Levotonal

Package leaflet: Information for the patient

Levotonal 25 mg, powder for injectable solution

levo-folinic acid (as levofolinate calcium)
Equivalent medicine
Please read this leaflet carefully before 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 or pharmacist.
• This medicine has been prescribed for you only. Do not give it to others, 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, contact your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What Levotonal is and what it is used for

Levotonal contains the active substance levofolinic acid (in the form of levofolinate calcium), which is a vitamin of the B group and can be used:

• to reduce the undesirable effects and to treat the effects of excessive doses of certain antitumour medicines (for example, methotrexate and aminopterin) or other substances that antagonise folic acid;
• to treat anaemias caused by folate deficiency (due to increased demand, reduced utilisation, or insufficient dietary intake of folates in the body).

2. What you need to know before taking Levotonal

Levoleucovorin acid must not be administered intrathecally (into the spinal canal).
Do not take Levotonal:

• if you have previously experienced symptoms of hypersensitivity (severe allergy) or are allergic to the active substance or to any of the other ingredients of this medicine (listed in section 6);
• if you suffer from a particular type of anaemia (pernicious anaemia) or other anaemias caused by vitamin B12 deficiency and you are not taking vitamin B12.

Levotonal MUST NOT be administered to neonates aged 28 days or younger who are receiving an antibiotic called ceftriaxone.
Warnings and precautions

Talk to your doctor or pharmacist before taking Levotonal:

• if you have cancer, metastases to the central nervous system, and are taking medicines belonging to the fluoropyrimidine family (e.g. 5-fluorouracil), as you may experience seizures or fainting, especially if you are already predisposed to such conditions;
• if you suffer from pernicious anaemia or other anaemias caused by vitamin B12 deficiency, because in such cases folic acid derivatives (such as Levotonal) should only be taken under strict medical supervision;
• if you are undergoing cancer treatment with any of the following medicines: hydroxycarbamide, cytarabine, mercaptopurine, thioguanine. These medicines may cause the formation in the blood of red blood cells larger than normal (a condition known as "macrocytosis"). This condition must not be treated with Levotonal;
• if you have epilepsy and are being treated with any of the following medicines: phenobarbital, phenytoin, primidone, succinimides. Concomitant use with Levotonal may increase the frequency of epileptic seizures. Your doctor will monitor you frequently and may adjust the dosage of your antiepileptic medication during and after discontinuation of Levotonal (see section Interactions with other medicines);

When Levotonal is used to treat side effects caused by an overdose of certain anticancer drugs, it must be administered within 1 hour, or in any case no later than 4 hours, after taking the drugs causing the problems.
Laboratory tests
If you are being treated with methotrexate (an anticancer medicine) and levoleucovorin acid, your doctor will perform daily blood tests and, if necessary, urine tests as well.
Other medicines and Levotonal
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, as some may interact with levoleucovorin acid, for example:

• Folic acid antagonists (e.g. methotrexate, cotrimoxazole, and pyrimethamine): levoleucovorin acid (in the form of levofolinic acid calcium) may reduce or completely neutralize the effectiveness of folic acid antagonists when administered concomitantly. For this reason, it is used as an antidote in cases of overdose with these medicines.
• Fluorouracil (an anticancer medicine): levoleucovorin acid may enhance both the efficacy and adverse effects of medicines belonging to the fluoropyrimidine family (e.g. 5-fluorouracil). 5-fluorouracil must not be mixed with Levotonal in the same intravenous infusion.
• Medicines used to treat epilepsy (phenobarbital, phenytoin, primidone, and succinimides): the effectiveness of these medicines may be reduced by levoleucovorin acid. Your doctor will monitor blood levels of these medicines and may adjust their dosage to prevent an increase in seizure frequency. Ceftriaxone: the use of levofolinic acid calcium together with ceftriaxone should be avoided in neonates aged 28 days or younger, because of the risk of calcium salt precipitates forming in the blood, which could be life-threatening. In all other patients, the two medicines may be administered sequentially, provided the doctor follows appropriate administration precautions.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
During breastfeeding, Levotonal should only be administered when the benefits to the mother outweigh the potential risks to the infant.
During pregnancy and breastfeeding, it is generally inappropriate to administer anticancer medicines, which are co-administered with levoleucovorin calcium as part of a specific therapeutic protocol. It is unlikely that your doctor will prescribe a folic acid antagonist during pregnancy or breastfeeding. However, if you are taking a folic acid antagonist during pregnancy or breastfeeding, this medicine (levoleucovorin acid) may be used to reduce its adverse effects.
Driving and using machines
Levotonal does not impair the ability to drive or operate machinery.

