Levofolic 50 mg/ml roztvur do vstzhikivani lub infuzii

Leaflet attached to the packaging: information for the user

Levofolic 50 mg/ml solution for injection/infusion

Levofolinic acid

You should carefully read the contents of the leaflet before using the medicine, as it contains important information for the patient.

• You should keep this leaflet, so that you can read it again if you need to.
• If you have any further questions, you should ask your doctor, pharmacist, or nurse.
• If you experience any side effects, including those not listed in this leaflet, you should tell your doctor, pharmacist, or nurse. See section 4.

Table of contents of the leaflet

• 1. What is Levofolic and what is it used for
• 2. Important information before using Levofolic
• 3. How to use Levofolic
• 4. Possible side effects
• 5. How to store Levofolic
• 6. Contents of the packaging and other information

1. What is Levofolic and what is it used for

Using Levofolic in combination with methotrexate

Levofolic 50 mg/ml solution for injection/infusion belongs to a group of medicines that reduce the toxicity of anticancer medicines. These are medicines used during cancer treatment (cytostatic treatment) to prevent the toxicity of cytostatics.
Levofolic is used in the treatment of cancer in adults and children to reduce toxicity and prevent the action of such medicines as methotrexate, which inhibits the action of endogenous folic acid (that's why it's called a folic acid antagonist). Overdose of folic acid antagonists can also be treated with Levofolic.

Using Levofolic in combination with 5-fluorouracil

It has been shown that Levofolic increases the action of some cytostatics. Therefore, it is used in the treatment of cancer to increase the damage to cells by the anticancer medicine called 5-fluorouracil.

2. Important information before using Levofolic

When not to use Levofolic

• if the patient is allergic to levofolinic acid or any of the other ingredients of this medicine (listed in section 6),
• in patients with megaloblastic anemia or other anemia due to vitamin B12 deficiency,
• in combination with 5-fluorouracil in cases where there are contraindications to the use of 5-fluorouracil, in particular in pregnant or breastfeeding women,
• in combination with 5-fluorouracil, if the patient has severe diarrhea.

Warnings and precautions

Before starting to use Levofolic, you should discuss it with your doctor, pharmacist, or nurse.
General information
Levofolic should only be used with methotrexate or 5-fluorouracil under the direct supervision of a doctor with experience in cancer treatment.
Levofolinic acid should not be administered into the spinal fluid (intrathecally), as severe side effects, including death, have been reported in connection with such treatment.
If the patient is being treated with certain cytotoxic medicines (cell-damaging) such as hydroxyurea, cytarabine, mercaptopurine, thioguanine, the patient may develop macrocytosis (enlargement of red blood cells). Such cases of macrocytosis should not be treated with levofolinic acid.
In the case of patients with epileptic seizures, treated with certain medicines (phenobarbital, phenytoin, or primidone), there may be a risk of increased frequency of seizures. This is due to the decreased concentration of antiepileptic medicines in the patient's blood. The attending doctor will likely perform blood tests during treatment with levofolinic acid and after completion of such treatment. It is possible to determine the concentration of the antiepileptic medicine in the blood and, if necessary, adjust the dose.
Special precautions when using Levofolic in combination with methotrexate
The attending doctor will ensure that levofolinic acid is not administered to the patient at the same time as folic acid antagonists (e.g., methotrexate), as the therapeutic effect of the antagonist may be reduced.
Furthermore, the doctor will avoid excessive doses of levofolinic acid, as this may worsen the anticancer effect of methotrexate.
However, accidental overdose of a folic acid antagonist such as methotrexate will be treated immediately as an emergency requiring emergency treatment.
The elimination of methotrexate may be delayed due to fluid accumulation, e.g., in the abdominal cavity or in the space between the chest and lungs, in patients with renal function disorders, inadequate hydration, or using certain anti-inflammatory or analgesic medicines (non-steroidal anti-inflammatory medicines, e.g., ibuprofen, diclofenac, or salicylates such as acetylsalicylic acid).
In such circumstances, higher doses of Levofolic or prolonged administration may be indicated.
Delayed elimination of methotrexate may, in turn, affect kidney function, causing an increase in methotrexate concentration in the blood.
In such a case, the patient may receive higher doses of Levofolic or the duration of levofolinic acid administration may be extended.
Special precautions when using Levofolic in combination with 5-fluorouracil
In combination with 5-fluorouracil, levofolinic acid may increase the risk of toxic effects of 5-fluorouracil.
The most common symptoms that may limit the dose include:

• •decrease in the number of white blood cells,
• •inflammation of the mucous membranes (e.g., in the mouth and/or stomach),
• •diarrhea.

