Calcium folinate Teva Generics: detailed information

Package leaflet: Information for the user

Calcio levofolinato Teva Generics 10 mg/ml solution for injection

levoleucovorin calcium
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.
This medicine has been prescribed for you only. Do not give it to other people, even if they have the same symptoms as yours, because it could be harmful.
If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet

What Calcio levofolinato Teva Generics is and what it is used for
What you need to know before using Calcio levofolinato Teva Generics
How to use Calcio levofolinato Teva Generics
Possible side effects
How to store Calcio levofolinato Teva Generics
Contents of the pack and other information

1. What Calcio levofolinato Teva Generics is and what it is used for

Calcio levofolinato Teva Generics contains the active substance calcio levofolinato, which belongs to the
vitamin B group. Calcio levofolinato plays a crucial role in the body in the
production of red blood cells, and in the synthesis of DNA (an organic substance containing all the
genetic information necessary for cell function) and proteins.
Calcio levofolinato Teva Generics is used:

to treat adverse effects caused by the use of high doses of other medicines (folic acid antagonists), such as methotrexate and aminopterin, used in the treatment of certain tumours;
as rescue therapy following treatment with the medicine methotrexate;
to enhance the effectiveness of another medicine, 5-fluorouracil, used in the treatment of certain tumours (cytotoxic chemotherapy).

2. What you need to know before using Calcio levofolinato Teva Generics

Calcio levofolinato Teva Generics must not be administered to you:

if you are allergic to levofolinic acid calcium or to any of the other ingredients of this medicine (listed in section 6).

Calcio levofolinato Teva Generics must not be administered concomitantly with ceftriaxone
(an antibiotic), even if separate infusion lines are used.
Warnings and precautions
Talk to your doctor, pharmacist or nurse before using Calcio levofolinato Teva Generics.
Inform your doctor before using Calcio levofolinato Teva Generics if you are being treated:

for cancer with any of the following medicines: hydroxycarbamide, cytarabine, mercaptopurine, thioguanine; a condition may occur in which red blood cells are larger than normal (macrocytosis) which should not be treated with folinic acid;
for epilepsy with any of the following medicines: phenobarbital, phenytoin, primidone and succinimides; an increase in epileptic seizures may occur.

This medicine may be used in combination with methotrexate or 5-fluorouracil
(anticancer medicines) only under the direct supervision of a physician experienced in the use of anticancer drugs.
Treatment with Calcio levofolinato Teva Generics and 5-fluorouracil
If you are to be treated simultaneously with calcium levofolinic acid and 5-fluorouracil (an anticancer medicine), pay special attention if:

you have undergone radiotherapy;
you have stomach or intestinal problems;
you are elderly or debilitated.

Inform your doctor if any of the above conditions apply to you before this medicine is administered.
Before and during combined treatment with Calcio levofolinato Teva Generics and 5-fluorouracil, your doctor will perform frequent checks to monitor:

calcium levels in the blood;
blood test results, particularly complete blood count and electrolytes;
whether your liver is functioning properly.

Treatment with Calcio levofolinato Teva Generics and methotrexate
Calcio levofolinato Teva Generics must not be administered by intrathecal injection (injection into the spinal canal). Intrathecal administration of Calcio levofolinato Teva Generics to counteract an excessive intrathecal dose of methotrexate may result in death.
Talk to your doctor before receiving Calcio levofolinato Teva Generics together with methotrexate (an anticancer medicine) if you think any of the following conditions apply to you:

your kidneys are not working properly (renal insufficiency). Your doctor may decide to increase the dose or duration of administration of this medicine;
you are taking other medicines that may interact with methotrexate, as these may alter the results of certain laboratory tests. Your doctor will determine the most appropriate dose of Calcio levofolinato Teva Generics for you to avoid damage to other organs (e.g. kidney, central nervous system).

If you have been treated with excessive doses of methotrexate, Calcio levofolinato Teva Generics must be administered as soon as possible to counteract the toxicity of this medicine. Calcio levofolinato Teva Generics is more effective the sooner it is administered after methotrexate.
Laboratory tests
Your doctor will perform frequent blood and urine tests during treatment with Calcio levofolinato Teva Generics together with methotrexate to monitor your condition.
Other medicines and Calcio levofolinato Teva Generics
Inform your doctor or nurse if you are taking, have recently taken or might take any other medicines.
Particular caution is required if you are taking/using other medicines that could interact with calcium levofolinic acid, for example:

folic acid antagonists, e.g. cotrimoxazole (an antibiotic used to treat bacterial infections), pyrimethamine (a medicine used for malaria), methotrexate (a medicine used to treat cancer, rheumatic diseases and skin conditions) – the effectiveness of these medicines will be reduced or completely neutralized by calcium levofolinic acid;
5-fluorouracil (a medicine used to treat cancer) and fluoropyrimidines (a group of medicines including 5-fluorouracil) – the effectiveness and side effects of this medicine will be increased by calcium levofolinic acid. 5-fluorouracil must not be mixed with Calcio levofolinato Teva Generics in the same injection or intravenous infusion;
medicines used to treat epilepsy, e.g. phenobarbital, phenytoin, primidone or succinimides – the effectiveness of these medicines may be reduced by calcium levofolinic acid. Your doctor may monitor blood levels of these medicines and adjust the dose to prevent an increase in seizures (epileptic attacks);
chloramphenicol (an antibiotic used to treat bacterial infections) because it may interfere with the action of folic acid;
ceftriaxone (an antibiotic used to treat bacterial infections). Do not use ceftriaxone concomitantly with calcium levofolinic acid, even if separate infusion lines are used, due to potentially fatal outcomes.

Calcio levofolinato Teva Generics with food and drink
During treatment, foods (e.g. cheese, egg yolk, white and red meat, fish; dried fruit, legumes and cereals), drinks (e.g. blueberry juice and yogurt) and medicines that may increase urinary acidity (e.g. those containing bicarbonate) should be avoided.
Pregnancy, breastfeeding and fertility
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before this medicine is administered to you.
Pregnancy
There are no adequate studies in pregnant women. Harmful effects of folic acid administered during pregnancy are not known.
Breastfeeding
Calcium levofolinic acid may be excreted in breast milk. Calcium levofolinic acid may be used during breastfeeding only if your doctor considers that the benefits to the mother outweigh the risks to the infant.
Fertility
No studies on reproductive toxicity have been conducted in animals with calcium levofolinic acid.
Driving and using machines
It is not known whether this medicine impairs the ability to drive or use machinery.
Calcio levofolinato Teva Generics contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per 2.5 ml vial, i.e. essentially “sodium-free”.
This medicine contains less than 1 mmol (23 mg) of sodium per 5 ml vial, i.e. essentially “sodium-free”.
This medicine contains 32 mg of sodium (the main component of table salt) per 10 ml vial. This corresponds to 1.6% of the maximum daily recommended dietary intake for an adult.
This medicine contains 56 mg of sodium (the main component of table salt) per 17.5 ml vial. This corresponds to 2.8% of the maximum daily recommended dietary intake for an adult.

3. How to use Calcium levofolinate Teva Generics

Calcium levofolinate Teva Generics is administered only in a hospital setting and under the close supervision of trained medical personnel. If you have any doubts, consult your doctor or nurse.
This medicine will be given to you exclusively by intravenous route (into a vein) by a doctor or nurse. It is important that no more than 80 mg of active substance per minute be administered, due to the presence of calcium in this medicine.
This medicine must not be administered by injection into the lower region of the spinal column (intrathecal route).
Calcium levofolinate Teva Generics may be used in combination with anticancer medicines such as methotrexate to reduce its side effects, as an antidote if you have received an excessive dose of methotrexate, and to enhance the effectiveness of 5-fluorouracil in the treatment of certain tumours. Your doctor will determine the dose, duration, and method of treatment with Calcium levofolinate Teva Generics based on your condition and other medicines you are taking.

If you have been given more Calcium levofolinate Teva Generics than you should have
It is very unlikely that you will receive more Calcium levofolinate Teva Generics than prescribed, as this medicine is administered under strict medical supervision.
Excessive amounts of calcium levofolinate may counteract the chemotherapeutic effect of folic acid antagonists.
In case of overdose with the combination of 5-fluorouracil and calcium levofolinate, follow the overdose instructions for 5-fluorouracil.

If you forget to use Calcium levofolinate Teva Generics
Since this medicine is administered under close medical supervision, it is unlikely that a dose will be missed. However, inform your doctor or nurse if you think a dose has been missed.

If you have any doubts about how this medicine is to be administered, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Contact your doctor immediately if you experience any of the following side effects, as they may be serious and sometimes fatal:

Stevens-Johnson syndrome, a severe acute hypersensitivity reaction affecting the skin and mucous membranes in various parts of the body, with areas of necrosis and skin peeling;
Toxic Epidermal Necrolysis, a severe acute hypersensitivity reaction causing almost complete necrosis of the skin and mucous membranes. Very rare (may affect up to 1 in 10,000 people)
severe allergic reaction (including anaphylactic shock) – you may experience a sudden rash with itching (urticaria), swelling of the hands, feet, ankles, face, lips, mouth and throat (which may cause difficulty swallowing and breathing), and may feel faint. This is a serious side effect. You may require urgent medical attention.

The following side effects may occur after administration of this medicine:
Uncommon (may affect up to 1 in 100 people)

fever.

