ISOVORIN 175 mg POWDER FOR INJECTABLE SOLUTION AND FOR INFUSION

Introduction

Package Leaflet: Information for the Patient

Isovorin 175 mg Powder for Solution for Injection and Infusion

Levofolinic Acid

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.

• Keep this leaflet, you may need to read it again.

If you have any further questions, ask your doctor, pharmacist, or nurse.

• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.

• If you experience any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the Package Leaflet

1. What Isovorin is and what it is used for
2. What you need to know before you use Isovorin
3. How to use Isovorin
4. Possible side effects

5. Storage of Isovorin

1. Contents of the pack and further information

1. What Isovorin is and what it is used for

Isovorin contains levofolinic acid, which is the active form of folic acid. Levofolinic acid acts as an antidote to folic acid antagonists and belongs to the group of medicines called detoxifying agents for the treatment of tumors.

This medicine is used in the following cases:

• To reduce the side effects and treat overdose of certain cancer medicines such as methotrexate (and other folic acid antagonists).
• Used in combination with 5-fluorouracil, as it increases the effect of the latter, in the treatment of patients with cancer.

2. What you need to know before you use Isovorin

Do not use Isovorin:

• if you are allergic to levofolinic acid or any of the other ingredients of this medicine (listed in section 6).
• if you have anemia (a disorder characterized by a decrease in the number of red blood cells and/or hemoglobin in the blood), whether pernicious or other megaloblastic anemias secondary to vitamin B12 deficiency.
• if you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before starting to use Isovorin.

Your doctor will inform you about the benefits and risks of treatment with Isovorin, as well as the symptoms that may indicate possible toxicity due to the medicine.

If you are in any of the following situations, consult your doctor before using this medicine:

• If you have pernicious anemia and other megaloblastic anemias resulting from vitamin B12 deficiency.
• If you have blood problems caused by cancer medicines.

• If you are being treated with methotrexate or 5-fluorouracil. It is essential that you strictly follow the dose of Isovorin prescribed by your doctor, as non-compliance may cause excessive toxicity or lack of efficacy of methotrexate.
• If you have diarrhea, as this may be a symptom of gastrointestinal toxicity.
• If you have received prior radiotherapy.
• If you have taken an accidental overdose of methotrexate.
• If you are epileptic and are being treated with phenobarbital, phenytoin, primidone, and succinimides, as there is a risk of increased frequency of seizures (see section "Other medicines and Isovorin").

Levofolinic acid should not be administered intrathecally (in the spinal cord).

Children and adolescents

There are no data on the efficacy and safety in children and adolescents under 18 years of age.

Other medicines and Isovorin

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines.

In particular, tell your doctor if you are using the following medicines:

• Folic acid antagonist medicines such as cotrimoxazole, pyrimethamine, or chloramphenicol, as levofolinic acid may reduce their efficacy.
• Antiepileptic medicines (such as phenobarbital, phenytoin, succinimides, or primidone), as high doses may partially reduce their effect and increase the frequency of seizures (see section "Warnings and precautions").
• Medicines such as methotrexate or 5-fluorouracil. Folinic acid calcium should only be used with methotrexate or 5-fluorouracil under the direct supervision of an experienced doctor in the use of cancer chemotherapeutic agents.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicine. No adequate and well-controlled clinical studies have been conducted in pregnant or breastfeeding women.

It is unknown whether calcium levofolinate passes into breast milk. Your doctor will decide whether it is necessary for you to take this medicine according to the therapeutic indications.

No fertility studies have been conducted with calcium folinate.

Driving and using machines

This medicine has no effects on the ability to drive vehicles or use machines.

This medicine contains sodium

This medicine contains less than 1 mmol (23 mg of sodium) per dose unit; i.e., it is essentially "sodium-free".

3. How to use Isovorin

Your doctor will determine the dose and duration of treatment, as well as the most suitable route of administration for you, according to your condition and response to treatment.

This medicine should not be administered intrathecally (in the spinal cord).

This medicine should only be administered intravenously or intramuscularly. In the case of intravenous administration, no more than 160 mg of calcium levofolinate should be injected per minute due to the calcium content of the solution.

Rescue with calcium levofolinate in methotrexate therapy

If you have been administered a dose of methotrexate greater than 500 mg/m2, you should receive levofolinate thereafter. When administering methotrexate doses between 100 mg/m2 - 500 mg/m2, your doctor may consider rescue administration.

Rescue with levofolinate will be started 12-24 hours after the start of methotrexate infusion, with doses of 7.5 mg (approximately 5 mg/m2) of levofolinate every 6 hours, for 72 hours.

Combined treatment with 5-fluorouracil

Since calcium levofolinate increases the activity and toxicity of 5-fluorouracil, treatment with the combination of both should be supervised by an experienced doctor in the use of cancer chemotherapeutic agents.

Antidote for folic acid antagonists

This medicine can be used to reverse toxicity due to trimetrexate, trimethoprim, or pyrimethamine. Your doctor will determine the treatment regimen.

If you use more Isovorin than you should

This medicine will be administered to you in the hospital, so it is unlikely that you will receive more than you should; no significant harm has been reported in patients who have received significantly higher doses of calcium levofolinate than recommended.