3. How to take Levotonal

Take this medicine exactly as instructed by your doctor or nurse.
If you have any doubts, consult your doctor or nurse.
Levotonal can be administered as follows:

• injected into a muscle (intramuscularly);
• injected into a vein, either directly (intravenously) or via an infusion.

The lyophilized powder in the vial can be reconstituted with 5 ml of water for injectable solutions; for infusion, physiological saline solution must be used.
When Levotonal is administered intravenously, no more than 80 mg of active substance should be administered per minute due to the presence of calcium. This medicine must not be administered intrathecally.

Treatment to counteract toxic effects caused by antitumor drugs (e.g. methotrexate)
In these cases, Levotonal may be administered at different doses depending on the desired effect and according to a specific therapeutic protocol that your doctor will define for you personally.
The required dose depends on your general condition and the dose of methotrexate administered. The use of Levotonal may help control the toxicity of antitumor drugs used at high doses in certain treatment regimens.

• To treat an accidental overdose of methotrexate: Your doctor will choose the dosage based on the desired effect. To achieve a competitive effect, the recommended dose may be up to 50 mg of Levotonal administered by infusion within 12 hours of methotrexate overdose. To achieve a biochemical-metabolic effect, the recommended dose is 5–6 mg of Levotonal injected directly into a muscle or vein every 6 hours, for 4 doses.
• To treat adverse effects caused by normal doses of methotrexate: The recommended dose is 5–6 mg of Levotonal injected directly into a muscle or vein every 6 hours, for 4 doses.
• To treat accidental administration of methotrexate: The recommended dose of Levotonal should be equal to or greater than the amount of methotrexate accidentally administered, within 1 hour after methotrexate administration. In such cases, if Levotonal is administered later, its antidotal effect will be less effective.

Treatment of folate-deficiency anemias
The recommended dose is 5 mg of Levotonal injected directly into a muscle for 10–15 days.
Subsequently, if your body responds positively to this initial phase of treatment, the dose may be reduced to 2.5 mg of Levotonal daily until blood tests return to normal and symptoms have disappeared.

If you forget to take Levotonal
Do not take a double dose to make up for the forgotten dose.

If you take more levo-folinic acid than you should
Excessive doses of levo-folinic acid may counteract the chemotherapeutic effect of folic acid antagonists.
If you have any questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Stop treatment immediately and contact your doctor if you experience any of the following symptoms:

• swelling of the face or throat, difficulty breathing (bronchospasm), or dizziness. These may be signs of a severe allergic reaction (anaphylactic shock);
• Stevens-Johnson syndrome, a serious acute hypersensitivity reaction affecting the skin and mucous membranes in various parts of the body, with areas of necrosis and skin detachment. This reaction can sometimes be fatal;
• toxic epidermal necrolysis, a serious acute hypersensitivity reaction, with almost complete necrosis of the skin and mucous membranes. This reaction can be fatal.

Other possible side effects include:

• urticaria;
• low blood pressure (arterial hypotension);
• increased heart rate (tachycardia).

Rare cases of serious adverse reactions, sometimes fatal, have been reported in preterm neonates and infants under or equal to 28 days of age treated with calcium folinate concomitantly with ceftriaxone (an antibiotic). Indeed, when administered together, these two medicines may lead to the formation of calcium-ceftriaxone salts, which may impair normal organ function (e.g. lungs or kidneys), particularly in immature organisms such as those of neonates.
Cases of precipitation of calcium-ceftriaxone salts have also been reported in children over 3 years of age receiving high doses, in patients with specific risk factors (e.g. dehydration or prolonged immobilization), or in patients receiving doses higher than recommended.
This effect usually causes no symptoms, but in rare cases pain, nausea, and vomiting have been reported. The effect is usually reversible upon discontinuation of treatment.

Very rare (may affect up to 1 in 10,000 people)

• severe allergic reactions that may present as sudden itchy rash (urticaria), swelling of hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty swallowing or breathing), and may make you feel like fainting. These signs may indicate a serious condition and require urgent medical attention.

Uncommon (may affect up to 1 in 100 people)

• fever.

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

• increased seizures (fits) in patients with epilepsy;
• syncope;
• depression;
• agitation;
• gastrointestinal problems;
• difficulty sleeping (insomnia).

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at the following website:
http://www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Levotonal

Before reconstitution:
this medicinal product requires no special storage conditions.
After reconstitution:
the reconstituted solution can be stored for 12 hours, protected from light.
Keep this medicine out of the sight and reach of children.
Do not use this medicinal product after the expiry date stated on the carton after "Exp.".
The expiry date refers to the last day of that month.
Do not dispose of any medicinal product via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Levotonal contains

• The active substance is calcium levofolinate (as levo-folinic acid). One vial contains 27 mg of calcium levofolinate (equivalent to 25 mg of levo-folinic acid).
• The other components are: mannitol, sodium hydroxide and/or hydrochloric acid.

Description of the appearance of Levotonal and package contents
Levotonal 25 mg, powder for injectable solution, is supplied in a box containing 1 glass vial with the powder.
Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
Pharmacare Srl, Via Marghera, 29 - 20149 Milan, Italy
Manufacturer
Biologici Italia Laboratories S.r.l. - Via F. Serpero, 2 - 20060 Masate (MI)

Patient information leaflet: information for the patient

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

levofolinic acid (as levofolinate calcium)
Generic medicine
Please read 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 nurse.
• 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 may be harmful.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor or nurse. See section 4.

Contents of this leaflet:

1. What Levotonal is and what it is used for
2. What you need to know before taking Levotonal
3. How to take Levotonal
4. Possible side effects
5. How to store Levotonal
6. Contents of the pack and other information

1. What Levotonal is and what it is used for

Levotonal contains the active substance levo-folinic acid (in the form of levofolinic calcium), which is a
vitamin of the B group that can be used:

• to reduce side effects and to treat the effects of excessive doses of certain anticancer drugs (for example methotrexate and aminopterin) or other substances that antagonize folic acid;
• to enhance the effects of 5-fluorouracil, an anticancer medicine.

2. What you need to know before taking Levotonal

Leucovorin acid must not be administered intrathecally (into the spinal canal).
Do not take Levotonal

• if you have previously experienced symptoms of hypersensitivity (severe allergy) or are allergic to the active substance or to any of the other ingredients of this medicine (listed in section 6);
• if you suffer from a particular type of anaemia caused by vitamin B12 deficiency.

Levotonal must NOT be given to neonates aged 28 days or younger
who are receiving an antibiotic called ceftriaxone.
Warnings and precautions

Talk to your doctor or nurse before taking Levotonal:

• if you have cancer, have metastases to the central nervous system, and are taking medicines belonging to the fluoropyrimidine family (e.g. 5-fluorouracil), because
  you may experience seizures or fainting, especially if you are already predisposed to such conditions;

• if you are also being treated with 5-fluorouracil and develop diarrhoea, mouth mucosal infections, or a reduced number of white blood cells in the blood;

• if you are undergoing cancer treatment with any of the following medicines: hydroxycarbamide, cytarabine, mercaptopurine, thioguanine. These medicines may cause the formation in the blood of red blood cells larger than normal (a condition known as "macrocytosis"). This condition must not be treated with Levotonal;

• if you have epilepsy and are being treated with any of the following medicines: phenobarbital, phenytoin, primidone, succinimides. Combination with Levotonal may increase the frequency of epileptic seizures. Your doctor will monitor you frequently and may adjust the dose of your antiepileptic medicine during and after treatment with Levotonal (see section "Other medicines and Levotonal").

If you are receiving concomitant treatment with leucovorin acid and fluorouracil, pay special attention if:

• you have undergone radiotherapy;
• you have stomach or intestinal problems.
  If any of the above conditions apply to you, inform your doctor before using this medicine.
  Particular caution is also required if you are elderly and receiving concomitant treatment with leucovorin acid and fluorouracil.
  Levotonal powder for infusion solution must be administered intravenously only via infusion (infusion administration). Other routes of administration must be avoided.

Laboratory tests
If you are being treated with methotrexate (an anticancer medicine) and leucovorin acid, your doctor will perform daily blood tests and, if necessary, urine tests.
Additionally, if you are receiving concomitant treatment with folinic acid and 5-fluorouracil, depending on your health status prior to taking these medicines and your response to therapy, your doctor will perform blood tests and certain medical checks before starting treatment and periodically thereafter to monitor liver function.

Other medicines and Levotonal
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, as some may interact with leucovorin acid, for example:

• Folic acid antagonists (e.g. methotrexate, cotrimoxazole, pyrimethamine): leucovorin acid (as levofolinic acid calcium) may reduce or completely neutralize the effectiveness of folic acid antagonists when administered concomitantly. For this reason, it is used as an antidote in cases of overdose with these medicines.
• Anticancer medicines such as fluorouracil and capecitabine: leucovorin acid enhances the effect of these medicines and may therefore increase both their efficacy and their adverse effects. 5-fluorouracil must not be mixed with Levotonal in the same intravenous infusion.
• Medicines used to treat epilepsy (phenobarbital, phenytoin, primidone, succinimides): the effectiveness of these medicines may be reduced by leucovorin acid. Your doctor will monitor blood levels of these medicines and adjust their dosage to prevent an increase in seizures (number of attacks).

Ceftriaxone: the use of calcium levofolinate together with ceftriaxone should be avoided in neonates under 28 days of age, as there is a risk of forming salt precipitates in the blood, which could be life-threatening for the infant. In all other patients, the two medicines may be administered sequentially, provided the doctor follows appropriate precautions regarding the administration method.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor or nurse before taking this medicine.
During breastfeeding, Levotonal should only be administered when the benefits of the medicine to the mother outweigh the potential risks to the infant.
During pregnancy and breastfeeding, it is generally inappropriate to administer anticancer medicines, which are co-administered with calcium leucovorinate as part of a specific therapeutic protocol.
It is unlikely that your doctor will prescribe a folic acid antagonist or fluorouracil during pregnancy or breastfeeding. However, if you are taking a folic acid antagonist during pregnancy or breastfeeding, this medicine (leucovorin acid) may be used to reduce its adverse effects.

Driving and using machines
Levotonal does not impair the ability to drive or operate machinery.

3. How to take Levotonal

Administration must be performed only by qualified healthcare personnel, and the dose will be determined according to the specific therapeutic protocol that your doctor will define for you personally.

Preparation of the solution
Levotonal 100 mg, powder for solution for infusion:
dissolve the contents of the vial in 10 ml of water for injections.
Levotonal 175 mg, powder for solution for infusion:
dissolve the contents of the vial in 15–20 ml of water for injections.
The resulting solutions are compatible with glucose solutions and sodium chloride solution (physiological saline).
When Levotonal is administered intravenously, no more than 80 mg of active substance should be administered per minute due to the presence of calcium. This medicine must not be administered by intrathecal route.

Combination therapy with fluoropyrimidines (e.g., for treatment of colorectal cancer)
The dosage will be chosen by the physician based on the adopted chemotherapy protocol. The most frequently used dose in combination with 5-fluorouracil is 100 mg/m²/day for 5 consecutive days by slow infusion (10 min.), every 4 weeks, or 250 mg/m²/week for 6 weeks, followed by a 2-week interval.

Treatment of toxic effects caused by high doses of antineoplastic drugs (e.g., methotrexate)
The recommended dose is 100 mg/m² for serum methotrexate levels of 10 M.
The dose may be proportionally increased according to higher blood methotrexate levels.

If you forget to take Levotonal
A double dose must not be administered to compensate for a missed dose.