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

increased frequency of seizures (crises);
seizures (sudden, uncontrolled, involuntary movements);
sudden and transient loss of consciousness (syncope);
depression, after high doses;
agitation, after high doses;
gastrointestinal problems (stomach and intestine), after high doses;
difficulty falling asleep, maintaining sleep, and poor sleep quality (insomnia), after high doses.

Side effects following administration of Calcium levofolinato Teva Generics together with 5-fluorouracil (an anticancer medicine)
The following side effects depend on the dose of 5-fluorouracil used.
Contact your doctor immediately if you experience any of the following side effects, as they may be serious (sometimes fatal), and your doctor may decide to discontinue treatment with Calcium levofolinato Teva Generics:

severe stomach and intestinal problems, which may also present as inflammation of the mucosa and diarrhea;
reduced production of blood cells such as red blood cells (anemia), white blood cells (increased susceptibility to infections), and platelets (bleeding) by the bone marrow (myelosuppression).

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

nausea;
vomiting;
diarrhea;
dehydration which may result from severe diarrhea, requiring hospitalization for treatment and even leading to death;
reduced production of blood cells such as red blood cells (anemia), white blood cells (increased susceptibility to infections), and platelets (bleeding) by the bone marrow (bone marrow failure), which may lead to death;
inflammation of the mucosa, including inflammation of the mouth (stomatitis) and inflammation of the lips manifesting as cracks, swelling, and ulcerations starting from the corners or edges and spreading over the lips (cheilitis). Life-threatening conditions have occurred as a consequence of mucositis.

Common (may affect up to 1 in 10 people)

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

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

elevated levels of ammonia in the blood (hyperammonemia).

Other side effects

excessive lowering of blood pressure (hypotension);
excessive acceleration of heart rate (tachycardia);
narrowing of the bronchi causing breathing difficulties (bronchospasm);
problems caused by calcium-ceftriaxone deposits which may lead to death in newborns.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at 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 Calcio levofolinato Teva Generics

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after "Exp.".
The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C – 8 °C).
Keep in the original packaging to protect the medicine from light.
Do not dispose of this medicine 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 Calcio levofolinato Teva Generics contains
Calcio levofolinato Teva Generics 10 mg/ml injectable solution

The active substance is levofolinic acid calcium hydrate. 1 ml of solution contains 10 mg of levofolinic acid.
The other components are sodium chloride, sodium hydroxide in pellets, hydrochloric acid 37%, water for injectable preparations.

Description of the appearance of Calcio levofolinato Teva Generics and package contents
Calcio levofolinato Teva Generics is an injectable solution, clear and colourless to yellow.
A 2.5 ml vial contains 25 mg of levofolinic acid.
A 5 ml vial contains 50 mg of levofolinic acid.
A 10 ml vial contains 100 mg of levofolinic acid.
A 17.5 ml vial contains 175 mg of levofolinic acid.
Each carton contains 1 or 5 vials.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Teva B.V.
Swensweg 5
2031 GA Haarlem
The Netherlands

Manufacturer
BIOLOGICI Italia Laboratories S.r.l.
Via Filippo Serpero, 2
Masate (MI)
Italy

The following information is intended exclusively for physicians or healthcare professionals

Therapeutic indications
Calcium levofolinate Teva Generics is useful as an antidote for excessive doses of folic acid antagonists and to counteract side effects induced by aminopterin (4-aminopteroyl-glutamic acid) and methotrexate (4-amino-N10-methyl-pteroyl-glutamic acid).
Calcium levofolinate Teva Generics is also indicated as "rescue" therapy following methotrexate treatment and as a potentiator of the effects of 5-fluorouracil in antineoplastic chemotherapy regimens.

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 of the SmPC;
Concomitant administration with ceftriaxone, even when separate infusion lines are used (see sections 4.5, 4.8 and 6.2 of the SmPC).

Posology and method of administration
Dosage
In high-dose methotrexate antineoplastic chemotherapy, therapeutic protocols typically involve parenteral administration of levoleucovorin in the first phase, corresponding to competitive antidotal action (doses used vary according to the regimen from 10 to 200 mg/m²/day); in the second phase, where the biochemical-metabolic component predominates, either parenteral or oral administration every 3–6 hours (10–12 mg/m²/day) may be used. However, general dosing regimens have not yet been definitively established.
Since calcium levofolinate is an antagonist of methotrexate, concomitant administration should only be performed after a specific therapeutic protocol has been defined for each individual case; consultation of the most recent literature on the subject is recommended.
In high-dose methotrexate "rescue", calcium levofolinate is effective in preventing myelosuppression at doses of 100 mg/m² for serum methotrexate levels of 10 µM. Doses may be proportionally increased for higher blood levels of the antineoplastic agent.
No specific recommendations are considered necessary during solution preparation, as calcium levofolinate lacks intrinsic cytotoxic activity.
In certain therapeutic protocols, calcium levofolinate may be used due to its ability to enhance the effects of 5-fluorouracil: under these conditions, dosages range from 15 to 25 mg/m²/day intravenously (low-dose folinate) up to 200–550 mg/m²/day via continuous infusion (high-dose folinate). The most commonly used dosages in combination with 5-fluorouracil are 100 mg/m²/day for 5 consecutive days via slow infusion (10 min.), every 4 weeks, or 250 mg/m²/week for 6 weeks followed by a 2-week break.
According to some therapeutic protocols, folinate infusion should begin 24 hours before and end 12 hours after completion of 5-fluorouracil treatment. However, even in this case, concomitant administration of calcium levofolinate and 5-fluorouracil should only be performed after a specific therapeutic protocol has been defined for each individual case; consultation of the most recent literature on the subject is recommended.

Antidote in case of methotrexate overdose
Calcium levofolinate must not be administered intrathecally.
Calcium levofolinate, the specific antidote for methotrexate, neutralizes the toxic effects of this antimetabolite on the hematopoietic system and gastrointestinal mucosa. As an antidote, calcium levofolinate is administered at various dosages depending on the desired effect.
In cases of accidental overdose, for competitive effect, intravenous infusion of calcium levofolinate is recommended (up to 50 mg within 12 hours); for a biochemical-metabolic effect, intravenous calcium levofolinate (5–6 mg every 6 hours for 4 doses) or oral administration (7.5 mg every 6 hours for 4 doses) is recommended. In cases of side effects from conventional methotrexate doses, intravenous calcium levofolinate (5–6 mg every 6 hours for 4 doses) or oral administration (7.5 mg every 6 hours for 4 doses) is recommended.
In cases of accidental administration, calcium levofolinate should be administered at doses equal to or higher than those of methotrexate within the first hour; administration at later times is less effective.

Method of administration
Calcium levofolinate Teva Generics 10 mg/ml solution for injection must be administered exclusively by intravenous route. It must not be administered intrathecally.
During intravenous administration, no more than 80 mg of calcium levofolinate per minute should be injected due to the calcium content of the solution.

Paediatric population
There are insufficient data on use in children and adolescents under 18 years of age.

Warnings and precautions
Calcium levofolinate Teva Generics must be administered only by intravenous injection and must not be administered intrathecally. Death has been reported when folic acid has been administered intrathecally following intrathecal overdose of methotrexate.

General recommendations
Calcium levofolinate Teva Generics should be used in combination with methotrexate or 5-fluorouracil only under the direct supervision of a physician experienced in the use of chemotherapeutic agents for cancer treatment.
Treatment with Calcium levofolinate Teva Generics may mask pernicious anemia and other anemias due to vitamin B12 deficiency.
Many cytotoxic medicinal products—direct or indirect inhibitors of DNA synthesis—cause macrocytosis (e.g., hydroxyurea, cytarabine, mercaptopurine, thioguanine). This macrocytosis should not be treated with folinic acid.
In epileptic patients treated with phenobarbital, phenytoin, primidone, and succinimides, there is a risk of increased seizure frequency due to decreased plasma concentrations of antiepileptic drugs. Monitoring of clinical and plasma concentrations is recommended, as dosage adjustment of the antiepileptic drug may be necessary during and after administration of calcium levofolinate (see section 4.5 of the SmPC).
In the treatment of overdose with folic acid antagonists, administration of calcium levofolinate should be performed as soon as possible, preferably within 1 hour, as administration after 4 hours is generally ineffective. Drug administration must be performed carefully to avoid risk of allergic reactions or adverse effects.

