Prospect: information for the patient

Isovorin 175 mg powder for injectable solution and for infusion

Levofolinic acid

Read this prospect carefully before starting to use this medication,because it contains important information for you.

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

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

• This medication has been prescribedonlyto you, and you should not give it to other people even if they have the same symptoms as you, as it may harm them.

• If you experience any adverse effects, consult your doctor, pharmacist or nurse,evenif they do not appear in this prospect. See section 4.

1.What Isovorin is and for what it is used

2.What you need to knowbefore starting to use Isovorin

3.How to use Isovorin

4.Possible adverse effects

5Storage of Isovorin

6.Content of the package andadditional information

Isovorin contains levofolic acid, which is the active form of folic acid. Levofolic acid acts as an antidote for folic acid antagonists and belongs to the group of medications known as detoxifying agents for tumor treatment.

This medication is used in the following cases:

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

No use Isovorin:

• If you are allergic to levofolic acid or any of the other components of this medication (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 it is pernicious or other megaloblastic anemias secondary to a lack of vitamin B12.
• If you are pregnant or breastfeeding, think you may be pregnant, or intend to become pregnant.

Warnings and precautions

Consult 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 symptoms that may indicate possible toxicity due to the medication.

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

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

• If you are being treated with methotrexate or 5-fluorouracil. It is essential to strictly follow the Isovorin dosage prescribed by your doctor, as non-compliance may cause excessive toxicity or a lack of efficacy of methotrexate.
• If you have diarrhea, as it may be a symptom of gastrointestinal toxicity.
• If you have previously received radiation therapy.
• 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 seizure frequency (see section “Other medications and Isovorin”).

Levofolic acid should not be administered intrathecally (into the spinal cord).

Children and adolescents

No data are available on efficacy and safety in children and adolescents under 18 years.

Other medications and Isovorin

Inform your doctor or pharmacist if you are using, have used recently, or may need to use any other medication.

In particular, inform your doctor if you are using the following medications:

• Antifolate medications such as cotrimoxazole, pyrimethamine, or chloramphenicol, as levofolic acid may reduce their efficacy.
• Antiepileptic medications (such as phenobarbital, phenytoin, succinimides, or primidone), as high doses may partially reduce their effect and increase seizure frequency (see section “Warnings and precautions”).
• Medications 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 chemotherapeutic agents.

Pregnancy, lactation, and fertility

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

The mechanism of action of levofolinic acid is unknown, and its passage into breast milk is unknown. Your doctor will decide whether to prescribe this medication in accordance with therapeutic indications.

No fertility studies have been conducted with folinic acid calcium.

Driving and operating machinery

This medication has no effect on the ability to drive vehicles or operate machinery.

This medication contains sodium

This medication contains less than 1 mmol (23 mg of sodium) per dose unit; it is essentially “sodium-free”.

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

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

This medication should only be administered intravenously or intramuscularly. If administered intravenously, do not inject more than 160 mg of levofolinic acid per minute due to the calcium content of the solution.

Levofolinic Acid Rescue in Methotrexate Therapy

If you have been administered a dose of methotrexate greater than 500 mg/m², you should receive levofolinic acid afterwards. Your doctor may consider administering rescue if you have been administered doses of methotrexate between 100 mg/m² and 500 mg/m².

Levofolinic acid rescue should be initiated 12-24 hours after the start of methotrexate perfusion, with doses of 7.5 mg (approximately 5 mg/m²) of levofolinic acid every 6 hours for 72 hours.

Combined Treatment with 5-Fluorouracil

Since levofolinic calcium 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 anticancer medications.

Antidote for Folic Acid Antagonists

This medication may be used to reverse toxicity caused by trimetrexate, trimethoprim, or pyrimethamine. Your doctor will establish the treatment regimen.

If You Take More Isovorin Than You Should

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

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

If You Forget to Use Isovorin

Your doctor or nurse has instructions on when to administer your medication. It is unlikely that you will not receive your medication as prescribed. If you are aware that you have not received your dose, contact your doctor or pharmacist immediately.

Like all medications, this medication may cause adverse effects, although not everyone will experience them.

The less common adverse effects (may affect up to 1 in 100 people) include:

• Fever.

The rare adverse effects (may affect up to 1 in 1,000 people) include:

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

The very rare adverse effects (may affect up to 1 in 10,000 people) include:

• 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 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 levofolinate acid in combination with 5-fluorouracil are:

The very frequent adverse effects(may affect more than 1 in 10 patients) include:

• Nausea, vomiting, diarrhea.
• Mucosal inflammation of the intestine and mouth (in some cases fatal).
• Decreased number of blood cells (in some cases fatal).

The frequent adverse effects (may affect up to 1 in 10 patients) include:

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

The adverse effects of unknown frequency (cannot be estimated from available data) include:

• Increased ammonia carbonate in blood.

Reporting Adverse Effects:

If you experience any type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is a possible adverse effect that does not appear in this prospectus. You can also report them directly through the Spanish System for Pharmacovigilance of Medicinal Products for Human Use:www.notificaram.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medication.

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

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

Do not use this medication after the expiration date that appears on the packaging after CAD. The expiration date is the last day of the month indicated.

Composition of Isovorin

• The active principle is folic acid. Each vial contains 175 mg of levofolic acid in the form of calcium levofolinate.
• The other components (excipients) are mannitol, hydrochloric acid, and sodium hydroxide.

Appearance of Isovorin and contents of the container

Lyophilized powder of white to pale yellow color packaged in a Type I transparent glass vial with a bromobutyl rubber stopper and an aluminum/plastic flip-off cap of green color.

It is presented in a single format of 1 vial.

Marketing Authorization Holder:

Wyeth Farma, S.A.

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

28700 San Sebastián de los Reyes, Madrid

Spain

Responsible for manufacturing:

Wyeth Lederle S.r.l.

Via Franco Gorgone, Industrial Zone

95100 Catania

Italy

Local Representative:

Pfizer, S.L.

Avda. de Europa, 20-B

Parque Empresarial La Moraleja

28108 Alcobendas (Madrid)

Last review date of this leaflet: October 2023

The detailed and updated information of this medication is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS) http://www.aemps.gob.es/

IMPORTANT INFORMATION FOR HEALTHCARE PROFESSIONALS

Instructions for the correct reconstitution of the medication

Each vial must be reconstituted with 17.5 ml of sterile diluent to obtain a concentration of levofolic acid of 10 mg per ml. This medication does not contain preservatives.

The reconstitution can be done in the following media:

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

It is not recommended to reconstitute only with injection water, as it does not provide an isotonic solution.

It is not recommended to use bacteriostatic saline solution 9 mg/ml (0.9%) for administering doses greater than 10 mg/m^2, due to its content of benzyl alcohol. If high doses are required, the medication must be reconstituted in sterile saline solution 9 mg/ml (0.9%).

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

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

Instructions for the correct conservation of the reconstituted medication

- The reconstituted solutions with sterile saline solution 9 mg/ml (0.9%) bacteriostatic, containing benzyl alcohol, are chemically and physically stable for one week at room temperature or for four weeks under refrigeration.

- The reconstituted solutions with sterile saline solution 9 mg/ml (0.9%), glucose solution 5%, or glucose saline solution (glucose 5% in saline solution) must be used within 24 hours, stored under refrigeration, due to sterility reasons (the vial does not contain preservatives).

- The reconstituted and diluted solutions in sterile saline solution 0.9%, glucose solution 5%, or glucose saline solution (glucose 5% in saline solution), 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, due to sterility reasons.

After reconstitution and before administration, the solution must be visually inspected. The injection or perfusion solution must be transparent and yellowish, and must be discarded if it is turbid or particles are observed inside. Each vial is designed for single use.

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