly as instructed by your doctor. If you have any doubts,
consult your doctor.
Lederfolin 7.5 mg tablets and Lederfolin 2.5 mg oral granules for solution are administered
by oral route. Lederfolin 25 mg powder for injectable solution may be administered
intravenously either rapidly (by intravenous injection) or slowly (by infusion).
In case of intravenous administration, no more than 80 mg of calcium leucovorin per minute
should be injected due to the calcium content of the solution.
Lederfolin must not be administered intrathecally (by injection into the lumbar region of the
spinal column).

Use in combination with other antitumour medicines
Lederfolin may be used in combination with antitumour medicines such as methotrexate to reduce its side effects. Your doctor will decide the most appropriate dose for you based on your condition and other medicines you are taking.
Treatment of folate deficiency anaemias
The recommended initial dose is 7.5 mg daily by oral route for 10–15 days.

If improvement occurs, your doctor may decide to halve the dose until anaemia and its
symptoms have resolved.

If you take more Lederfolin than you should
If you take more Lederfolin than recommended, contact your doctor immediately.
No side effects have been reported in individuals who have taken much higher doses of calcium
leucovorin than recommended.
If you have any questions about the use of this medicine, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.
Contact your doctor immediately if you experience any of the following side effects, as they may be serious, and the doctor may decide to discontinue treatment with Lederfolin:

Stevens-Johnson syndrome, a severe acute hypersensitivity reaction affecting the skin and mucous membranes in various parts of the body, with formation of necrotic areas 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;
Very rare (may affect up to 1 in 10,000 people): severe allergic reaction (anaphylactic shock) – you may experience hives, swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing), and you may feel like you are about to faint. This is a serious side effect. You may need urgent medical treatment.

Uncommon side effects (may affect up to 1 in 100 people):

fever

Rare side effects (may affect up to 1 in 1,000 people):

seizures (involuntary, sudden and uncontrolled movements);
increased frequency of epileptic seizures (uncontrolled body movements and loss of consciousness);
sudden and transient loss of consciousness (syncope);
depression;
agitation;
gastrointestinal problems (stomach and intestine);
insomnia (difficulty falling asleep, staying asleep, poor sleep quality).

Side effects occurring with the use of Lederfolin 25 mg powder for injectable solution in combination with the anticancer medicine 5-fluorouracil:
The following side effects depend on the dose of 5-fluorouracil used. Contact your doctor immediately if you experience any of the following side effects, as they may be serious (sometimes fatal), and the doctor may decide to discontinue treatment with Lederfolin:

severe stomach and intestinal problems, which may also include inflammation of the mucous membranes and diarrhea;
Very common (may affect more than 1 in 10 people): reduced production of blood cells such as red blood cells (anemia), white blood cells (increased susceptibility to infections), and platelets (bleeding) by the bone marrow (myelosuppression), including fatal cases;
Very common (may affect more than 1 in 10 people): inflammation of the mouth and throat (mucositis, stomatitis) (deaths due to mucositis have occurred), and
inflammation of the skin of the lips, manifesting as cracks, swelling, and small ulcerations starting from the corners or edges and spreading to the lips (cheilitis).

Very common side effects (may affect more than 1 in 10 people):

nausea;
vomiting;
severe diarrhea;
dehydration, which may result from diarrhea, requiring hospitalization for treatment and, in some cases, leading to death.

Common side effects (may affect up to 1 in 10 people):

redness and swelling of the palms of the hands and soles of the feet, which may lead to peeling (hand-foot syndrome).

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

excessive ammonia levels in the blood (hyperammonemia).

Other side effects:

low blood pressure (hypotension);
increased heart rate (tachycardia);
bronchial constriction causing breathing difficulties (bronchospasm).

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 the following website:
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Lederfolin

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton, blister pack, and bottle after "Exp.". The expiry date refers to the last day of that month.

Lederfolin 7.5 mg tablets
Store below 25°C.
Keep the blister pack in the outer packaging to protect the medicine from light.

Lederfolin 2.5 mg oral granules for solution
Do not store above 25°C.