Calcium levofolinate/5-fluorouracil
Calcium levofolinate may enhance the toxicity profile of 5-fluorouracil, especially in elderly or debilitated patients. The most common manifestations are leukopenia, mucositis, stomatitis, and/or diarrhea, which may limit the dose. When Calcium levofolinate Teva Generics and 5-fluorouracil are used in combination, the dosage of 5-fluorouracil should be reduced more than when 5-fluorouracil is used as monotherapy, particularly in cases of toxicity.
Combined treatment with 5-fluorouracil/calcium levofolinate must not be initiated or continued in patients with gastrointestinal toxicity symptoms, regardless of severity, until all such symptoms have completely resolved.
Since diarrhea may be a sign of gastrointestinal toxicity, patients experiencing diarrhea must be closely monitored until symptoms fully resolve, as rapid clinical deterioration leading to death may occur.
If diarrhea and/or stomatitis occur, reduction of the 5-fluorouracil dose is recommended until symptoms completely resolve.
Elderly patients and those with poor performance status due to disease are particularly prone to this type of toxicity. Therefore, particular caution is required when treating these patients.
In elderly patients and those who have undergone prior radiotherapy, it is recommended to start with a reduced dose of 5-fluorouracil.
Calcium levofolinate must not be combined with 5-fluorouracil in the same injection or intravenous infusion (see section 6.2 of the SmPC). Calcium levels must be monitored in patients receiving combined 5-fluorouracil/calcium levofolinate treatment, and calcium supplements should be administered if calcium levels are low.
A complete blood count with differential leukocyte count and platelet count must be performed before each treatment and weekly during the first two cycles; in all subsequent cycles, the complete blood count should be performed at the expected leukocyte nadir.
Electrolyte levels and liver function must be monitored: before each treatment for the first 3 cycles and subsequently at alternate cycles.
The occurrence of adverse effects (most commonly diarrhea, mucositis, leukopenia) resulting from calcium levofolinate’s potentiation of fluoropyrimidine activity requires prompt implementation of necessary therapeutic countermeasures.
Seizures and/or syncope have been rarely reported in cancer patients treated with calcium levofolinate, usually in combination with fluoropyrimidines, particularly in patients with central nervous system metastases or those predisposed; however, a direct correlation with these events has not been established.

Calcium levofolinate/methotrexate
Calcium levofolinate has no effect on non-hematological toxicity of methotrexate, such as nephrotoxicity caused by methotrexate and/or its metabolite precipitation in the kidney. Patients with delayed early elimination of methotrexate are more likely to develop reversible renal failure and all methotrexate-associated toxicities. Pre-existing or methotrexate-induced renal insufficiency may delay methotrexate excretion and may increase the need for higher doses or prolonged use of calcium levofolinate.
Excessive doses of calcium levofolinate must be avoided, as they may impair the antitumor activity of methotrexate, especially in CNS tumors where calcium levofolinate accumulates after repeated cycles.
Resistance to methotrexate due to reduced membrane transport also implies resistance to "rescue" with levofolinate acid, as both drugs share the same transport system.
Accidental overdose with a folate antagonist such as methotrexate must be treated as a medical emergency. The longer the interval between methotrexate administration and "rescue" with calcium levofolinate, the lower the efficacy of calcium levofolinate in counteracting toxicity.
The possibility that the patient is taking other drugs interacting with methotrexate (e.g., drugs interfering with methotrexate elimination or serum albumin binding) must always be considered when laboratory abnormalities or clinical toxicity are observed.

Laboratory tests
Serum creatinine and serum methotrexate levels should be monitored at least once daily.
In cases of methotrexate overdose or delayed excretion, monitor urine pH to ensure maintenance of a value ≥ 7.0. During treatment with Calcium levofolinate Teva Generics, foods, beverages, and medicinal products that may increase urinary acidity should be avoided.

Calcium levofolinate Teva Generics contains sodium
This medicinal product contains less than 1 mmol (23 mg) of sodium per 2.5 ml vial, i.e., essentially "sodium-free".
This medicinal product contains less than 1 mmol (23 mg) of sodium per 5 ml vial, i.e., essentially "sodium-free".
This medicinal product contains 32 mg of sodium per 10 ml vial, equivalent to 1.6% of the maximum daily intake recommended by the WHO (2 g of sodium for an adult).
This medicinal product contains 56 mg of sodium per 17.5 ml vial, equivalent to 2.8% of the maximum daily intake recommended by the WHO (2 g of sodium for an adult).

Interactions with other medicinal products and other forms of interaction
When administered concomitantly with folic acid antagonists (such as co-trimoxazole, pyrimethamine, and methotrexate), the efficacy of these agents may be reduced or completely neutralized.
Calcium levofolinate may reduce the effects of antiepileptic drugs such as phenobarbital, primidone, phenytoin, and succinimides and may increase seizure frequency due to increased hepatic metabolism of these drugs (see sections 4.4 and 4.8 of the SmPC).
Concomitant administration of chloramphenicol and folic acid in patients with folate deficiency may cause antagonism of the hematopoietic response to folic acid.
Calcium levofolinate may increase the toxicity of 5-fluorouracil and other fluoropyrimidines (see sections 4.2, 4.4 and 4.8 of the SmPC).
Combined treatment with ceftriaxone is contraindicated, even when separate infusion lines are used, due to the risk of fatal precipitation of calcium-ceftriaxone salt in the neonatal bloodstream (see sections 4.3 and 4.8 of the SmPC).
When using the same line for sequential administration, the line must be flushed with a compatible fluid between infusions.
Post-mortem detection of calcium-ceftriaxone salt precipitation has been observed in lungs and kidneys. The high risk of precipitation in neonates is due to their low blood volume and longer ceftriaxone half-life compared to adults. Cases of renal precipitation have been reported, primarily in children over 3 years of age receiving high daily doses (e.g., ≥ 80 mg/kg/day) or total doses exceeding 10 grams, and who had other risk factors (e.g., fluid restriction, bedridden patients). The risk of precipitate formation increases in immobilized or dehydrated patients. This event may be symptomatic or asymptomatic, may cause renal failure and anuria, and is reversible upon discontinuation of administration. Precipitation of calcium-ceftriaxone salt in the gallbladder has also been observed, mainly in patients treated with doses above the recommended standard dose. In children, prospective studies have shown variable incidence of precipitation with intravenous administration; in some studies, incidence exceeded 30%. This incidence appears lower when infusions are administered slowly (20–30 minutes). This effect is usually asymptomatic, but in rare cases precipitation has been associated with clinical symptoms such as pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. Precipitation is generally reversible upon discontinuation of administration.

Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Physical incompatibility has been reported with ceftriaxone (see sections 4.3, 4.5 and 4.8 of the SmPC).

Fluorouracil
Calcium levofolinate must not be mixed in the same injection or infusion as 5-fluorouracil, as a precipitate may form. If the two medicinal products are administered sequentially through the same infusion line, the line should be flushed with 9 mg/ml (0.9%) sodium chloride solution for injection.

Special precautions for disposal and handling
Calcium levofolinate Teva Generics 10 mg/ml solution for injection may be diluted in 0.9% sodium chloride or 5% glucose.
Unused medicinal product and waste material derived from this medicinal product must be disposed of in accordance with local regulations.

For further information, please consult the Summary of Product Characteristics.

Package leaflet: information for the user

Calcium levofolinato Teva Generics 25 mg powder for injectable solution

Calcium levofolinato
Generic medicinal product
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.
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 effect, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet

What Calcio levofolinato Teva Generics is and what it is used for
What you need to know before using Calcio levofolinato Teva Generics
How to use Calcio levofolinato Teva Generics
Possible side effects
How to store Calcio levofolinato Teva Generics
Contents of the pack and other information

1. What Calcio levofolinato Teva Generics is and what it is used for

Calcio levofolinato Teva Generics contains the active substance calcio levofolinato, which belongs to the
B group of vitamins. Calcio levofolinato plays a fundamental role in the body in the
production of red blood cells, and in the synthesis of DNA (an organic substance containing all the
genetic information necessary for cell function) and proteins.
Calcio levofolinato Teva Generics is used:

to treat certain types of anaemia, a condition in which red blood cell levels are low. This condition may occur as a consequence of folate deficiency due to increased bodily demand, reduced utilisation, or insufficient dietary intake of folates;
to treat adverse effects caused by the use of high doses of other medicinal products that are antagonists of folic acid, such as methotrexate and aminopterin, used in the treatment of certain tumours;
as rescue therapy following treatment with methotrexate;
to enhance the effectiveness of another medicinal product, 5-fluorouracil, used in the treatment of certain tumours (antiblastic chemotherapy).

2. What you should know before using Calcio levofolinato Teva Generics

Calcio levofolinato Teva Generics must not be administered to you:

if you are allergic to calcium levofolinate or to any of the other ingredients of this medicine (listed in section 6).

Calcio levofolinato Teva Generics must not be administered concomitantly with ceftriaxone
(an antibiotic), even when separate infusion lines are used.
.
Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Calcio levofolinato Teva Generics.
Inform your doctor before using Calcio levofolinato Teva Generics if you are undergoing treatment:

for cancer with any of the following medicines: hydroxycarbamide, cytarabine, mercaptopurine, thioguanine; a condition may occur in which red blood cells are larger than normal (macrocytosis), which should not be treated with folinic acid;
for epilepsy with any of the following medicines: phenobarbital, phenytoin, primidone, and succinimides; an increase in epileptic seizures may occur.

If you suffer from pernicious anemia or other forms of megaloblastic anemia due to vitamin
B12 deficiency, the use of Calcio levofolinato Teva Generics is not recommended.
This medicine may be used in combination with methotrexate or 5-fluorouracil
(anticancer medicines) only under the direct supervision of a physician experienced in the use of anticancer drugs.
Treatment with Calcio levofolinato Teva Generics and 5-fluorouracil
If you are to be treated simultaneously with calcium levofolinate and 5-fluorouracil (an anticancer medicine), pay particular attention if:

you have undergone radiotherapy;
you have stomach or intestinal problems;
you are elderly or debilitated.

calcium levels in the blood;
blood test results, particularly complete blood count and electrolytes;
whether your liver is functioning properly.

