LEVOTONAL 25 mg Порошок Для Инъекционного Раствора

Содержание инструкции

1. Levotonal 25 mg, powder for injectable solution
   1. What is Levotonal and what is it used for
   2. What you need to know before you take Levotonal
   3. How to take Levotonal
   4. Possible side effects
   5. How to store Levotonal
   6. Contents of the pack and other information
2. Levotonal 100 mg, powder for infusion solution, 175 mg, powder for infusion solution
   1. What is Levotonal and what is it 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

Levotonal 25 mg, powder for injectable solution

levo-folinic acid (in the form of calcium levofolinate)
Generic medicine

Read this leaflet carefully before you start to use 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 pass it on to others, even if they have the same symptoms as you, as it may be harmful.
• If you get any side effects, even those not listed in this leaflet, tell 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 you use 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 is Levotonal and what is it used for

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

• to reduce the undesirable effects and to treat the effects of excessive doses of some antineoplastic medicines (for example methotrexate and aminopterin) or other substances that counteract folic acid;
• to treat anemias caused by a deficiency of folates (due to increased demand, reduced utilization, insufficient dietary intake of folates in the body).

2. What you need to know before you take Levotonal

Levo-folinic acid should not be administered via the intrathecal route (into the spinal cord).

Do not take Levotonal:

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

Levotonal must NOT be administered to newborns, aged 28 days or less, who are taking an antibiotic called ceftriaxone.

Warnings and precautions
Talk to your doctor or pharmacist before taking Levotonal:

• if you have cancer, have metastases to the central nervous system and are taking medicines that belong to the fluoropyrimidine family (e.g. 5-fluorouracil), because you may experience convulsions or be subject to fainting, especially if you are already predisposed to these conditions;
• if you suffer from pernicious anemia or other anemias caused by vitamin B12 deficiency, because in this case any intake of folates (such as Levotonal) must only occur under strict medical supervision.
• are undergoing treatment for cancer with one of the following medicines: hydroxycarbamide, cytarabine, mercaptopurine, thioguanine. These medicines can cause the formation of red blood cells with a diameter larger than normal in the blood (a condition known as “macrocytosis”). This condition should not be treated with Levotonal;
• suffer from epilepsy and are undergoing treatment with one of the following medicines: phenobarbital, phenytoin, primidone, succinimide. The combination with Levotonal may cause an increase in the frequency of epileptic seizures. Your doctor will subject you to frequent checks and may modify the dosage of the medicine against epilepsy during and after discontinuation of Levotonal (see section Other medicines and Levotonal);

When Levotonal is used to treat side effects caused by an excessive dose of certain anticancer drugs, it will be administered within 1 hour, or in any case no later than 4 hours, after taking the drugs that caused you problems.

Laboratory tests
If you are being treated with methotrexate (an anticancer medicine) and levo-folinic acid, your doctor will subject you to daily blood tests and possibly also urine tests.

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

• Folic acid antagonists(e.g. methotrexate, cotrimoxazole and pyrimethamine): levo-folinic acid (in the form of calcium levofolinate) when administered in combination with a folic acid antagonist can reduce or completely neutralize its effectiveness. For this reason, it is used as an antidote in cases of overdose of these medicines.
• Fluorouracil(an anticancer medicine): levo-folinic acid can enhance the effectiveness and undesirable 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 for the treatment of epilepsy(phenobarbital, phenytoin, primidone and succinimide): the effectiveness of these medicines may be reduced by levo-folinic acid. Your doctor will check the levels of these medicines in the blood and modify the dose of the latter to prevent an increase in convulsions (number of seizures). Ceftriaxone: the use of calcium levofolinate together with ceftriaxone should be avoided in newborns, aged 28 days or less, because there is a risk that salt precipitates may form in the blood, endangering the child's life. In all other patients, the two medicines can be administered, one after the other, only if the doctor adopts the correct precautions regarding the method of administration.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant or are planning a pregnancy, or if you are breastfeeding, ask your doctor or pharmacist for advice before taking this medicine.
During breastfeeding, Levotonal should only be administered when the benefits of the medicine for the mother outweigh the possible risks to the infant.
During pregnancy and breastfeeding, it is generally inadvisable to administer anticancer drugs, with which calcium levofolinate is co-administered within a specific therapeutic protocol. It is unlikely that your doctor will prescribe a folic acid antagonist during pregnancy or breastfeeding. In any case, if you are taking a folic acid antagonist during pregnancy or breastfeeding, this medicine (levo-folinic acid) can be used to reduce its undesirable effects.