Lederfolin 25 mg powder for injectable solution
Do not store above 25°C.
The reconstituted solution must be used within 12 hours and stored in the refrigerator (2°C – 8°C).

Do not dispose of medicines 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 Lederfolin contains
The active substance is calcium levo-folinato hydrate.
Each Lederfolin 7.5 mg tablet contains 9.53 mg of calcium levo-folinate hydrate, equivalent to
7.5 mg of levo-folinic acid.
The other components are: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate,
anhydrous colloidal silicon dioxide, magnesium stearate.
Each sachet of Lederfolin 2.5 mg granules for oral solution contains 3.18 mg of calcium levo-
folinate hydrate, equivalent to 2.5 mg of levo-folinic acid.
The other components are: sucrose, strawberry flavoring.
Each vial of Lederfolin 25 mg powder for injectable solution contains 31.77 mg of calcium
levo-folinate hydrate, equivalent to 25 mg of levo-folinic acid.
The other components are: mannitol, sodium hydroxide and/or hydrochloric acid (for pH adjustment).

Description of the appearance of Lederfolin and contents of the pack
Lederfolin 7.5 mg tablets are oval-shaped, whitish tablets, marked “LL” on one side and “7.5” on the other. The tablets are available in blisters, packs containing 10 tablets.
Lederfolin 2.5 mg granules for oral solution are packed in sachets containing light yellow granules. This medicinal product is available in packs of 20 and 30 sachets.
Lederfolin 25 mg powder for injectable solution is supplied in a pack containing 1 glass vial.
Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
Pfizer Italia S.r.l.
Via Isonzo, 71
04100 Latina
Italy

Manufacturer
Lederfolin 7.5 mg tablets
Farmasierra Manufacturing S.L.(CM)
Carretera de Irun, Km. 26,200
28700 San Sebastián de los Reyes
Madrid (Spain)

Lederfolin 2.5 mg granules for oral solution
Pfizer Consumer Manufacturing Italy S.r.l.
Via Nettunense, 90
Aprilia (LT)
Italy

Lederfolin 25 mg powder for injectable solution
Wyeth Lederle S.r.l.
Via F. Gorgone 6
Z.na Ind.le Catania
95030 Catania
Italy

The following information is intended exclusively for doctors and healthcare professionals

There is no indication for the use of Lederfolin in pernicious anemia or in other
megaloblastic anemias due to vitamin B12 deficiency.
Dosage
Lederfolin may be administered orally, intravenously, or by infusion. In case of
intravenous administration, no more than 80 mg of calcium levofolinate per
minute should be injected due to the calcium content of the solution.
Use of calcium levo-folinate (Lederfolin) within specific antineoplastic chemotherapy protocols
involving high-dose methotrexate.
Based on the most recent evidence, Lederfolin is used in a sequential antidote regimen (Lederfolin "rescue") to improve the therapeutic index of methotrexate. By adopting treatment regimens involving high-dose methotrexate and Lederfolin, better control of tumor forms can be achieved without significant increases in toxicity. The therapeutic protocol includes intravenous administration of Lederfolin in the initial phase, corresponding to competitive antidotal action, followed by oral administration (tablets) in the second phase, where the biochemical-metabolic component predominates. However, standardized dosage regimens have not yet been definitively established.
Since calcium levo-folinate is an antagonist of methotrexate, their concomitant
administration should only be performed after defining a specific therapeutic protocol for each individual case. For this purpose, consultation of the most recent literature on the subject is recommended.
Antidote in case of methotrexate overdose.
Lederfolin must not be administered intrathecally.
Lederfolin (calcium levo-folinate), the specific antidote for methotrexate, can neutralize the toxic effects exerted by the antimetabolite on the hematopoietic system and on the mucous membranes of the digestive tract. In its role as an antidote, Lederfolin is used at different dosages depending on the desired effect. In cases of accidental overdose, to achieve a competitive effect, intravenous infusion of Lederfolin is recommended (up to 50 mg within 12 hours); to achieve a biochemical-metabolic effect, intravenous Lederfolin (5–6 mg every 6 hours for 4 doses) or oral administration (7.5 mg every 6 hours for 4 doses) is recommended. In cases of accidental administration, Lederfolin should be administered at doses equal to or higher than those of methotrexate within the first hour; administration of Lederfolin at later times is less effective.
Lederfolin must not be administered intrathecally. Death has been reported following intrathecal administration of calcium levo-folinate after intrathecal overdose of methotrexate.
Calcium (levo-) folinate must not be combined with 5-fluorouracil in the same injection or intravenous infusion.
Reconstitution