If you take more leucovorin acid than you should
Excessive doses of leucovorin acid may counteract the chemotherapeutic effect of folic acid antagonists.
In case of overdose due to combination of 5-fluorouracil and leucovorin acid, follow the instructions provided for 5-fluorouracil overdose.

If you have any doubts about the use of this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Stop treatment immediately and contact your doctor if you experience any of the following symptoms:

• swelling of the face or throat, difficulty breathing (bronchospasm), or dizziness. These may be signs of a severe allergic reaction (anaphylactic shock);
• Stevens-Johnson syndrome, a serious 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 serious acute hypersensitivity reaction, with almost complete necrosis of the skin and mucous membranes. This reaction can be fatal.

Other possible side effects include:

• urticaria;
• low blood pressure (arterial hypotension);
• increased heart rate (tachycardia).

Very rare (may affect up to 1 in 10,000 people)

• severe allergic reactions which may present as sudden itchy rash (urticaria), swelling of hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing), and may make you feel faint. These signs may indicate a serious condition and require urgent medical attention.

Uncommon (may affect up to 1 in 100 people)

• fever.

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

• increased frequency of seizures (number of attacks) in patients with epilepsy;
• syncope;
• depression;
• agitation;
• gastrointestinal problems;
• difficulty sleeping (insomnia).

If you are taking levo-folinic acid in combination with anticancer medicines containing fluoropyrimidines, the following side effects are more likely:

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

• nausea;
• vomiting;
• severe diarrhoea;
• dehydration probably caused by diarrhoea;
• inflammation of the lining of the intestine and mouth (which may be life-threatening);
• decreased number of blood cells (including conditions that may be life-threatening).

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 cause skin peeling (palmar-plantar syndrome).

Frequency not known (frequency cannot be estimated from the available data)

• elevated levels of ammonia in the blood.

Serious adverse reactions, sometimes fatal, have been rarely reported in premature infants and in infants aged 28 days or younger treated with calcium levofolinate together with ceftriaxone (an antibiotic). In fact, when these two medicines are administered together, they may lead to the formation of calcium-ceftriaxone salts, which may impair normal organ function (e.g. lungs or kidneys), especially in immature organisms such as those of newborn infants.
Cases of precipitation of calcium-ceftriaxone salts have also been reported in children over 3 years of age receiving high doses, in patients with specific risk factors (e.g. dehydration or prolonged immobilization), or in patients receiving doses higher than recommended.
This effect usually causes no symptoms, but in rare cases pain, nausea and vomiting have been reported. The effect is usually reversible upon discontinuation of administration.

Reporting of side effects
If you experience any side effect, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at the following website:
http://www.agenziafarmaco.gov.it/it/responsabili.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Levotonal

Before reconstitution:
this medicinal product requires no special storage conditions.
After reconstitution:
the reconstituted solution can be stored for 12 hours, protected from light.
Keep this medicinal product out of the sight and reach of children.
Do not use this medicinal product after the expiry date which is stated on the carton after “Exp.”.
The expiry date refers to the last day of that month.
Do not dispose of any medicinal product via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Levotonal contains
Levotonal 100 mg, powder for solution for infusion:

• The active substance is calcium levofolinate (as levo-folinic acid). One vial contains 108 mg of calcium levofolinate (equivalent to 100 mg of levo-folinic acid).
• The other components are: mannitol, sodium hydroxide and/or hydrochloric acid.

Levotonal 175 mg, powder for solution for infusion:

• The active substance is calcium levofolinate (as levo-folinic acid). One vial contains 189 mg of calcium levofolinate (equivalent to 175 mg of levo-folinic acid).
• The other components are: mannitol, sodium hydroxide and/or hydrochloric acid.

Description of the appearance of Levotonal and contents of the pack
Levotonal powder for solution for infusion is presented in a box containing 1 glass vial with the powder.
Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
Pharmacare Srl, Via Marghera, 29 - 20149 Milan, Italy
Manufacturer
Biologici Italia Laboratories S.r.l. - Via F. Serpero, 2 - 20060 Masate (MI)