Treatment with Calcio levofolinato Teva Generics and methotrexate
Calcio levofolinato Teva Generics must not be administered by injection into the lumbar region of the spine (intrathecal administration). Intrathecal administration of
Calcio levofolinato Teva Generics to counteract an excessive intrathecal dose of
methotrexate may result in death.
Talk to your doctor before Calcio levofolinato Teva Generics is administered to you together with
methotrexate (an anticancer medicine) if you think any of the following conditions apply to you:

your kidneys are not working properly (renal insufficiency). Your doctor may decide to increase the dose or duration of administration of this medicine;
you are taking other medicines that may interact with methotrexate, as they may alter the results of certain laboratory tests. Your doctor will determine the most appropriate dose of Calcio levofolinato Teva Generics for you to avoid damage to other organs (e.g. kidney, central nervous system).

If you have been treated with excessive doses of methotrexate, Calcio levofolinato Teva Generics should be
administered as soon as possible to counteract the toxicity of this medicine. Calcio levofolinate
Teva Generics is more effective the sooner it is administered after methotrexate.
Laboratory tests
Your doctor will perform frequent blood and urine tests during treatment with Calcio
levofolinato Teva Generics together with methotrexate to monitor your condition.
Other medicines and Calcio levofolinato Teva Generics
Inform your doctor or nurse if you are taking, have recently taken, or might take any other medicines.
Particular caution is required if you are taking/using other medicines that may interact
with calcium levofolinate, for example:

folic acid antagonists, e.g. cotrimoxazole (an antibiotic used to treat bacterial infections), pyrimethamine (a medicine used for malaria), methotrexate (a medicine used to treat cancers, rheumatic diseases, and skin conditions) – the effectiveness of these medicines will be reduced or completely neutralized by calcium levofolinate;
5-fluorouracil (a medicine used to treat cancers) and fluoropyrimidines (a group of medicines including 5-fluorouracil) – the effectiveness and side effects of this medicine will be increased by calcium levofolinate. 5-fluorouracil must not be mixed with Calcio levofolinato Teva Generics in the same injection or intravenous infusion;
medicines used to treat epilepsy, e.g. phenobarbital, phenytoin, primidone, or succinimides – the effectiveness of these medicines may be reduced by calcium levofolinate. Your doctor may monitor blood levels of these medicines and adjust the dose to prevent increased seizures (epileptic attacks);
chloramphenicol (an antibiotic used to treat bacterial infections), because it may interfere with the action of folic acid;
ceftriaxone (an antibiotic used to treat bacterial infections). Do not use ceftriaxone concomitantly with calcium levofolinate, even when separate infusion lines are used, due to potentially fatal outcomes.

Calcio levofolinato Teva Generics with food and drink
During treatment, foods (e.g. cheese, egg yolk, white and red meat, fish; dried fruit, legumes, and cereals), drinks (e.g. blueberry fruit juices and yogurt), and medicines that may increase urinary acidity (e.g. those containing bicarbonate) should be avoided.
Pregnancy, breastfeeding, and fertility
If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor or pharmacist before this medicine is administered to you.
Pregnancy
There are no adequate studies conducted in pregnant women. Harmful effects of folic acid administered during pregnancy are not known.
Breastfeeding
Calcium levofolinate may be excreted in breast milk. Calcium levofolinate may be used
during breastfeeding only if your doctor considers that the benefits to the mother outweigh the risks to the infant.
Fertility
No studies on reproductive toxicity have been conducted in animals with calcium levofolinate.
Driving and using machines
It is not known whether this medicine affects the ability to drive vehicles or operate machinery.

3. How to use Calcium levofolinate Teva Generics

Calcium levofolinate Teva Generics is administered only in a hospital setting and under the close supervision of trained medical personnel. If you have any doubts, please consult your doctor or nurse.
This medicine will be given to you by a doctor or nurse either into a muscle (intramuscular route), or rapidly into a vein (intravenous route), or slowly by infusion (intravenous infusion). When this medicine is administered intravenously, it is important that no more than 80 mg of active substance per minute be administered, due to the presence of calcium in this medicine.
This medicine must not be administered by injection into the spinal canal (intrathecal route).
Calcium levofolinate Teva Generics may be used in combination with anticancer medicines such as methotrexate to reduce its side effects, as an antidote in case you have received an excessive dose of methotrexate, or to enhance the effectiveness of 5-fluorouracil in the treatment of certain tumours. Your doctor will determine the dose, duration, and method of treatment with Calcium levofolinate Teva Generics based on your condition and other medicines you are taking.
If you have been given more Calcium levofolinate Teva Generics than you should have
It is highly unlikely that you will receive more Calcium levofolinate Teva Generics than prescribed, as this medicine will be administered under strict medical supervision.
Excessive amounts of calcium levofolinate may counteract the chemotherapeutic effect of folic acid antagonists.
If overdose occurs with the combination of fluorouracil and calcium levofolinate, the instructions for 5-fluorouracil overdose should be followed.
If you forget to use Calcium levofolinate Teva Generics
Since this medicine will be administered under close medical supervision, it is unlikely that a dose will be missed. However, inform your doctor or nurse if you think a dose has been missed.
If you have any doubts about how this medicine is administered, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Immediately contact your doctor if you experience any of the following side effects, as they may be serious and sometimes fatal:

Stevens-Johnson syndrome, a severe acute hypersensitivity reaction affecting the skin and mucous membranes in various parts of the body, with areas of necrosis and skin peeling;
Toxic Epidermal Necrolysis, a severe acute hypersensitivity reaction with almost complete necrosis of the skin and mucous membranes. Very rare (may affect up to 1 in 10,000 people)
severe allergic reaction (including anaphylactic shock) – you may experience a sudden rash with itching (urticaria), swelling of the hands, feet, ankles, face, lips, mouth and throat (which may cause difficulty swallowing and breathing), and you may feel faint. This is a serious side effect and may require urgent medical attention.

The following side effects may occur after administration of this medicine:
Uncommon (may affect up to 1 in 100 people)

fever.

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

increased frequency of seizures (crises);
seizures (sudden, uncontrolled, involuntary movements);
sudden and transient loss of consciousness (syncope);
depression, after high doses;
agitation, after high doses;
gastrointestinal problems (stomach and intestine), after high doses;
difficulty falling asleep, staying asleep, and poor sleep quality (insomnia), after high doses.

Side effects following administration of Calcium levofolinato Teva Generics together with 5-fluorouracil (an anticancer medicine)
The following side effects depend on the dose of 5-fluorouracil used.
Immediately contact your doctor if you experience any of the following side effects, as they may be serious (sometimes fatal); your doctor may decide to stop treatment with Calcium levofolinato Teva Generics:

severe stomach and intestinal problems, which may include inflammation of the mucosa and diarrhea;
reduced production of blood cells such as red blood cells (anaemias), white blood cells (increased susceptibility to infections), and platelets (bleeding) by the bone marrow (myelosuppression).

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

nausea;
vomiting;
diarrhea;
dehydration, which may result from severe diarrhea, requiring hospitalization for treatment and, in some cases, leading to death;
inflammation of the mucosa, including inflammation of the mouth (stomatitis) and inflammation of the lips, characterized by cracks, swelling, and ulcerations starting from the corners or edges and spreading onto the lips (cheilitis). Life-threatening conditions have occurred as a consequence of mucositis;
reduced production of blood cells such as red blood cells (anaemias), white blood cells (increased susceptibility to infections), and platelets (bleeding) by the bone marrow (bone marrow failure), which may lead to death.

Common (may affect up to 1 in 10 people)

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

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

severe stomach and intestinal problems, after high doses.

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

elevated levels of ammonia in the blood (hyperammonaemia).

Other side effects

excessive lowering of blood pressure (hypotension);
excessive increase in heart rate (tachycardia);
narrowing of the bronchi causing breathing difficulties (bronchospasm);
problems caused by calcium-ceftriaxone deposits, which may lead to death in newborns.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist.
You can also report side effects directly via the national reporting system at 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 Calcio levofolinato Teva Generics

Keep this medicine out of the sight and reach of children.
This medicine does not require any special storage temperature.
Do not use this medicine after the expiry date stated on the packaging after “Exp.”.
The expiry date refers to the last day of that month.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Calcio levofolinato Teva Generics contains
Calcio levofolinato Teva Generics 25 mg powder for injectable solution

The active substance is calcium levofolinate. Each vial contains 27 mg calcium levofolinate (equivalent to 25 mg levofolinic acid).
The other components are mannitol, hydrochloric acid.

Description of the appearance of Calcio levofolinato Teva Generics and contents of the pack
Pack containing one vial of 25 mg powder for injectable solution.
Marketing Authorization Holder
Teva B.V.
Swensweg 5
2031 GA Haarlem
The Netherlands
Manufacturer
BIOLOGICI Italia Laboratories S.r.l.
Via Filippo Serpero, 2
Masate (MI)
Italy

The following information is intended exclusively for physicians or healthcare professionals

Therapeutic indications
. Calcio levofolinato Teva Generics is useful as an antidote for excessive doses of folic acid antagonists and to counteract side effects induced by aminopterin (4-aminopteroyl-glutamic acid) and methotrexate (4-amino-N10-methyl-pteroyl-glutamic acid). Calcio levofolinato Teva Generics is also indicated as "rescue" therapy following methotrexate treatment and as an enhancer of the effects of 5-fluorouracil during antineoplastic chemotherapy regimens.
There are no indications for the use of Calcio levofolinato Teva Generics in pernicious anemia or other megaloblastic anemias due to vitamin B12 deficiency.
Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 of the SmPC;
Concomitant treatment with ceftriaxone, even when using separate infusion lines (see sections 4.5, 4.8 and 6.2 of the SmPC).