Driving and operating machinery
Levotonal does not impair the ability to drive vehicles and operate machinery.

3. How to take Levotonal

Take this medicine following exactly the instructions of your doctor or nurse. If you have any doubts, ask your doctor or nurse.
Levotonal can be administered as follows:

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

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

Therapy to neutralize the toxic effects caused by anticancer drugs (e.g. methotrexate)
In these cases Levotonal can be administered with different doses according to the effect you want to
achieve and based on a specific therapeutic protocol that the doctor will define for you personally.
The necessary dose depends on your general condition and the dose administered of
methotrexate. The use of Levotonal can help control the toxicity of anticancer drugs
used at high dosage in some therapeutic regimens.

• To treat an accidental overdose of methotrexate:The doctor will choose the dosage based on the effect he/she wants to achieve. To obtain a competitive effect, the recommended dose can reach up to 50 mg of Levotonal, administered with an infusion, within 12 hours of methotrexate abuse. To obtain, instead, a biochemical-metabolic effect, the recommended dose is 5 - 6 mg of Levotonal, injected directly into a muscle or into a vein every 6 hours, for 4 times.
• To treat side effects caused by normal doses of methotrexate:The recommended dose is 5 - 6 mg of Levotonal, injected directly into a muscle or into a vein every 6 hours, for 4 times.
• To treat an accidental administration of methotrexate:The recommended dose of Levotonal must be equal to or greater than that of methotrexate accidentally administered, within 1 hour of the administration of the latter. In these cases if Levotonal were administered later, its antidote action will be less effective.

Therapy for folate deficiency anemias
The recommended dose is 5 mg of Levotonal, injected directly into a muscle, for 10 - 15 days.
Subsequently, in case of a positive response of the body to this first phase of therapy, the dose
may be halved to 2.5 mg of Levotonal per day, until blood tests return to normal and symptoms disappear.

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

If you take more levofolinic acid than you should
Excessive doses of levofolinic acid can cancel out the chemotherapeutic effect of folic acid antagonists.
If you have any doubts about the use of this medicine, ask 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 doctorif 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 severe acute hypersensitivity reaction of the skin and mucous membranes in various parts of the body, with the formation of areas of necrosis and peeling. This reaction can sometimes be fatal;
• toxic epidermal necrolysis, a severe acute hypersensitivity reaction, with almost total necrosis of the skin and mucous membranes. This reaction can be fatal.

Other side effects may be:

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

Rarely, cases of serious adverse reactions, sometimes fatal, have been reported in premature infants and in
infants aged 28 days or less, treated with calcium levofolinate simultaneously with
ceftriaxone (an antibiotic). These two medicines, in fact, if administered together, can lead to
the formation of salts that can compromise the normal function of organs such as the lungs or
kidneys, especially in immature organisms such as those of newborns.
Cases of precipitation of calcium-ceftriaxone salts have also been reported in children over 3 years of
age treated with high doses, in patients with particular risk factors (e.g. dehydration or
prolonged immobilization) or in patients treated with doses higher than those recommended.
This effect usually does not cause any symptoms, but in rare cases pain, nausea and
vomiting have been reported. The effect is usually reversible with discontinuation of administration.
Very rare (may affect up to 1 in 10,000)

• severe allergic reactions that can manifest with a sudden itchy rash (urticaria), swelling of the hands, feet, ankles, face, lips, mouth or throat (which can cause difficulty swallowing or breathing), and give you a feeling of fainting. These signs may be a symptom of a serious condition and require urgent medical attention.

Not Common (may affect up to 1 in 100)

• fever.

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

• increased seizures (attacks) in patients suffering from 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
through the national reporting system at:
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 medicine does not require any particular 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 medicine after the expiry date which is stated on the pack after “Exp.”.
The expiry date refers to the last day of that month.
Do not dispose of any medicine in wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack and other information

What Levotonal contains

• The active ingredient 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 ingredients are: mannitol, sodium hydroxide and/or hydrochloric acid.