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, phone: 91 562 04 20, indicating the medicine and the amount ingested.

If you forget to use Isovorin

Your doctor or nurse has the instructions for when to administer your medicine. It is unlikely that you will not be administered the medicine as prescribed. If you are aware that you have not been administered your dose, contact your doctor or pharmacist immediately.

4. Possible side effects

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

The following side effects are uncommon (may affect up to 1 in 100 people):

• Fever.

The following side effects are rare (may affect up to 1 in 1,000 people):

• Seizures and/or fainting.
• Depression.
• Agitation.
• Digestive problems.
• Difficulty sleeping (insomnia).

The following side effects are very rare (may affect up to 1 in 10,000 people):

• Severe allergic reaction: you may experience a sudden rash with itching (urticaria), 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 going to faint. This is a serious side effect. You may need urgent medical attention.

The adverse reactions when administering levofolinic acid in combination with 5-fluorouracil are:

The following side effects are very common (may affect more than 1 in 10 patients):

• Nausea, vomiting, diarrhea.
• Inflammation of the mucous membranes of the intestine and mouth (in some cases fatal).
• Decrease in the number of blood cells (in some cases fatal).

The following side effects are common (may affect up to 1 in 10 patients):

• Redness and swelling on the palms of the hands or soles of the feet, which can cause the skin to peel (hand-foot syndrome).

The following side effects have a frequency that cannot be estimated from the available data:

• Increased ammonia levels in the blood.

Reporting of side effects:

If you experience any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly through the Spanish Medicines and Healthcare Products Agency (AEMPS) website: www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Isovorin

Keep this medicine out of the sight and reach of children.

Do not store above 30°C and protect from light.

Do not use this medicine after the expiry date stated on the packaging after EXP. The expiry date is the last day of the month indicated.

6. Contents of the pack and further information

Composition of Isovorin

• The active substance is folinic acid. Each vial contains 175 mg of levofolinic acid in the form of calcium levofolinate.
• The other ingredients (excipients) are mannitol, hydrochloric acid, and sodium hydroxide.

Appearance of Isovorin and contents of the pack

White to pale yellow lyophilized powder in a Type I transparent glass vial with a bromobutyl rubber stopper and a green aluminum/plastic flip-off cap.

It is available in a single format of 1 vial.

Marketing authorization holder:

Wyeth Farma, S.A.

Carretera A-1, Km. 23. Desvío Algete, Km. 1

28700 San Sebastián de los Reyes, Madrid

Spain

Manufacturer

Wyeth Lederle S.r.l.

Via Franco Gorgone, Zona Industriale

95100 Catania

Italy

Local representative

Pfizer, S.L.

Avda. de Europa, 20-B

Parque Empresarial La Moraleja

28108 Alcobendas (Madrid)

Date of the last revision of this leaflet: October 2023

Detailed and updated information on this medicine is available on the website of the Spanish Agency for Medicines and Healthcare Products (AEMPS) http://www.aemps.gob.es/

IMPORTANT INFORMATION FOR HEALTHCARE PROFESSIONALS

Instructions for the correct reconstitution of the medicine

Each vial should be reconstituted in 17.5 ml of sterile diluent to obtain a concentration of levofolinic acid of 10 mg per ml. This medicine does not contain preservatives.

Reconstitution can be done in the following media:

• 9 mg/ml (0.9%) bacteriostatic saline (containing benzyl alcohol)
• 9 mg/ml (0.9%) saline
• 50 mg/ml (5%) glucose solution
• Glucosaline (50 mg/ml (5%) glucose in saline)

Reconstitution with water for injection alone is not recommended, as it does not provide an isotonic solution.

The use of 9 mg/ml (0.9%) bacteriostatic saline is not recommended for administering doses greater than 10 mg/m2, due to its benzyl alcohol content. If high doses are required, the medicine should be reconstituted in 9 mg/ml (0.9%) saline.

The reconstituted solutions can, in turn, be diluted to concentrations ranging from:

• 0.5 mg/ml to 5 mg/ml, in 9 mg/ml (0.9%) saline
• 50 mg/ml (5%) glucose solution
• 50 mg/ml (5%) glucose in saline (glucosaline)

Instructions for the correct storage of the reconstituted medicine

• The solutions reconstituted with 9 mg/ml (0.9%) bacteriostatic saline, which contain benzyl alcohol, are chemically and physically stable for one week at room temperature or for four weeks under refrigeration.
• The solutions reconstituted with 9 mg/ml (0.9%) saline, 5% glucose solution, or glucosaline (5% glucose in saline) should be used within 24 hours, stored under refrigeration, for reasons of sterility (the vial does not contain preservatives).
• The reconstituted and subsequently diluted solutions in 0.9% saline, 5% glucose solution, or glucosaline (5% glucose in saline), if stored in PVC bags, are chemically and physically stable for at least 14 days at room temperature or under refrigeration. However, it is recommended to use them within 24 hours, stored under refrigeration, for reasons of sterility.

After reconstitution and before administration, the solution should be visually inspected. The solution for injection or infusion should be clear and yellowish and should be discarded if it is cloudy or particles are observed inside. Each vial is designed for single use.

Disposal of unused medicine and all materials that have come into contact with it will be carried out in accordance with local regulations.