Dosage and method of administration
Dosage
In the context of high-dose methotrexate antineoplastic chemotherapy, therapeutic protocols include the parenteral use of levoleucovorin acid in the first phase, corresponding to competitive antidotal action (doses used vary according to the regimen from 10 to 200 mg/m²/day); in the second phase, where the biochemical-metabolic component predominates, parenteral or oral administration every 3–6 hours (10–12 mg/m²/day) may be used. However, general dosage regimens have not yet been definitively established.
Based on the most recent evidence, to improve the therapeutic index of methotrexate, calcium levofolinic acid is used in a sequential antidotal ("rescue") treatment. By adopting therapeutic regimens involving high-dose methotrexate and calcium levofolinic acid, better control of tumor forms can be achieved without significant increases in toxicity.
Since calcium levofolinic acid is an antagonist of methotrexate, their concomitant administration should only be performed when a specific therapeutic protocol has been defined for individual cases; for this purpose, consultation of the most recent literature on the subject is recommended.
.
No specific recommendations are considered necessary during solution preparation, as calcium levofolinic acid lacks intrinsic cytotoxic activity.
In certain types of therapeutic protocols, calcium levofolinic acid may be used due to its ability to enhance the effects of 5-fluorouracil: under these conditions, dosages range from 15 to 25 mg/m²/day intravenously (low-dose folinate) up to 200–550 mg/m²/day via continuous infusion (high-dose folinate). According to some protocols, folinate infusion should begin 24 hours before and end 12 hours after completion of 5-fluorouracil treatment. However, even in this case, concomitant administration of calcium levofolinic acid and 5-fluorouracil should only be performed after defining a specific therapeutic protocol for individual cases; consultation of the most recent literature is recommended.
Antidote in case of methotrexate overdose
Calcium levofolinic acid must not be administered intrathecally.
Calcium levofolinic acid, the specific antidote for methotrexate, neutralizes the toxic effects of the antimetabolite on the hematopoietic system and gastrointestinal mucosa. In its antidotal role, calcium levofolinic acid is used at various dosages depending on the desired effect.
In cases of accidental overdose, for competitive effect, intravenous infusion of calcium levofolinic acid is recommended (up to 50 mg within 12 hours); for biochemical-metabolic effect, intravenous administration (5–6 mg every 6 hours for 4 doses) or oral administration (7.5 mg every 6 hours for 4 doses) is recommended. In cases of side effects from conventional methotrexate doses, intravenous (5–6 mg every 6 hours for 4 doses) or oral (7.5 mg every 6 hours for 4 doses) calcium levofolinic acid is recommended.
In cases of accidental administration, calcium levofolinic acid should be administered at doses equal to or higher than methotrexate within the first hour; administration at later times is less effective.
In the treatment of folate deficiency anemias
For certain pathologies, intramuscular administration is recommended. Treatment should begin with a 5 mg dose of Calcio levofolinato Teva Generics, followed by daily administration of the same dose for 10–15 days. If a favorable response occurs, the dose may be halved and continued until hematological parameters normalize and clinical signs disappear.
Method of administration
Calcio levofolinato Teva Generics can be administered intramuscularly, by infusion, or intravenously. Calcium levofolinic acid must not be administered intrathecally.
During intravenous administration, no more than 80 mg of calcium levofolinic acid should be injected per minute due to the calcium content of the solution.
Warnings and precautions
Calcio levofolinato Teva Generics must be administered only by intramuscular and intravenous injection and must not be administered intrathecally. When folic acid has been administered intrathecally, death has been reported following intrathecal overdose of methotrexate.
General recommendations
Calcio levofolinato Teva Generics should be used in combination with methotrexate or 5-fluorouracil only under the direct supervision of a physician experienced in the use of chemotherapeutic agents for cancer treatment.
Treatment with Calcio levofolinato Teva Generics may mask pernicious anemia and other anemias due to vitamin B12 deficiency.
Many cytotoxic medicinal products—direct or indirect inhibitors of DNA synthesis—cause macrocytosis (hydroxyurea, cytarabine, mercaptopurine, thioguanine). This macrocytosis should not be treated with folinic acid.
In epileptic patients treated with phenobarbital, phenytoin, primidone, and succinimides, there is a risk of increased seizure frequency due to decreased plasma concentrations of antiepileptic drugs. Clinical monitoring of plasma concentrations is recommended, as dose adjustment of the antiepileptic drug may be necessary during and after administration of calcium levofolinic acid (see section 4.5 of the SmPC).
Calcium levofolinic acid is not indicated for the treatment of pernicious anemia or other megaloblastic anemias due to vitamin B12 deficiency: hematological remission may occur while neurological manifestations continue to progress. Therefore, therapy should be conducted under hematological monitoring.
In the treatment of overdose with folic acid antagonists, administration of calcium levofolinic acid should be performed within 1 hour if possible, as administration beyond 4 hours is generally ineffective. Drug administration must be performed carefully to avoid the risk of allergic reactions or side effects.
Calcium levofolinic acid / 5-fluorouracil
Calcium levofolinic acid may enhance the toxicity profile of 5-fluorouracil, especially in elderly or debilitated patients. The most common manifestations are leukopenia, mucositis, stomatitis, and/or diarrhea, which may limit dosing. When Calcio levofolinato Teva Generics and 5-fluorouracil are used in combination, the dosage of 5-fluorouracil should be reduced more than in cases of toxicity when 5-fluorouracil is used as monotherapy.
Combined treatment with 5-fluorouracil/calcium levofolinic acid must not be initiated or continued in patients with gastrointestinal toxicity symptoms, regardless of severity, until all such symptoms have completely resolved.
Since diarrhea may be a sign of gastrointestinal toxicity, patients experiencing diarrhea must be closely monitored until symptoms fully resolve, as rapid clinical deterioration leading to death may occur.
If diarrhea and/or stomatitis occur, it is advisable to reduce the dose of 5-fluorouracil until symptoms completely disappear.
Elderly patients and those with low performance status due to disease are particularly prone to this type of toxicity. Therefore, special attention should be paid when treating these patients.
In elderly patients and those who have undergone prior radiotherapy, it is recommended to start with a reduced dose of 5-fluorouracil.
Calcium levofolinic acid must not be combined with 5-fluorouracil in the same injection or intravenous infusion (see section 6.2 of the SmPC). Calcium levels should be monitored in patients receiving combined 5-fluorouracil/calcium levofolinic acid treatment, and calcium supplements should be administered if calcium levels are low.
A complete blood count with differential leukocyte and platelet counts should be performed before each treatment and weekly during the first two cycles; in all subsequent cycles, the complete blood count should be performed at the expected leukocyte nadir time.
Electrolyte levels and liver function should be monitored: before each treatment for the first 3 cycles and subsequently at alternate cycles.
The occurrence of adverse effects (most commonly diarrhea, mucositis, leukopenia) resulting from the enhancement of fluoropyrimidine activity by calcium levofolinic acid requires prompt therapeutic countermeasures.
Seizures and/or syncope have been rarely reported in cancer patients treated with calcium levofolinic acid, usually in association with fluoropyrimidines, particularly in patients with central nervous system metastases or those predisposed; however, a direct correlation with these events has not been established.
Calcium levofolinic acid / methotrexate
Calcium levofolinic acid has no effect on non-hematological toxicity of methotrexate, such as nephrotoxicity caused by precipitation of methotrexate and/or its metabolite in the kidney. Patients with delayed early elimination of methotrexate are more likely to develop reversible renal failure and all associated methotrexate toxicities. Pre-existing or methotrexate-induced renal impairment may be associated with delayed methotrexate excretion and may increase the need for higher doses or prolonged use of calcium levofolinic acid.
Excessive doses of calcium levofolinic acid should be avoided, as they may impair the antitumor activity of methotrexate, especially in CNS tumors where calcium levofolinic acid accumulates after repeated cycles.
Resistance to methotrexate due to reduced membrane transport also implies resistance to "rescue" with levoleucovorin acid, as both drugs share the same transport system.
An accidental overdose with a folic acid antagonist such as methotrexate must be treated as a medical emergency. The longer the interval between methotrexate administration and "rescue" with calcium levofolinic acid, the lower the efficacy of calcium levofolinic acid in counteracting toxicity.
The possibility that the patient is taking other drugs interacting with methotrexate (e.g., drugs that may interfere with methotrexate elimination or serum albumin binding) must always be considered when laboratory abnormalities or clinical toxicities are observed.
Laboratory tests
Serum creatinine and serum methotrexate levels should be monitored at least once daily.
In cases of methotrexate overdose or delayed excretion, monitor urine pH to ensure maintenance of a value ≥7. During treatment with Calcio levofolinato Teva Generics, foods, beverages, and medications that may increase urinary acidity should be avoided.
Interactions with other medicinal products and other forms of interaction
When administered concomitantly with folic acid antagonists (such as cotrimoxazole, pyrimethamine, and methotrexate), the efficacy of these agents may be reduced or completely neutralized.
Calcium levofolinic acid may reduce the effects of antiepileptic drugs such as phenobarbital, primidone, phenytoin, and succinimides and may increase seizure frequency by enhancing their hepatic metabolism (see sections 4.4 and 4.8 of the SmPC).
Concomitant administration of chloramphenicol and folic acid in patients with folate deficiency may result in antagonism of the hematopoietic response to folic acid.
Calcium levofolinic acid may increase the toxicity of 5-fluorouracil and other fluoropyrimidines (see sections 4.2, 4.4 and 4.8 of the SmPC).
Combined treatment with ceftriaxone is contraindicated, even when using separate infusion lines, due to the risk of fatal precipitation of calcium-ceftriaxone salt in the neonatal bloodstream (see sections 4.3, 4.5 and 4.8 of the SmPC).
When using the same line for sequential administration, the line must be flushed with a compatible fluid between infusions.
Post-mortem detection of calcium-ceftriaxone salt precipitation has been reported in the lungs and kidneys. The high risk of precipitation in neonates is due to their low blood volume and longer ceftriaxone half-life compared to adults. Cases of renal precipitation have been reported, primarily in children over 3 years of age receiving high daily doses (e.g., ≥80 mg/kg/day) or total doses exceeding 10 grams, and who had other risk factors (e.g., fluid restriction, bedridden patients). The risk of precipitate formation increases in immobilized or dehydrated patients. This event may be symptomatic or asymptomatic, may cause renal failure and anuria, and is reversible upon discontinuation of administration. Precipitation of calcium-ceftriaxone salt in the gallbladder has been observed, mainly in patients treated with doses above the recommended standard dose. Prospective studies in children have shown variable incidence of precipitation with intravenous administration; in some studies, the incidence exceeded 30%. This incidence appears lower when infusions are administered slowly (20–30 minutes). This effect is usually asymptomatic, but in rare cases, precipitation has been associated with clinical symptoms such as pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. Precipitation is generally reversible upon discontinuation of administration.
Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. Physical incompatibility has been reported with ceftriaxone (see sections 4.3, 4.5 and 4.8 of the SmPC).
Fluorouracil
Calcium levofolinic acid must not be mixed in the same injection or infusion as 5-fluorouracil, as a precipitate may form. If the two medicinal products are administered sequentially through the same infusion line, it is recommended to flush the line with 9 mg/ml (0.9%) sodium chloride solution for injection.
Special precautions for disposal and handling
The lyophilized powder must be reconstituted with 5 ml of water for injectable preparations. Unused medicine and waste materials derived from this medicine must be disposed of in accordance with local regulations.
For further information, please consult the Summary of Product Characteristics.