Description of the appearance of Levotonal and contents of the pack
Levotonal 25 mg, powder for injectable solution is presented in a box containing 1 vial
of glass with the powder.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder
Pharmacare Srl, Via Marghera, 29- 20149 Milano Italia

Manufacturer
Biologici Italia Laboratories S.r.l. - Via F. Serpero, 2 - 20060 Masate (MI)

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

levo-folinic acid (in the form of calcium levofolinate)
Equivalent medicinal product

Read this leaflet carefully before you start to use this medicine as 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 pass it on to others, even if their symptoms are the same as yours, as it could be harmful.
• If you get any side effects, even those not listed in this leaflet, tell 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 you use 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 is Levotonal and what is it used for

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

• to reduce the undesirable effects and to treat the effects of excessive doses of some antineoplastic medicines (for example methotrexate and aminopterin) or other substances that counteract folic acid;
• to enhance the effects of 5-fluorouracil, an antineoplastic medicine.

2. What you need to know before taking Levotonal

Levo-folinic acid must not be administered via the intrathecal route (into the spinal cord).
Do not take Levotonal

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

Levotonal must NOT be administered to newborns, aged 28 days or less, who
are taking 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 that belong to the fluoropyrimidine family (e.g. 5-fluorouracil), because

you may experience convulsions or be subject to fainting, especially if you are a person already
predisposed to these conditions of discomfort;

• if you are also being treated with 5-fluorouracil and should experience diarrhea, infections of the mucous membranes of the mouth or a decrease in the number of white blood cells in the blood.
• you are undergoing treatment for cancer with one of the following medicines: hydroxycarbamide, cytarabine, mercaptopurine, thioguanine. These medicines can cause the formation of red blood cells with a diameter larger than normal in the blood (a condition known as “macrocytosis”). This condition should not be treated with Levotonal;
• suffer from epilepsy and are taking one of the following medicines: phenobarbital, phenytoin, primidone, succinimide. Combination with Levotonal may cause an increase in the frequency of epileptic seizures. Your doctor will subject you to frequent checks and may modify the dosage of the anti-epileptic medicine during and after discontinuation of Levotonal (see section Other medicines and Levotonal);

If you are undergoing concomitant treatment with levo-folinic acid and fluorouracil, pay particular
attention if:

• you have undergone radiotherapy;
• you have problems with your stomach or intestines. If any of the above conditions apply to you, inform your doctor before using this medicine. Particular attention is also required if you are elderly and are taking levo-folinic acid and fluorouracil together. Levotonal powder for solution for infusion must be injected exclusively into a vein with an infusion (infusion administration). Other routes of administration must be avoided.

Laboratory tests
If you are being treated with methotrexate (an anti-cancer medicine) and levo-folinic acid, your doctor will
subject you to daily blood tests and possibly also urine tests.
Furthermore, if you are receiving concomitant treatment with folinic acid and 5-fluorouracil, based on your previous health status before taking these medicines and your response to therapy, your doctor will subject you to blood tests and some
medical checks to verify your liver function before
starting treatment and then periodically.

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

• Folic acid antagonists(e.g. methotrexate, cotrimoxazole and pyrimethamine): levo-folinic acid (in the form of calcium levofolinate) if administered in combination with a folic acid antagonist may reduce or completely neutralize its effectiveness. For this reason, it is used as an antidote in cases of overdose of these medicines.
• Anticancer drugs, such as fluorouracil and capecitabine):levo-folinic acid is a potentiator of these medicines and can therefore increase their effectiveness and undesirable effects. 5-fluorouracil must not be mixed with Levotonal in the same intravenous infusion.
• Medicines used for the treatment of epilepsy(phenobarbital, phenytoin, primidone and succinimide): the effectiveness of these medicines may be reduced by levo-folinic acid. The doctor will check the levels of these medicines in the blood and modify the dose of the latter to prevent an increase in convulsions (number of attacks).

Ceftriaxone: the use of calcium levofolinate together with ceftriaxone should be avoided in newborns, aged
less than 28 days, because there is a risk that salt precipitates may form in the blood,
endangering the child's life. In all other patients, the two medicines can be
administered, one after the other, only if the doctor adopts the correct precautions regarding the method
of administration.

Pregnancy and breastfeeding
If you are pregnant, suspect you are pregnant or are planning to become pregnant, or if you are breastfeeding with
breast milk, ask your doctor or nurse for advice before taking this medicine.
During breastfeeding, Levotonal should only be administered when the benefits of the medicine for the
mother outweigh the possible risks to the infant.
During pregnancy and breastfeeding, it is generally inadvisable to administer anticancer drugs,
with which calcium levo-folinate is co-administered within a specific therapeutic protocol.
It is unlikely that your doctor will prescribe a folic acid antagonist or fluorouracil during
pregnancy or breastfeeding. In any case, if you are taking a folic acid antagonist
during pregnancy or breastfeeding, this medicine (levo-folinic acid) can be used
to reduce its undesirable effects.