If the patient experiences watery stools twice a day and/or inflammation of the gastric mucosa (mild or moderate ulcers), they should immediately consult a doctor.

If the patient experiences gastrointestinal side effects, regardless of their severity, they will not be given 5-fluorouracil in combination with levofolinic acid, or such treatment will not be continued.
In particular, if the patient experiences diarrhea, they will be under close observation, as their condition may rapidly deteriorate and severe side effects may occur. After the complete disappearance of gastrointestinal symptoms, treatment with 5-fluorouracil in combination with levofolinic acid can be started or resumed.
Patients who are elderly or in a severe condition or patients who have undergone radiotherapy should be particularly cautious, as levofolinic acid may increase the risk of toxic effects of 5-fluorouracil.

Levofolic and other medicines

You should tell your doctor or pharmacist about all medicines you are currently taking or have recently taken, as well as any medicines you plan to take.
The action of the following medicines may be affected if Levofolic is used at the same time:
phenobarbital, primidone, phenytoin, and succinic acid imides (medicines used to treat epilepsy).
The doctor may check the concentration of these medicines in the blood and change the dose to prevent the worsening of seizures (epileptic seizures).
If Levofolic is administered at the same time as methotrexate, it may disrupt the proper action of this medicine.
Concomitant use of Levofolic with 5-fluorouracil increases the efficacy and side effects of 5-fluorouracil.
When Levofolic is administered with a folic acid antagonist (e.g., cotrimoxazole, pyrimethamine), the efficacy of the folic acid antagonist may be reduced or completely abolished.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or plan to have a child, you should consult your doctor before using this medicine.
It is unlikely that your doctor will recommend taking/using a folic acid antagonist or 5-fluorouracil during pregnancy or breastfeeding. However, if you have taken/used a folic acid antagonist during pregnancy or breastfeeding, this medicine (Levofolic) may be used to alleviate side effects.
Pregnancy
There are no reports that Levofolic causes harmful effects when administered to pregnant women.
In the case of pregnant women, methotrexate is administered only when the benefits of treatment outweigh the potential risk to the child.
There are no restrictions on the use of levofolinic acid to reduce or prevent the action of methotrexate in pregnant women.
Pregnant women should not be given Levofolic in combination with 5-fluorouracil.
Breastfeeding
Before starting treatment with methotrexate or 5-fluorouracil, breastfeeding should be stopped.
Levofolic can be used in monotherapy during breastfeeding if necessary.

Driving and using machines

There is no evidence that Levofolic in monotherapy affects the ability to drive and use machines. The patient's general condition is more important than the effect caused by Levofolic.

Levofolic medac contains sodium

The medicine contains less than 1 mmol (23 mg) of sodium per vial, which means that the medicine is considered "sodium-free".

3. How to use Levofolic

Only trained medical personnel are responsible for the preparation and administration of Levofolic.

Levofolic is administered intravenously without dilution in an injection or after dilution during an infusion.

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

Dose of Levofolic to prevent symptoms of toxicity during methotrexate treatment
Patients receiving methotrexate anticancer in a dose greater than 500 mg/m² body surface area should be given levofolinic acid after methotrexate administration. The doctor may also consider administering levofolinic acid in case of methotrexate administration in a dose of 100 mg/m² body surface area - 500 mg/m² body surface area.
Adjusting the dose according to the patient's condition is the responsibility of the doctor.
Dose of Levofolic to increase the cytotoxic effect of 5-fluorouracil
Various treatment regimens are used with Levofolic in combination with 5-fluorouracil (weekly, bi-monthly, and monthly regimens).
The responsibility for adjusting the dose according to the patient's condition within the relevant treatment regimen lies with the doctor.