Patient Information Leaflet: Information for the User

Calcium levofolinate Teva Generics 100 mg powder for solution for infusion, 175 mg powder for solution for infusion

Calcium levofolinate
Generic medicine
Please read this leaflet carefully before using 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, pharmacist, or nurse.
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 may be harmful.
If you experience any side effect, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

What Calcium levofolinate Teva Generics is and what it is used for
What you need to know before using Calcium levofolinate Teva Generics
How to use Calcium levofolinate Teva Generics
Possible side effects
How to store Calcium levofolinate Teva Generics
Contents of the pack and other information

1. What Calcio levofolinato Teva Generics is and what it is used for

Calcio levofolinato Teva Generics contains the active substance calcio levofolinato, which belongs to the group B vitamins. Calcio levofolinato plays a fundamental role in the body in the production of red blood cells and in the synthesis of DNA (an organic substance containing all the genetic information necessary for cell function) and proteins.
Calcio levofolinato Teva Generics is used:

to treat adverse effects caused by the use of high doses of other medicines (folic acid antagonists), such as methotrexate and aminopterin, used in the treatment of certain tumours;
as rescue therapy following treatment with the medicine methotrexate;
to increase the effectiveness of another medicine, 5-fluorouracil, used in the treatment of certain tumours (antiblastic chemotherapy).

2. What you need to know before using Calcio levofolinato Teva Generics

Calcio levofolinato Teva Generics must not be administered to you:

if you are allergic to levoleucovorin calcium or to any of the other ingredients of this medicine (listed in section 6).

Calcio levofolinato Teva Generics must not be administered concomitantly with ceftriaxone
(an antibiotic), even if separate infusion lines are used.
Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Calcio levofolinato Teva Generics.
Inform your doctor before using Calcio levofolinato Teva Generics if you are undergoing treatment:

for cancer with any of the following medicines: hydroxycarbamide, cytarabine, mercaptopurine, thioguanine; a condition may occur in which red blood cells are larger than normal (macrocytosis) that should not be treated with folic acid;
for epilepsy with any of the following medicines: phenobarbital, phenytoin, primidone, and succinimides; an increase in epileptic seizures may occur.

This medicine may be used in combination with methotrexate or 5-fluorouracil
(anticancer medicines) only under the direct supervision of a physician experienced in the use of anticancer drugs.
Treatment with Calcio levofolinato Teva Generics and 5-fluorouracil
If you are to be treated simultaneously with levoleucovorin calcium and 5-fluorouracil (an anticancer medicine), pay special attention if:

you have undergone radiotherapy;
you have stomach or intestinal problems;
you are elderly or debilitated.

calcium levels in the blood;
blood test values, particularly complete blood count and electrolytes;
whether your liver is functioning properly.

Treatment with Calcio levofolinato Teva Generics and methotrexate
Calcio levofolinato Teva Generics must not be administered by injection into the lumbar region of the spine (intrathecal administration). Intrathecal administration of Calcio levofolinato Teva Generics to counteract an excessive intrathecal dose of methotrexate may result in death.
Talk to your doctor before receiving Calcio levofolinato Teva Generics together with methotrexate (an anticancer medicine) if you think any of the following conditions apply to you:

your kidneys are not functioning well (renal insufficiency). Your doctor may decide to increase the dose or duration of administration of this medicine;
you are taking other medicines that may interact with methotrexate, as they may alter the results of certain laboratory tests. Your doctor will determine the most appropriate dose of Calcio levofolinato Teva Generics for you to avoid damage to other organs (e.g., kidney, central nervous system).

If you have been treated with excessive doses of methotrexate, Calcio levofolinato Teva Generics must be administered as soon as possible to counteract the toxicity of this medicine. Calcio levofolinato Teva Generics is more effective the sooner it is administered after methotrexate.
Laboratory tests
Your doctor will perform frequent blood and urine tests during treatment with Calcio levofolinato Teva Generics together with methotrexate to monitor your condition.
Other medicines and Calcio levofolinato Teva Generics
Inform your doctor or nurse if you are taking, have recently taken, or might take any other medicines.
Particular care is needed if you are taking/using other medicines that may interact with levoleucovorin calcium, for example:

folic acid antagonists, e.g., cotrimoxazole (an antibiotic used to treat bacterial infections), pyrimethamine (a medicine used for malaria), methotrexate (a medicine used to treat cancers, rheumatic diseases, and skin disorders) – the effectiveness of these medicines will be reduced or completely neutralized by levoleucovorin calcium;
5-fluorouracil (a medicine used to treat cancers) and fluoropyrimidines (a group of medicines to which 5-fluorouracil belongs) – the effectiveness and side effects of this medicine will be increased by levoleucovorin calcium. 5-fluorouracil must not be mixed with Calcio levofolinato Teva Generics in the same intravenous infusion;
medicines used to treat epilepsy, e.g., phenobarbital, phenytoin, primidone, or succinimides – the effectiveness of these medicines may be reduced by levoleucovorin calcium. Your doctor may monitor blood levels of these medicines and adjust the dose to prevent an increase in seizures (epileptic attacks);
chloramphenicol (an antibiotic used to treat bacterial infections) because it may interfere with the action of folic acid;
ceftriaxone (an antibiotic used to treat bacterial infections). Do not use ceftriaxone concomitantly with levoleucovorin calcium, even if separate infusion lines are used, due to potentially fatal consequences.

Calcio levofolinato Teva Generics with food and drinks
During treatment, foods (e.g., cheese, egg yolk, white and red meat, fish; nuts, legumes, and cereals), drinks (e.g., blueberry fruit juices and yogurt), and medicines that may increase urinary acidity (e.g., those containing bicarbonate) should be avoided.
Pregnancy, breastfeeding, and fertility
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or breastfeeding, consult your doctor or pharmacist before this medicine is administered to you.
Pregnancy
There are no adequate studies in pregnant women. Harmful effects of folic acid administered during pregnancy are not known.
Breastfeeding
Levoleucovorin calcium may be excreted in breast milk. Levoleucovorin calcium may be used during breastfeeding only if your doctor determines that the benefits to the mother outweigh the risks to the infant.
Fertility
No studies on reproductive toxicity have been conducted in animals with levoleucovorin calcium.
Driving and using machines
It is not known whether this medicine affects the ability to drive or use machinery.

3. How to use Calcio levofolinato Teva Generics

Calcio levofolinato Teva Generics is administered only in a hospital setting and under the close supervision of trained medical personnel. If you have any doubts, please consult your doctor or nurse.
This medicine will be given to you exclusively by intravenous route (endovenous) by a doctor or nurse. It is important that no more than 80 mg of active substance per minute be administered due to the presence of calcium in this medicine.
This medicine must not be administered by injection into the lumbar region of the spinal column (intrathecal route).
Calcio levofolinato Teva Generics may be used in combination with anticancer medicines such as methotrexate to reduce its side effects, as an antidote in case you have received an excessive dose of methotrexate, and to enhance the effectiveness of 5-fluorouracil in the treatment of certain tumours. Your doctor will determine the dose, duration, and method of treatment with Calcio levofolinato Teva Generics based on your condition and other medicines you are taking.