Driving and operating machinery
Levotonal does not impair the ability to drive vehicles and operate machinery.

3. How to take Levotonal

Administration must be carried out only by qualified healthcare personnel and the dose will be established based on the specific therapeutic protocol that the doctor will define for you personally.

Preparation of the solution

Levotonal 100 mg, powder for solution for infusion:
dilute the contents of the vial in 10 ml of water for injectable preparations.

Levotonal 175 mg, powder for solution for infusion:
dilute the contents of the vial in 15 - 20 ml of water for injectable preparations.
The solutions thus obtained are compatible with glucose solution and physiological solution.
When Levotonal is administered intravenously, it is important that no more than 80 mg of active ingredient per minute are administered due to the presence of calcium. This medicine must not be administered by the intrathecal route.

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

Therapy of toxic effects caused by high doses of anticancer drugs (for example methotrexate)
The recommended dose is 100 mg/m² for methotrexate serum levels equal to 10 M.
The dose can be increased proportionally to the higher levels of methotrexate present in the
blood.

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

If you take more levo-folinic acid than you should
Excessive doses of levo-folinic acid can cancel out the chemotherapeutic effect of folic acid antagonists.
In case of overdose due to the combination of 5-fluorouracil and levo-folinic acid, it is
necessary to follow the instructions provided for 5-fluorouracil overdose.
If you have any doubts about the use of this medicine, please contact 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 doctorif 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 severe acute hypersensitivity reaction of the skin and mucous membranes in various parts of the body, with the formation of areas of necrosis and peeling. This reaction can sometimes be fatal;
• Toxic Epidermal Necrolysis, a severe acute hypersensitivity reaction, with almost total necrosis of the skin and mucous membranes. This reaction can be fatal.

Other side effects may be:

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

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

• severe allergic reactions that can manifest with a sudden itchy rash (urticaria), swelling of the hands, feet, ankles, face, lips, mouth or throat (which can cause difficulty swallowing or breathing), and give you a feeling of fainting. These signs may be a symptom of a serious condition and require urgent medical attention.

Not Common (may affect up to 1 in 100 people)

• fever.

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

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

If you take levo-folinic acid in combination with anticancer medicines containing fluoropyrimidines,
you are more likely to experience the following side effects:
Very Common (may affect more than 1 in 10 people)

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

Common (may affect up to 1 in 10 people)

• redness and swelling of the palms of the hands, or the soles of the feet, which may cause peeling of the skin (palmo-plantar syndrome).

Not known (frequency cannot be estimated from available data)

• elevated levels of ammonia in the blood

Rarely, serious adverse reactions, sometimes fatal, have been reported in premature infants and in
infants aged 28 days or less, treated with calcium levofolinate simultaneously with
ceftriaxone (an antibiotic). These two medicines, in fact, if administered together, can lead to
the formation of salts that can compromise the normal functioning of organs such as the lungs or
kidneys, especially in immature organisms like those of newborns.
Cases of precipitation of calcium-ceftriaxone salts have also been reported in children over 3 years of
age treated with high doses, in patients with particular risk factors (e.g. dehydration or
prolonged immobilization) or in patients treated with doses higher than the recommended one.
This effect usually does not cause any symptoms, but in rare cases pain, nausea and
vomiting have been reported. The effect is usually reversible with discontinuation of administration.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. You can also report side effects directly
through the national reporting system at: 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 medicine does not require any particular 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 medicine after the expiry date which is stated on the pack after “Exp.”.
The expiry date refers to the last day of that month.
Do not dispose of any medicine in wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack and other information

What Levotonal contains

Levotonal 100 mg, powder for solution for infusion:

• The active ingredient 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 ingredients are: mannitol, sodium hydroxide and/or hydrochloric acid.

Levotonal 175 mg, powder for solution for infusion:

• The active ingredient 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 ingredients 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 vial of
glass with the powder.

Marketing authorisation holder and manufacturer

Marketing authorisation holder
Pharmacare Srl, Via Marghera, 29- 20149 Milano Italia

Manufacturer
Biologici Italia Laboratories S.r.l. - Via F. Serpero, 2 - 20060 Masate (MI)