Using a higher dose of Levofolic than recommended

Excessive amounts of Levofolic may eliminate the efficacy of folic acid antagonists such as methotrexate. If an overdose of 5-fluorouracil occurs in combination with Levofolic, you should follow the instructions in case of an overdose of 5-fluorouracil.
If you have any further questions about the use of this medicine, you should ask your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you experience any of the following symptoms, you should stop using Levofolic immediately and contact your doctor or go to the nearest emergency department.
Very rare (may affect less than 1 in 10,000 people)

• Severe allergic reactions - the patient may suddenly develop an itchy rash (hives), swelling of the hands, feet, ankles, face, lips, mouth, or throat (which may cause difficulty swallowing or breathing) and the patient may feel like they are about to faint. This is a serious side effect that may require immediate medical attention.

Other side effects that may occur:
Not very common (may affect less than 1 in 100 people):

• fever.

Rare (may affect less than 1 in 1,000 people):

• sleep disorders (insomnia), excitement, and depression after administration of high doses,
• gastrointestinal problems (after administration of high doses),
• increased frequency of seizures (epileptic seizures) in patients with epilepsy.

Levofolinic acid in combination with 5-fluorouracil
When levofolinic acid is used in combination with anticancer medicines containing fluoropyrimidines, there is a greater likelihood of the following side effects of the other medicine.
Very common (may affect more than 1 in 10 people):

• decrease in the number of blood cells (including life-threatening conditions),
• inflammation (painful swelling and redness) of the mucous membranes of the intestines and mouth (life-threatening conditions occurred).

Common (may affect less than 1 in 10 people):

• redness and swelling of the palms and soles, which can cause skin peeling (palmar-plantar syndrome).

Unknown (frequency cannot be estimated from the available data):

• exceeding the norm of ammonia concentration in the blood (a metabolic product produced by the body).

Usually, the safety profile depends on the 5-fluorouracil treatment regimen used, in connection with the intensification of toxic effects caused by 5-fluorouracil.
Monthly regimen:
Very common (may affect more than 1 in 10 people):

• vomiting, nausea.

No intensification of other toxic effects caused by 5-fluorouracil (e.g., neurotoxicity) was observed.
Weekly regimen:
Very common (may affect more than 1 in 10 people):

• severe diarrhea and dehydration, which may be caused by diarrhea, requiring hospitalization for treatment, and even death.

Reporting side effects

If you experience any side effects, including those not listed in this leaflet, you should tell your doctor, pharmacist, or nurse. Side effects can be reported directly to the Department of Monitoring of Adverse Reactions to Medicinal Products of the Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products:
Al. Jerozolimskie 181C, PL-02-222 Warsaw, Tel.: 22 49-21-301, Fax: 22 49-21-309, website: https://smz.ezdrowie.gov.pl
Side effects can also be reported to the marketing authorization holder.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Levofolic

The medicine should be stored out of sight and reach of children.
Do not use this medicine after the expiry date stated on the label after EXP. The expiry date refers to the last day of the month.
Store in a refrigerator (2°C – 8°C).
Store the vial in the outer packaging to protect from light.

6. Contents of the packaging and other information

What Levofolic contains

The active substance of the medicine is levofolinic acid.
One ml of the solution contains 54.65 mg of levofolinic acid disodium equivalent to 50 mg of levofolinic acid.
One vial of 1 ml contains 54.65 mg of levofolinic acid disodium equivalent to 50 mg of levofolinic acid.
One vial of 4 ml contains 218.6 mg of levofolinic acid disodium equivalent to 200 mg of levofolinic acid.
One vial of 9 ml contains 491.85 mg of levofolinic acid disodium equivalent to 450 mg of levofolinic acid.
The other ingredients of the medicine are sodium hydroxide, hydrochloric acid, and water for injections.