If you have been given more Calcio levofolinato Teva Generics than you should have
It is highly unlikely that you will receive more Calcio levofolinato Teva Generics than prescribed, as this medicine is administered under strict medical supervision.
Excessive amounts of calcium levofolinato may counteract the chemotherapeutic effect of folic acid antagonists.
In case of overdose with the combination of 5-fluorouracil and calcium levofolinato, the overdose management instructions for 5-fluorouracil should be followed.

If you forget to use Calcio levofolinato Teva Generics
Since this medicine is administered under close medical supervision, it is unlikely that a dose will be missed. However, inform your doctor or nurse if you think a dose has been missed.
If you have any doubts about the administration of this medicine, please consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
Contact your doctor immediately if you experience any of the following side effects, as they may be serious and sometimes fatal:

Stevens-Johnson syndrome, a severe acute hypersensitivity reaction affecting the skin and mucous membranes in various parts of the body, with areas of necrosis and skin peeling;
Toxic Epidermal Necrolysis, a severe acute hypersensitivity reaction with almost complete necrosis of the skin and mucous membranes. Very rare (may affect up to 1 in 10,000 people)
severe allergic reaction (including anaphylactic shock) – you may develop a sudden rash with itching (urticaria), swelling of the hands, feet, ankles, face, lips, mouth and throat (which may cause difficulty swallowing and breathing), and you may feel faint. This is a serious side effect and may require urgent medical attention.

The following side effects may occur after administration of this medicine:
Uncommon (may affect up to 1 in 100 people)

fever.

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

increased frequency of seizures (crises);
seizures (sudden, uncontrolled, involuntary movements);
sudden and transient loss of consciousness (syncope);
depression, after high doses;
agitation, after high doses;
gastrointestinal problems (stomach and intestine), after high doses;
difficulty falling asleep, staying asleep, and poor sleep quality (insomnia), after high doses.

Side effects following administration of Calcium levofolinato Teva Generics together with 5-fluorouracil (anticancer medicine)
The following side effects depend on the dose of 5-fluorouracil used.
Contact your doctor immediately if you experience any of the following side effects, as they may be serious (sometimes fatal), and your doctor may decide to stop treatment with Calcium levofolinato Teva Generics:

severe stomach and intestinal problems, which may include inflammation of the mucosa and diarrhea;
reduced production of blood cells such as red blood cells (anemia), white blood cells (increased susceptibility to infections), and platelets (bleeding) by the bone marrow (myelosuppression).

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

nausea;
vomiting;
diarrhea;
dehydration, which may result from severe diarrhea requiring hospitalization for treatment and, in some cases, leading to death;
inflammation of the mucosa, including inflammation of the mouth (stomatitis) and inflammation of the lips manifesting as cracks, swelling, and ulcers starting from the corners or edges and spreading to the lips (cheilitis). Life-threatening conditions have occurred as a consequence of mucositis;
reduced production of blood cells such as red blood cells (anemia), white blood cells (increased susceptibility to infections), and platelets (bleeding) by the bone marrow (bone marrow failure), which may lead to death.

Common (may affect up to 1 in 10 people)

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

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

elevated levels of ammonia in the blood (hyperammonemia).

Other side effects

excessive lowering of blood pressure (hypotension);
excessive increase in heart rate (tachycardia);
narrowing of the bronchi causing breathing difficulties (bronchospasm);
problems caused by calcium-ceftriaxone deposits, which may lead to death in newborns.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You may also report side effects directly via the national reporting system at 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 Calcio levofolinato Teva Generics

Keep this medicine out of the sight and reach of children.
This medicine does not require any special storage temperature.
Do not use this medicine after the expiry date stated on the packaging after "Exp.".
The expiry date refers to the last day of that month.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Calcio levofolinato Teva Generics contains
Calcio levofolinato Teva Generics 100 mg powder for solution for infusion

The active substance is calcium levofolinate. Each vial contains calcium levofolinate 108 mg (equivalent to levofolinic acid 100 mg).
The other components are mannitol, hydrochloric acid.

Calcio levofolinato Teva Generics 175 mg powder for solution for infusion

The active substance is calcium levofolinate. Each vial contains calcium levofolinate 189 mg (equivalent to levofolinic acid 175 mg).
The other components are mannitol, hydrochloric acid.

Description of the appearance of Calcio levofolinato Teva Generics and contents of the pack
Pack containing 1 vial of 100 mg or 1 vial of 175 mg of powder for solution for infusion.

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
Teva B.V.
Swensweg 5
2031 GA Haarlem
The Netherlands

Manufacturer
BIOLOGICI Italia Laboratories S.r.l.
Via Filippo Serpero, 2
Masate (MI)
Italy

The following information is intended exclusively for physicians or healthcare professionals

Therapeutic indications
Calcium levofolinic acid Teva Generics is useful as an antidote for excessive doses of folic acid antagonists and to counteract the side effects induced by aminopterin (4-aminopteroyl-glutamic acid) and methotrexate (4-amino-N10-methyl-pteroic acid).
Calcium levofolinic acid Teva Generics is also indicated as "rescue" therapy following methotrexate treatment and as a potentiator of the effects of 5-fluorouracil during antineoplastic chemotherapy regimens.

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 of the SmPC;
Concomitant treatment with ceftriaxone, even when administered via separate infusion lines (see sections 4.5, 4.8 and 6.2 of the SmPC).

Dosage and administration

Dosage
In high-dose methotrexate antineoplastic chemotherapy regimens, therapeutic protocols typically involve parenteral administration of levofolinic acid in the first phase, corresponding to competitive antidotal action (doses used vary according to the regimen from 10 to 200 mg/m²/day); in the second phase, where the biochemical-metabolic component predominates, either parenteral or oral administration every 3–6 hours (10–12 mg/m²/day) may be used. However, standardized general dosing regimens have not yet been definitively established.

Since calcium levofolinic acid is an antagonist of methotrexate, their concomitant administration should only be performed when a specific therapeutic protocol has been defined for individual cases; consultation of the most recent literature on the subject is recommended.

In high-dose methotrexate "rescue" therapy, calcium levofolinic acid is effective in preventing myelosuppression at doses of 100 mg/m² for serum methotrexate levels of 10 µM. Doses may be proportionally increased for higher blood levels of the antineoplastic agent.

No specific recommendations are considered necessary during solution preparation, as calcium levofolinic acid lacks intrinsic cytotoxic activity.

In certain chemotherapy regimens, calcium levofolinic acid may be used due to its ability to enhance the effects of 5-fluorouracil: under these conditions, dosages range from 15 to 25 mg/m²/day intravenously (low-dose folinate) up to 200–550 mg/m²/day as continuous infusion (high-dose folinate). The most frequently used dosages in combination with 5-fluorouracil are 100 mg/m²/day for 5 consecutive days via slow infusion (10 min.), repeated every 4 weeks, or 250 mg/m²/week for 6 weeks followed by a 2-week interval.

According to some therapeutic protocols, folinate infusion should begin 24 hours before and end 12 hours after completion of 5-fluorouracil treatment. However, even in this case, concomitant administration of calcium levofolinic acid and 5-fluorouracil should only be performed after defining a specific therapeutic protocol for individual cases; consultation of the most recent literature on the subject is recommended.

Antidote in case of methotrexate overdose
Calcium levofolinic acid must not be administered intrathecally.

Calcium levofolinic acid, the specific antidote for methotrexate, neutralizes the toxic effects of this antimetabolite on the hematopoietic system and gastrointestinal mucosa. As an antidote, calcium levofolinic acid is administered at various dosages depending on the desired effect.

In cases of accidental overdose, to achieve a competitive effect, intravenous infusion of calcium levofolinic acid is recommended (up to 50 mg within 12 hours); to achieve a biochemical-metabolic effect, intravenous (5–6 mg every 6 hours for 4 doses) or oral (7.5 mg every 6 hours for 4 doses) administration is recommended. In cases of side effects from conventional methotrexate doses, intravenous (5–6 mg every 6 hours for 4 doses) or oral (7.5 mg every 6 hours for 4 doses) calcium levofolinic acid is recommended.

In cases of accidental administration, calcium levofolinic acid should be administered at doses equal to or higher than those of methotrexate within the first hour; administration at later times is less effective.

Method of administration
Calcium levofolinic acid Teva Generics 100 mg powder for solution for infusion and Calcium levofolinic acid Teva Generics 175 mg powder for solution for infusion must be administered exclusively by intravenous route. Calcium levofolinic acid must not be administered intrathecally.

During intravenous administration, no more than 80 mg of calcium levofolinic acid per minute should be injected due to the calcium content of the solution.

Warnings and precautions

Calcium levofolinic acid Teva Generics must be administered only by intravenous injection and must not be administered intrathecally. Death has been reported when folic acid was administered intrathecally following intrathecal overdose of methotrexate.

General recommendations
Calcium levofolinic acid Teva Generics should be used in combination with methotrexate or 5-fluorouracil only under the direct supervision of a physician experienced in the use of chemotherapeutic agents for cancer treatment.

Treatment with Calcium levofolinic acid Teva Generics may mask pernicious anemia and other anemias due to vitamin B12 deficiency.

Many cytotoxic medicinal products—direct or indirect inhibitors of DNA synthesis—cause macrocytosis (hydroxycarbamide, cytarabine, mercaptopurine, thioguanine). This macrocytosis should not be treated with folinic acid.

In epileptic patients treated with phenobarbital, phenytoin, primidone, and succinimides, there is a risk of increased frequency of epileptic seizures due to decreased plasma concentrations of antiepileptic drugs. Clinical monitoring and plasma concentration monitoring are recommended, as dose adjustment of the antiepileptic drug may be necessary during and after administration of calcium levofolinic acid (see section 4.5 of the SmPC).

In the treatment of overdose with folic acid antagonists, administration of calcium levofolinic acid should be performed preferably within 1 hour, as administration after 4 hours is generally ineffective. Drug administration must be performed carefully to avoid the risk of allergic reactions or side effects.

Calcium levofolinic acid / 5-fluorouracil
Calcium levofolinic acid may enhance the toxicity profile of 5-fluorouracil, especially in elderly or debilitated patients. The most common manifestations are leucopenia, mucositis, stomatitis, and/or diarrhea, which may limit dosing. When Calcium levofolinic acid Teva Generics and 5-fluorouracil are used in combination, the dosage of 5-fluorouracil must be reduced more in cases of toxicity than when 5-fluorouracil is used as monotherapy.

Combined treatment with 5-fluorouracil/calcium levofolinic acid must not be initiated or continued in patients with gastrointestinal toxicity symptoms, regardless of severity, until all such symptoms have completely resolved.

Since diarrhea may be a sign of gastrointestinal toxicity, patients experiencing diarrhea must be closely monitored until symptoms have completely resolved, as rapid clinical deterioration may occur, potentially leading to death.

If diarrhea and/or stomatitis occur, reduction of the 5-fluorouracil dose is recommended until symptoms have completely resolved.

Elderly patients and those with poor performance status due to disease are particularly prone to this type of toxicity. Therefore, particular caution is required when treating these patients.

In elderly patients and in patients who have undergone prior radiotherapy, it is recommended to start with a reduced dose of 5-fluorouracil.

Calcium levofolinic acid must not be combined with 5-fluorouracil in the same intravenous infusion (see section 6.2 of the SmPC). Calcium levels must be monitored in patients receiving combined 5-fluorouracil/calcium levofolinic acid treatment, and calcium supplements should be administered if calcium levels are low.

A complete blood count with differential leukocyte and platelet counts must be performed before each treatment and weekly during the first two cycles; in all subsequent cycles, the complete blood count should be performed at the expected leukocyte nadir.

Electrolyte levels and liver function must be monitored: before each treatment for the first 3 cycles and subsequently at alternate cycles.

The occurrence of adverse effects (most commonly diarrhea, mucositis, leucopenia) resulting from the potentiation of fluoropyrimidine activity by calcium levofolinic acid requires prompt implementation of necessary therapeutic countermeasures.

Seizures and/or syncope have been rarely reported in cancer patients treated with calcium levofolinic acid, usually in combination with fluoropyrimidines, particularly in patients with central nervous system metastases or those predisposed; however, a direct correlation with these events has not been established.

Calcium levofolinic acid / methotrexate
Calcium levofolinic acid has no effect on non-hematological toxicity of methotrexate, such as nephrotoxicity caused by precipitation of methotrexate and/or its metabolite in the kidney. Patients with delayed early elimination of methotrexate are more likely to develop reversible renal failure and all associated methotrexate toxicities. Pre-existing or methotrexate-induced renal insufficiency may be associated with delayed methotrexate excretion and may increase the need for higher doses or prolonged use of calcium levofolinic acid.

Excessive doses of calcium levofolinic acid must be avoided, as they may impair the antitumor activity of methotrexate, especially in CNS tumors where calcium levofolinic acid accumulates after repeated cycles.

Resistance to methotrexate due to reduced membrane transport also implies resistance to "rescue" with levofolinic acid, as both drugs share the same transport system.

An accidental overdose with a folate antagonist such as methotrexate must be treated as a medical emergency. The longer the interval between methotrexate administration and "rescue" with calcium levofolinic acid, the lower the efficacy of calcium levofolinic acid in counteracting toxicity.

The possibility that the patient is taking other drugs that interact with methotrexate (e.g., drugs that may interfere with methotrexate elimination or serum albumin binding) must always be considered when laboratory abnormalities or clinical toxicities are observed.

Laboratory tests
Serum creatinine and serum methotrexate levels should be monitored at least once daily.

In cases of methotrexate overdose or delayed excretion, urine pH should be monitored to ensure maintenance of a value ≥7.0. Foods, beverages, and medicinal products that may increase urinary acidity must be avoided during treatment with Calcium levofolinic acid Teva Generics.

Interactions with other medicinal products and other forms of interaction
When administered concomitantly with folic acid antagonists (such as cotrimoxazole, pyrimethamine, and methotrexate), the efficacy of these agents may be either reduced or completely neutralized.

Calcium levofolinic acid may reduce the effects of antiepileptic drugs such as phenobarbital, primidone, phenytoin, and succinimides and may increase the frequency of epileptic seizures due to increased hepatic metabolism of these drugs (see sections 4.4 and 4.8 of the SmPC).

Concomitant administration of chloramphenicol and folic acid in patients with folate deficiency may cause antagonism of the hematopoietic response to folic acid.

Calcium levofolinic acid may increase the toxicity of 5-fluorouracil and other fluoropyrimidines (see sections 4.2, 4.4 and 4.8 of the SmPC).

Combined treatment with ceftriaxone is contraindicated, even when separate infusion lines are used, due to the risk of fatal precipitation of calcium-ceftriaxone salt in the neonatal bloodstream (see sections 4.3 and 4.8 of the SmPC).

When using the same line for sequential administrations, the line must be flushed with a compatible fluid between infusions.

Post-mortem findings have revealed precipitation of calcium-ceftriaxone salt in the lungs and kidneys. The high risk of precipitation in neonates is due to their low blood volume and longer ceftriaxone half-life compared to adults. Cases of renal precipitation have been reported, primarily in children over 3 years of age receiving high daily doses (e.g., ≥80 mg/kg/day) or total doses exceeding 10 grams, and who had other risk factors (e.g., fluid restriction, bedridden patients). The risk of precipitate formation increases in immobilized or dehydrated patients. This event may be symptomatic or asymptomatic, may cause renal failure and anuria, and is reversible upon discontinuation of administration. Precipitation of calcium-ceftriaxone salt has also been observed in the gallbladder, primarily in patients treated with doses above the recommended standard dose. Prospective studies in children have shown variable incidence of precipitation with intravenous administration; in some studies, the incidence exceeded 30%. This incidence appears lower when infusions are administered slowly (20–30 minutes). This effect is usually asymptomatic, but in rare cases, precipitations have been associated with clinical symptoms such as pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. Precipitation is generally reversible upon discontinuation of administration.

Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. Physical incompatibility has been reported with ceftriaxone (see sections 4.3, 4.5 and 4.8 of the SmPC).

Fluorouracil
Calcium levofolinic acid must not be mixed in the same injection or infusion as 5-fluorouracil, as precipitation may occur. If the two medicinal products are administered sequentially through the same infusion line, the line should be flushed with 9 mg/ml (0.9%) sodium chloride injection solution.

Special precautions for disposal and handling
Calcium levofolinic acid Teva Generics 100 mg powder for solution for infusion: the powder must be reconstituted with 10 ml of water for injections.
Calcium levofolinic acid Teva Generics 175 mg powder for solution for infusion: the powder must be reconstituted with 15–20 ml of water for injections.
Unused medicinal product and waste material must be disposed of in accordance with local regulations.

For further information, consult the Summary of Product Characteristics.

Calcium folinate Teva Generics

Package leaflet: Information for the user

Calcio levofolinato Teva Generics 10 mg/ml solution for injection

1. What Calcio levofolinato Teva Generics is and what it is used for

2. What you need to know before using Calcio levofolinato Teva Generics

3. How to use Calcium levofolinate Teva Generics

4. Possible side effects

5. How to store Calcio levofolinato Teva Generics

6. Package contents and other information

Manufacturer BIOLOGICI Italia Laboratories S.r.l. Via Filippo Serpero, 2 Masate (MI) Italy

The following information is intended exclusively for physicians or healthcare professionals

Package leaflet: information for the user

Calcium levofolinato Teva Generics 25 mg powder for injectable solution

1. What Calcio levofolinato Teva Generics is and what it is used for

2. What you should know before using Calcio levofolinato Teva Generics

3. How to use Calcium levofolinate Teva Generics

4. Possible side effects

5. How to store Calcio levofolinato Teva Generics

6. Package contents and other information

The following information is intended exclusively for physicians or healthcare professionals

Patient Information Leaflet: Information for the User

Calcium levofolinate Teva Generics 100 mg powder for solution for infusion, 175 mg powder for solution for infusion

1. What Calcio levofolinato Teva Generics is and what it is used for

2. What you need to know before using Calcio levofolinato Teva Generics

3. How to use Calcio levofolinato Teva Generics

4. Possible side effects

5. How to store Calcio levofolinato Teva Generics

6. Package contents and other information

The following information is intended exclusively for physicians or healthcare professionals

Manufacturer
BIOLOGICI Italia Laboratories S.r.l.
Via Filippo Serpero, 2
Masate (MI)
Italy