The powder for injectable solution can be reconstituted with 5.3 ml of water for injectable preparations;
For infusion, use physiological saline solution.
The resulting solution may be stored for a maximum of 12 hours and must be kept refrigerated (2°C–8°C). Instructions for use
After reconstitution, the solution must be clear and yellowish. Do not administer if the solution appears cloudy or contains suspended particles;
The reconstituted solution must be used only once. Any unused portion of the solution must be disposed of in accordance with local regulations. Incompatibilities Incompatibility has been reported between injectable forms of calcium levo-folinate and injectable forms of the following drugs: droperidol, foscarnet, methotrexate, and fluorouracil. The following solutions must not be administered through the same infusion line due to the risk of precipitate formation:
Droperidol 1.25 mg/0.5 ml and calcium levo-folinate 5 mg/0.5 ml
Droperidol 2.5 mg/0.5 ml and calcium levo-folinate 10 mg/0.5 ml
Foscarnet 24 mg/ml and calcium levo-folinate 20 mg/ml
5-fluorouracil must not be mixed with calcium levo-folinate in the same injection or intravenous infusion. If the two drugs are administered sequentially through the same infusion line, it is recommended to flush the line with 9 mg/ml (0.9%) sodium chloride injectable solution.

Package leaflet: Information for the user

LEDERFOLIN 100 mg powder for solution for infusion, 175 mg powder for solution for infusion

Calcium levo-folinato
Please read this leaflet carefully before this medicine is administered to you 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 nurse.
If you experience any side effects, including those not listed in this leaflet, tell your doctor or nurse. See section 4.

Contents of this leaflet:

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

1. What Lederfolin is and what it is used for

Lederfolin contains the active substance calcium levo-folinate, which belongs to a group of medicines called “antidotes for cytostatic treatments”. Calcium levo-folinate is derived from folic acid and is essential for DNA synthesis, an organic substance containing all the genetic information required for cell function.
Lederfolin is used in combination with anticancer drugs called fluoropyrimidines for:

the treatment of colon and rectal cancer when it has spread to various parts of the body (metastases) and when it no longer responds to specific treatments;
the prevention of recurrence of colon and rectal cancer after complete surgical removal of the tumour.
Lederfolin is also used for:
counteracting the side effects of methotrexate and other similar anticancer medicines when administered at high doses in the treatment of tumours that no longer respond to specific therapies.

2. What you need to know before Lederfolin is administered

Lederfolin must not be administered:

if you are allergic to calcium leucovorin or to any of the other ingredients of this medicine (listed in section 6); Lederfolin must not be used concomitantly with ceftriaxone (an antibiotic), even when separate infusion lines are used, due to the occurrence of kidney problems caused by calcium-ceftriaxone deposits.

Warnings and precautions
Consult your doctor or nurse before this medicine is administered.

This medicine must not be administered by injection into the lower spine (intrathecal administration). Intrathecal administration of Lederfolin, when used to counteract an excessive intrathecal dose of methotrexate, may result in death.
Consult your doctor before Lederfolin is administered if you think any of the following apply to you:

you are undergoing cancer treatment with any of the following medicines: hydroxyurea, cytarabine, mercaptopurine, thioguanine, methotrexate, 5-fluorouracil, or similar medicines; you have epilepsy and are being treated with any of the following medicines: phenobarbital, phenytoin, primidone, succinimides. The combination with Lederfolin may increase the frequency of epileptic seizures.