What Levofolic looks like and contents of the packaging

Levofolic is a clear, colorless or slightly yellow solution for injection/infusion. The medicine is available in colorless glass vials type I with a bromobutyl rubber stopper, aluminum flip-off cap.
Pack sizes:
Vials containing 1 ml, 4 ml, or 9 ml of solution for injection/infusion in packs of 1 or 5 vials. Not all pack sizes may be marketed.

Marketing authorization holder and manufacturer:

medac
Gesellschaft für klinische Spezialpräparate mbH
Theaterstr. 6
22880 Wedel
Germany




<22880 wedel>


medac s.a.s.
23 rue Pierre Gilles de Gennes
69007 Lyon, France

This medicinal product is authorized in the Member States of the European Economic Area under the following names:

Belgium
Levofolic 50 mg/ml solution injectable/pour perfusion
Levofolic 50 mg/ml oplossing voor injectie / infusie
Levofolic 50 mg/ml Injektions-/Infusionslösung
Estonia
Levofolinic acid medac50 mg/ml süste-/infusioonilahus
Finland
Levofolic 50 mg/ml injektio-/infuusioneste, liuos
Levofolic 50 mg/ml injektions-/infusionsvätska, lösning
France
Levofolinate de sodium medac 50 mg/ml, solution injectable/pour perfusion
Lithuania
Levofolino rūgštis medac 50 mg/ml injekcinis ar infuzinis tirpalas
Latvia
Levofolic 50 mg/ml šķīdums injekcijai/ infūzijai
Germany
Levofolic 50 mg/ml Injektions-/Infusionslösung
Poland
Levofolic 50 mg/ml roztwór do wstrzykiwań / do infuzji
Portugal
Levofolic 50 mg/ml solução injetável ou para perfusão
Slovakia
Levofolic 50 mg/ml injekčný/infúzny roztok
Slovenia
Levofolic 50 mg/ml raztopina za injiciranje/infundiranje
Sweden
Natriumlevofolinat medac
United Kingdom
Levofolinic acid 50 mg/ml solution for injection/infusion
Italy
Sodio Levofolinato medac 50 mg/ml soluzione iniettabile o per infusione

Date of last revision of the leaflet: 03/2020.

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Information intended only for healthcare professionals:

Instructions for preparing Levofolic for use

Preparation of the infusion solution should be performed under aseptic conditions.
The solution for injection/infusion can be diluted with a 9 mg/ml (0.9%) sodium chloride solution or a 5% glucose solution.
The medicinal product Levofolic is compatible with 5-fluorouracil.
Only use a solution that does not contain visible particles.
For single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
For intravenous administration.

Shelf life after first opening or dilution

After dilution with 5-fluorouracil or dilution with a 9 mg/ml (0.9%) sodium chloride solution or 5% glucose solution:
Chemical and physical stability of the medicine has been demonstrated for 72 hours at a temperature of 20-25°C.
From a microbiological point of view, the product should be used immediately. Otherwise, the user is responsible for the subsequent storage period and conditions of the medicinal product before use, which should not normally exceed 24 hours at a temperature of 2°C-8°C, unless the dilution has been performed in controlled and validated aseptic conditions.

