Sodium leucovorin Medac

Package leaflet: Information for the user

Sodio Levofolinato medac 50 mg/ml injection solution or infusion solution

levofolinic acid
Please 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.
• If you have any questions, ask your doctor, pharmacist or nurse.
• If you get 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 this leaflet:

1. What Sodio Levofolinato medac is and what it is used for
2. What you need to know before using Sodio Levofolinato medac
3. How to use Sodio Levofolinato medac
4. Possible side effects
5. How to store Sodio Levofolinato medac
6. Contents of the pack and other information

1. What Sodio Levofolinato medac is and what it is used for

Use of Sodio Levofolinato medac in combination with methotrexate
Sodio Levofolinato medac 50 mg/ml solution for injection or infusion is a medicine that
belongs to the group of so-called antidotes. These are substances used in cancer therapy
(cytostatic therapy) to neutralize the toxicity of cytotoxic agents.
Sodio Levofolinato medac is used in cancer therapy in adults and children to
reduce toxicity and counteract the effects of substances such as methotrexate, which inhibit the activity
of endogenous folic acid (so-called folic acid antagonists). Sodio Levofolinato medac can also
be used to treat overdosage of folic acid antagonists.
Use of Sodio Levofolinato medac in combination with 5-fluorouracil
It has been shown that Sodio Levofolinato medac enhances the action of certain cytostatic agents, and is therefore also used in cancer therapy to increase the cytotoxic effects of an anticancer drug called 5-fluorouracil.

2. What you need to know before using Sodio Levofolinato medac

Do not use Sodio Levofolinato medac

• if you are allergic to levofolinic acid or to any of the other ingredients of this medicine (listed in section 6);
• if you have pernicious anemia or any other anemia caused by vitamin B__ deficiency;
• in combination with 5-fluorouracil if there are contraindications to 5-fluorouracil, particularly during pregnancy or breastfeeding;
• in combination with 5-fluorouracil if you have severe diarrhea.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Sodio Levofolinato medac.
General considerations
Sodio Levofolinato medac, when used in combination with 5-fluorouracil or methotrexate, must only be administered under the direct supervision of a physician experienced in cancer therapy.
Levofolinic acid must not be administered into the spinal fluid (intrathecally), as serious adverse effects, including death, have been observed with this route of administration.
If you are receiving certain cytotoxic agents (which damage cells), such as hydroxycarbamide, cytarabine, mercaptopurine, or thioguanine, you may develop macrocytosis (excessively large red blood cells). Such cases of macrocytosis should not be treated with levofolinic acid.
If you have epilepsy and are being treated with certain medications (phenobarbital, phenytoin, or primidone), your risk of epileptic seizures may increase due to reduced blood concentrations of the anti-epileptic drugs. Your doctor will likely perform blood tests during and after levofolinic acid administration to monitor the blood levels of your anti-epileptic medications and adjust the dose if necessary.
Special precautions for the use of Sodio Levofolinato medac in combination with methotrexate
Your doctor will ensure that levofolinic acid is not administered simultaneously with a folic acid antagonist (e.g., methotrexate), as this could reduce the therapeutic effect of the antagonist.
Your doctor will also avoid excessive doses of levofolinic acid, which could compromise the antitumor activity of methotrexate.
However, accidental overdose of a folic acid antagonist such as methotrexate must be treated immediately as a pharmacological emergency.
If you already have impaired renal function, are inadequately hydrated, or are taking certain anti-inflammatory or pain medications (non-steroidal anti-inflammatory drugs, e.g., ibuprofen, diclofenac, or salicylates such as acetylsalicylate or aspirin), methotrexate excretion may be delayed due to fluid accumulation, for example in the peritoneal cavity or in the space between the chest and the lung.
In such cases, administration of Sodio Levofolinato medac at higher doses or for a longer duration may be indicated.
Delayed excretion of methotrexate may in turn affect kidney function and lead to increased blood levels of methotrexate.
In this case as well, Sodio Levofolinato medac may be administered at higher doses or the duration of levofolinic acid administration may be prolonged.
Special precautions for the use of Sodio Levofolinato medac in combination with 5-fluorouracil
In combination therapy with 5-fluorouracil, levofolinic acid may increase the risk of 5-fluorouracil toxicity. The most common manifestations, which may limit dosing, are:

• reduced white blood cell count,
• mucosal inflammation (e.g., in the mouth and/or stomach),
• diarrhea.

If you have loose stools twice a day and/or suffer from inflammation of the stomach mucosa (mild to moderate ulcers), you must consult your doctor immediately.
If you experience gastrointestinal adverse effects, regardless of severity, combination therapy with 5-fluorouracil and levofolinic acid will not be initiated or, if already ongoing, will be discontinued.
In particular, if diarrhea occurs, your doctor will monitor you closely, as your condition may deteriorate rapidly with the onset of severe adverse effects. Your doctor will initiate or resume combination therapy with levofolinic acid and 5-fluorouracil only after gastrointestinal symptoms have completely resolved.
Elderly or debilitated patients, or those who have previously undergone radiotherapy, should exercise particular caution, as levofolinic acid may increase the risk of 5-fluorouracil toxicity.
Other medicines and Sodio Levofolinato medac
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
The effect of the following medicines may be affected by concomitant use of Sodio Levofolinato medac: phenobarbital, primidone, phenytoin, succinimides (medicines used to treat epilepsy). Your doctor may monitor blood levels of these medicines and adjust the dose to prevent an increase in seizures (convulsions).
Concomitant administration of Sodio Levofolinato medac and methotrexate may prevent methotrexate from working properly.
Concomitant use of Sodio Levofolinato medac and 5-fluorouracil will increase both the efficacy and the adverse effects of 5-fluorouracil.
When Sodio Levofolinato medac is administered concomitantly with a folic acid antagonist (e.g., cotrimoxazole, pyrimethamine), the efficacy of the folic acid antagonist may be reduced or completely neutralized.
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or breastfeeding, consult your doctor before taking this medicine.
It is unlikely that your doctor will prescribe a folic acid antagonist or 5-fluorouracil during pregnancy or breastfeeding. However, if you have taken or used a folic acid antagonist during pregnancy or breastfeeding, this medicine (Sodio Levofolinato medac) may be used to reduce its adverse effects.
Pregnancy
There is no evidence that Sodio Levofolinato medac causes harmful effects when administered alone during pregnancy.
If you are pregnant, methotrexate should only be administered if the benefits of treatment outweigh the potential risks to the fetus.
If you are administered methotrexate despite being pregnant, there are no restrictions on the use of disodium levofolinato to reduce or neutralize the effects of methotrexate.
If you are pregnant, you must not take combination therapy with Sodio Levofolinato medac and 5-fluorouracil.
Breastfeeding
You must stop breastfeeding before treatment with methotrexate or 5-fluorouracil.
If considered necessary, use of Sodio Levofolinato medac alone may be permitted during breastfeeding.
Driving and using machines
There is no evidence that Sodio Levofolinato medac alone affects the ability to drive or operate machinery. General health conditions are significantly more relevant than any effects induced by Sodio Levofolinato medac.

3. How to use Sodio Levofolinato medac

The preparation and administration of Sodio Levofolinato medac must be performed exclusively by
qualified healthcare personnel.
Sodio Levofolinato medac must always be administered intravenously, either as an injection if undiluted,
or by infusion after dilution.
Sodio Levofolinato medac must not be administered into the spinal fluid (intrathecally).

Dose of Sodio Levofolinato medac for prevention of toxic symptoms during methotrexate therapy
If you are administered a methotrexate dose exceeding 500 mg/m² body surface area as antitumor therapy,
you must subsequently receive leucovorin (levofolinic acid). With methotrexate doses between 100 mg/m²
and 500 mg/m² body surface area, your doctor may consider administering leucovorin.
Your doctor will ensure that you receive the correct dose appropriate for your condition.

Dose of Sodio Levofolinato medac to enhance the cytotoxic effects of 5-fluorouracil
Several combination regimens exist for therapy with Sodio Levofolinato medac and 5-fluorouracil
(weekly, biweekly, and monthly).
Your doctor will ensure that you receive the correct dose appropriate for your condition within the chosen regimen.

If you are administered more Sodio Levofolinato medac than prescribed
Excessive amounts of Sodio Levofolinato medac may counteract the efficacy of folic acid antagonists such as methotrexate. In case of overdose with the combination of 5-fluorouracil and Sodio Levofolinato medac, follow the overdose instructions for 5-fluorouracil.
If you have any doubts about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
If you experience any of the following symptoms, stop treatment with Sodio Levofolinato medac and contact a doctor immediately or go to the nearest emergency room:
Very rare (may affect up to 1 in 10,000 people):

• severe allergic reaction – you may experience sudden itchy rash (urticaria), swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty swallowing or breathing) and feeling faint. This is a serious side effect. Urgent medical treatment may be required.

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

• fever

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

• difficulty sleeping (insomnia), agitation and depression after administration of high doses
• digestive system problems (after administration of high doses)
• increased frequency of seizures (fits) in epileptic patients

Sodium levofolinate in combination with 5-fluorouracil:
If you are receiving leucovorin acid in combination with an antitumor drug containing fluoropyrimidine, the following side effects of that other medicine are more likely to occur.
Very common (may affect more than 1 in 10 people):

• reduction in the number of blood cells (including potentially life-threatening conditions)
• inflammation (swelling and redness accompanied by pain) of the lining of the intestine and mouth (potentially life-threatening conditions have occurred)

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

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

Not known (frequency cannot be estimated from the available data):

• higher than normal level of ammonia in the blood (a breakdown product formed in the body)
  The overall safety profile usually depends on the dosing regimen used for 5-fluorouracil, due to the enhancement of toxic effects induced by 5-fluorouracil itself.

Monthly regimen:
Very common (may affect more than 1 in 10 people):

• vomiting, nausea
  No enhancement of other toxic effects induced by 5-fluorouracil (e.g. neurotoxicity) has been observed.

Weekly regimen:
Very common (may affect more than 1 in 10 people):

• severe diarrhoea and dehydration which may result from diarrhoea, requiring hospitalisation for treatment and even leading to death

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, please inform your doctor or pharmacist. You may also report side effects directly via
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 Sodio Levofolinato medac

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and carton after "Exp". The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C - 8 °C).
Keep the vial in the outer packaging to protect the medicine from light.

6. Package Contents and Other Information

What Sodio Levofolinato medac Contains
The active substance is levofolinic acid. Each ml of solution contains 54.65 mg of disodium
levofolinato, equivalent to 50 mg of levofolinic acid.
Each 1 ml vial contains 54.65 mg of disodium levofolinato, equivalent to 50 mg of levofolinic acid.
Each 4 ml vial contains 218.6 mg of disodium levofolinato, equivalent to 200 mg of levofolinic acid.
Each 9 ml vial contains 491.85 mg of disodium levofolinato, equivalent to 450 mg of levofolinic acid.
The excipients are sodium hydroxide, hydrochloric acid, and water for injections.

Description of the Appearance of Sodio Levofolinato medac and Package Contents
Sodio Levofolinato medac is a clear, colourless or slightly yellow solution for injection or infusion. It is marketed in colourless type I glass vials with bromobutyl rubber stoppers and aluminium flip-off caps.
Pack sizes:
1 ml, 4 ml or 9 ml vials of injectable or infusion solution in packs of 1 or 5 vials. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
medac
Gesellschaft für klinische Spezialpräparate mbH
Theaterstr. 6
22880 Wedel
Germany

This medicinal product is authorised 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 medac 50 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
Germany: Levofolic 50 mg/ml Injektions-/Infusionslösung
Italy: Sodio Levofolinato medac 50 mg/ml soluzione iniettabile o per infusione
Latvia: Levofolic 50 mg/ml šķīdums injekcijai/infūzijai
Lithuania: Levofolino rūgštis medac 50 mg/ml injekcinis ar infuzinis tirpalas
Poland: Levofolic 50 mg/ml roztwór do wstrzykiwań / do infuzji
Portugal: Levofolic 50 mg/ml solução injetável ou para perfusão
United Kingdom: Levofolinic acid 50 mg/ml solution for injection/infusion
Slovakia: Levofolic 50 mg/ml injekčný/infúzny roztok
Slovenia: Levofolic 50 mg/ml raztopina za injiciranje/infundiranje
Sweden: Natriumlevofolinat medac

The following information is intended exclusively for physicians or healthcare professionals:

Instructions for Use and Handling of Sodio Levofolinato medac
The preparation of the infusion solution must be carried out under aseptic conditions.
The injectable or infusion solution may be diluted in 9 mg/ml (0.9%) sodium chloride solution or in 5% glucose solution.
Sodio Levofolinato medac is compatible with 5-fluorouracil.
Use only clear solutions without visible particles.
For single use only. Unused medicine and waste material must be disposed of in accordance with local regulations.
For intravenous use only.

Stability after First Opening or Dilution
After mixing with 5-fluorouracil or dilution with 9 mg/ml (0.9%) sodium chloride solution or 5% glucose solution:
Chemical and physical in-use stability has been demonstrated for 72 hours at 20–25 °C.
From a microbiological standpoint, the product should be used immediately. If not used immediately, the user is responsible for storage duration and conditions prior to use, which should generally not exceed 24 hours at 2–8 °C, unless dilution was performed under controlled and validated aseptic conditions.

Dosage and Administration

Enhancement of 5-Fluorouracil Cytotoxicity
Various therapeutic regimens and doses have been used, without definitive evidence that any single dose is optimal.
The following regimens have been used in adults and elderly patients for the treatment of advanced or metastatic colorectal carcinoma and are provided as examples:

Biweekly regimen: 100 mg/m² of levofolinic acid (= 109.3 mg/m² of disodium levofolinato) administered by intravenous infusion over 2 hours, followed by a bolus of 400 mg/m² of 5-fluorouracil and a 22-hour infusion of 5-fluorouracil (600 mg/m²) for 2 consecutive days, repeated every 2 weeks on days 1 and 2.

Weekly regimen: 10 mg/m² of levofolinic acid (= 10.93 mg/m² of disodium levofolinato) administered as an intravenous bolus injection, or 100–250 mg/m² of levofolinic acid (= 109.30–273.25 mg/m² of disodium levofolinato) by intravenous infusion over 2 hours, followed by 500 mg/m² of 5-fluorouracil administered as an intravenous bolus injection either midway or at the end of the disodium levofolinato infusion.

Monthly regimen: 10 mg/m² of levofolinic acid (= 10.93 mg/m² of disodium levofolinato) administered as an intravenous bolus injection, or 100–250 mg/m² of levofolinic acid (= 109.30–273.25 mg/m² of disodium levofolinato) by intravenous infusion over 2 hours, immediately followed by 425 or 370 mg/m² of 5-fluorouracil administered as an intravenous bolus injection for 5 consecutive days.

For combination therapy with 5-fluorouracil, based on the patient's condition, clinical response, and dose-limiting toxicity, the dose of 5-fluorouracil and the treatment-free interval may need to be adjusted as described in the product information. Dose reduction of disodium levofolinato is not required.
The number of cycles to be repeated is at the physician's discretion.

Paediatric Population
Data on the use of these combinations are not available.

Rescue Therapy with Disodium Levofolinato in Methotrexate Treatment
The dosing regimen for rescue with disodium levofolinato is closely dependent on the dosage and administration method (intermediate or high dose) of methotrexate. Therefore, the methotrexate administration protocol determines the disodium levofolinato rescue regimen. For dosing and administration of disodium levofolinato, reference should be made to the protocol used for intermediate- or high-dose methotrexate.

The following guidelines may provide examples of regimens used in adults, elderly patients, and children:
In patients with malabsorption syndromes or other gastrointestinal disorders that impair enteral absorption, rescue with disodium levofolinato must be administered parenterally.
Doses exceeding 12.5–25 mg of levofolinic acid must be administered parenterally due to saturation of enteral absorption of disodium levofolinato.

Rescue with disodium levofolinato is required when methotrexate is administered at doses exceeding 500 mg/m² body surface area and should be considered at doses of 100–500 mg/m² body surface area.

The dose and duration of disodium levofolinato rescue depend primarily on the type and dose of methotrexate therapy, the onset of toxicity symptoms, and the individual's ability to excrete methotrexate. Generally, the first dose of levofolinic acid is 7.5 mg (3–6 mg/m²), administered within 12 hours or no later than 24 hours after the start of methotrexate infusion. The same dose is repeated every 6 hours for a period of 72 hours. After several parenteral doses, oral formulation may be used.

In addition to levofolinic acid administration, it is important to take measures to ensure rapid methotrexate excretion, such as:
a. Urine alkalinization to raise urinary pH above 7.0 before methotrexate infusion, to increase the solubility of the drug and its metabolites.
b. Maintenance of a urinary output of 1800–2000 ml/m²/24 hours by increasing oral or intravenous fluid intake on days 2, 3, and 4 after methotrexate therapy.
c. Measurement of plasma methotrexate concentration, blood urea nitrogen, and creatinine on days 2, 3, and 4.
These measurements must be repeated until the plasma methotrexate level falls below 10 nmol/L (0.1 µM).

In some patients, delayed methotrexate excretion may occur, possibly due to accumulation in the third space (e.g., ascites or pleural effusions), renal insufficiency, or inadequate hydration. In such cases, higher doses or prolonged administration of disodium levofolinato may be indicated. Patients with delayed initial methotrexate elimination may develop reversible renal failure.

Forty-eight hours after the start of methotrexate infusion, the residual methotrexate level should be measured. If this level is > 0.5 µmol/L, disodium levofolinato doses should be adjusted according to the following table.