Laboratory tests
If your condition requires treatment with Lederfolin in combination with methotrexate or 5-fluorouracil, your doctor will prescribe frequent blood and urine tests. During treatment, you should avoid foods (e.g. cheese, egg yolk, white and red meat, fish; nuts, legumes, and cereals), beverages (e.g. fruit juices such as cranberry juice and yogurt), and medicines that may increase urinary acidity (e.g. those containing bicarbonate).

Other medicines and Lederfolin
Inform your doctor if you are taking, have recently taken, or might take any other medicines.
Inform your doctor if you are being treated with:

methotrexate (a medicine used to treat certain cancers, rheumatic diseases, and skin conditions);
cotrimoxazole, ceftriaxone, and chloramphenicol (antibiotics used to treat bacterial infections);
pyrimethamine (a medicine used for malaria);
phenobarbital, primidone, phenytoin, succinimides (medicines used to treat epilepsy);
5-fluorouracil (an anticancer medicine) and similar medicines. 5-fluorouracil must not be combined with Lederfolin in the same injection or intravenous infusion.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor or nurse before this medicine is administered.

Pregnancy
Anemias during pregnancy due to increased folate requirements may be improved or normalized with Lederfolin.

Breastfeeding
Calcium leucovorin passes into breast milk. Your doctor will prescribe Lederfolin only if clearly necessary.

Driving and using machines
It is not known whether Lederfolin affects the ability to drive vehicles or use machinery.

Lederfolin contains sodium
Lederfolin contains less than 1 mmol (23 mg) of sodium per vial, i.e. it is essentially ‘sodium-free’.

3. How to use Lederfolin

Your doctor will decide the amount of medicine to use based on the disease being treated and any other medicines you may be taking.
If you have been given more Lederfolin than you should have
No side effects are known in subjects who have received much higher doses of calcium levo-folinate than recommended.
If you have any doubts about the use of this medicine, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although
not everyone experiences them.
Contact your doctor immediately if you experience any of the following side effects,
as they may be serious, and your doctor may decide to stop treatment with Lederfolin:

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; Very rare (may affect up to 1 in 10,000 people): severe allergic reaction (anaphylactic shock) – symptoms may include hives, swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty swallowing or breathing), and you may feel like you are about to faint. This is a serious side effect and may require urgent medical treatment. Uncommon side effects (may affect up to 1 in 100 people):
fever Rare side effects (may affect up to 1 in 1,000 people):
seizures (sudden, involuntary, uncontrolled movements);
increased frequency of epileptic seizures (uncontrolled body movements and loss of consciousness)
sudden and transient loss of consciousness (syncope)
depression
agitation
gastrointestinal problems (stomach and intestine)
insomnia (difficulty falling asleep, staying asleep, poor sleep quality) Side effects following administration of Lederfolin together with the anticancer medicine 5-fluorouracil. The following side effects depend on the dose of 5-fluorouracil used.

Contact your doctor immediately if you experience any of the following side effects,
as they may be serious (sometimes fatal), and your doctor may decide to stop
treatment with Lederfolin:

severe stomach and intestinal problems, which may also include inflammation of the mucous membranes and diarrhea; Very common (may affect more than 1 in 10 people): reduced production of blood cells such as red blood cells (anemia), white blood cells (increased susceptibility to infections), and platelets (bleeding) by the bone marrow (myelosuppression), including fatal cases;
inflammation of the mouth and throat (mucositis, stomatitis) (deaths due to mucositis have occurred) and inflammation of the skin of the lips, manifesting as cracks, swelling, and small ulcers starting from the corners or edges and spreading onto the lips (cheilitis);
nausea
vomiting
severe diarrhea
dehydration, which may result from diarrhea, requiring hospitalization for treatment and, in some cases, leading to death
Common side effects (may affect up to 1 in 10 people):
redness and swelling of the palms of the hands and soles of the feet, which may lead to skin peeling (hand-foot syndrome)
Side effects with unknown frequency (frequency cannot be estimated from the available data):
excessive levels of ammonia in the blood (hyperammonemia)
Other side effects:
low blood pressure (hypotension)
increased heart rate (tachycardia)
bronchospasm (constriction of the airways causing breathing difficulties)

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or nurse. You can also report side effects directly via the national reporting system at the following website:
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Lederfolin

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 carton and
vial after “Exp.”. The expiry date refers to the last day of that month.
Do not store above 25°C.
The reconstituted solution must be used within 12 hours and stored in the refrigerator
(2°C – 8°C).
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 Lederfolin contains
The active substance is calcium levo-leucovorin.
Each vial of Lederfolin 100 mg powder for solution for infusion contains
127.08 mg of hydrated calcium levo-leucovorin, equivalent to 100 mg of levo-folic acid.
Each vial of Lederfolin 175 mg powder for solution for infusion contains
222.39 mg of hydrated calcium levo-leucovorin, equivalent to 175 mg of levo-folic acid.
The other components are: mannitol, hydrochloric acid (for pH adjustment),
sodium hydroxide (for pH adjustment).

Description of the appearance of Lederfolin and contents of the pack
Lederfolin 100 mg powder for solution for infusion is available in packs
containing 1 colourless glass vial with rubber stopper and aluminium seal.
Lederfolin 175 mg powder for solution for infusion is available in packs
containing 1 colourless glass vial with rubber stopper and aluminium seal.
Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
Pfizer Italia S.r.l.
Via Isonzo, 71
04100 Latina
Italy

Manufacturer
Wyeth Lederle S.r.l.
Via F. Gorgone 6
Z.na Ind.le Catania
95030 Catania
Italy

The following information is intended exclusively for physicians and healthcare professionals

Healthcare professionals
There is no indication for the use of Lederfolin in pernicious anemia or in other megaloblastic anemias due to vitamin B12 deficiency.
Dosage
During intravenous administration, no more than 80 mg of calcium leucovorin should be injected per minute due to the calcium content of the solution.
In the treatment of colorectal carcinoma in combination with fluoropyrimidines, the dosage of calcium leucovorin is determined according to the adopted chemotherapy protocols.
The most frequently used dosages in combination with 5-fluorouracil are:
100 mg/m²/day for 5 consecutive days as slow infusion (10 min.) every 4 weeks, or
250 mg/m²/week for 6 weeks followed by a 2-week interval.
In high-dose methotrexate "rescue", calcium leucovorin is effective in preventing myelosuppression at doses of 100 mg/m² for serum methotrexate levels of 10 M. Doses may be proportionally increased for higher blood levels of the cytotoxic agent. Lederfolin must not be administered intrathecally.
Lederfolin must not be administered intrathecally. Death has been reported following intrathecal administration of calcium leucovorin after intrathecal overdose of methotrexate.
Calcium (levo-)folinate must not be combined with 5-fluorouracil in the same injection or intravenous infusion.

Reconstitution:

Lederfolin 100 mg powder for solution for infusion: the powder can be reconstituted with 10 ml of water for injectable preparations.
Lederfolin 175 mg powder for solution for infusion: the powder can be reconstituted with 15–20 ml of water for injectable preparations.

Instructions for use:

After reconstitution, the solution must be clear and yellowish in color. Do not administer if the solution appears cloudy or contains suspended particles.
The reconstituted solution must be used only once. Any unused portion of the solution must be disposed of according to local regulations.
The reconstituted solution may be stored for up to 12 hours and must be kept refrigerated (2°C–8°C).

Compatibility
The reconstituted solution is compatible with glucose solution and physiological saline solution.

Incompatibilities
Incompatibility has been reported between injectable forms of calcium leucovorin and injectable forms of the following drugs: droperidol, foscarnet, methotrexate, and fluorouracil.
The following solutions must not be administered through the same infusion line due to the formation of precipitates:

Droperidol 1.25 mg/0.5 ml and calcium leucovorin 5 mg/0.5 ml
Droperidol 2.5 mg/0.5 ml and calcium leucovorin 10 mg/0.5 ml
Foscarnet 24 mg/ml and calcium leucovorin 20 mg/ml
Fluorouracil 50 mg/ml and calcium leucovorin

If the two drugs are administered sequentially through the same infusion line, the line should be flushed with 9 mg/ml (0.9%) sodium chloride solution for injection.