Dosage and administration

Increasing the cytotoxicity of 5-fluorouracil

Various regimens and different doses are used, without a dose being considered optimal.
The following regimens used in adult and elderly patients, in the treatment of advanced or metastatic colorectal cancer, are given as examples.
Bi-monthly regimen: a dose of 100 mg/m² body surface area of levofolinic acid (= 109.3 mg/m² body surface area of levofolinic acid disodium) in a 2-hour intravenous infusion, followed by a bolus dose of 400 mg/m² body surface area of 5-fluorouracil and a 22-hour infusion of 5-fluorouracil (600 mg/m² body surface area) for 2 consecutive days, every 2 weeks on days 1 and 2.
Weekly regimen: a dose of 10 mg/m² body surface area of levofolinic acid (= 10.93 mg/m² body surface area of levofolinic acid disodium) as a bolus or from 100 to 250 mg/m² body surface area of levofolinic acid (= from 109.3 mg/m² body surface area to 273.25 mg/m² body surface area of levofolinic acid disodium) in a 2-hour intravenous infusion plus 500 mg/m² body surface area of 5-fluorouracil as an intravenous bolus in the middle or after the end of the levofolinic acid disodium infusion.
Monthly regimen: a dose of 10 mg/m² body surface area of levofolinic acid (= 10.93 mg/m² body surface area of levofolinic acid disodium) as an intravenous bolus or from 100 to 250 mg/m² body surface area of levofolinic acid (= from 109.3 mg/m² body surface area to 273.25 mg/m² body surface area of levofolinic acid disodium) in a 2-hour intravenous infusion, followed by an immediate dose of 425 or 370 mg/m² body surface area of 5-fluorouracil as an intravenous bolus during 5 consecutive days.
In combination with 5-fluorouracil, it may be necessary to modify the dosing of 5-fluorouracil and the interval between treatment cycles, depending on the patient's condition, clinical response, and dose-limiting toxicities listed in the summary of product characteristics of 5-fluorouracil. It is not necessary to reduce the dose of levofolinic acid disodium.
The number of repeated cycles used depends on the doctor's decision.
Children and adolescents
Data are not available on the use of such combination therapies.

Protective use of levofolinic acid during methotrexate treatment

Since the protective treatment with levofolinic acid depends to a large extent on the dosing and route of administration of high and medium doses of methotrexate, the methotrexate treatment regimen is an indicator of the dosing of levofolinic acid in protective treatment. Therefore, the dosing and route of administration of levofolinic acid should be best adapted to the high or medium doses and route of administration used in the methotrexate treatment regimen.
The following guidelines can serve as examples of regimens used in adults, the elderly, and children:
In patients with malabsorption syndrome or other gastrointestinal disorders, levofolinic acid disodium should be administered parenterally, as intestinal absorption is not guaranteed.
Doses above 12.5 - 25 mg of levofolinic acid should be administered parenterally, due to the possibility of saturation of intestinal absorption of levofolinic acid disodium.
Administration of levofolinic acid disodium is necessary when methotrexate is used in doses greater than 500 mg/m² body surface area. If methotrexate is administered in doses of 100 mg - 500 mg/m² body surface area, the administration of levofolinic acid disodium should be considered.
The dosing and duration of protective treatment depend on the methotrexate treatment regimen used, the occurrence of toxic symptoms, and the individual patient's ability to eliminate methotrexate. The initial dose of levofolinic acid is usually 7.5 mg (3 - 6 mg/m² body surface area) and is administered 12 - 24 hours (no later than 24 hours) after the start of methotrexate infusion. The same dose is repeated every 6 hours for 72 hours. After several parenteral doses, oral administration can be started.
In addition to the administration of levofolinic acid disodium, it is important to take measures to ensure the rapid elimination of methotrexate.
Such measures include:

• a. Alkalization of the urine, so that the pH is greater than 7.0 before methotrexate infusion (to increase the solubility of methotrexate and its metabolites).
• b. Maintaining urine output at a level of 1800 - 2000 cm³/m²/24 hours by increasing the volume of fluids administered orally or intravenously on days 2, 3, and 4 after methotrexate administration.
• c. Measuring the concentration of methotrexate in the blood, blood urea nitrogen (BUN), and creatinine concentration on days 2, 3, and 4. Such measurements should be continued until a methotrexate concentration in the blood below 10 micromoles (0.1 μmol) is achieved.

In some patients, delayed elimination of methotrexate may occur. The cause of this may be fluid accumulation in the third space (observed, for example, in the form of ascites or pleural effusion), renal function disorders, inadequate hydration, or the use of certain anti-inflammatory or analgesic medicines (non-steroidal anti-inflammatory medicines, e.g., ibuprofen, diclofenac, or salicylates such as acetylsalicylic acid).
In such circumstances, higher doses of levofolinic acid disodium or prolonged administration may be indicated.
Forty-eight hours after the start of methotrexate infusion, the residual concentration of methotrexate should be determined. If it is greater than > 0.5 μmol/l, the dosing of levofolinic acid disodium should be adjusted as follows: