- Approval Id
- e14567afc5f88c7d
- Drug Approval Emc Name
- Isovorin Solution for Injection 10 mg/ml
- Drug Name
- Isovorin Solution for Injection 10 mg/ml
- Company Address
- Ramsgate Road, Sandwich, Kent, CT13 9NJ
- Company Telephone
- +44 (0)1304 616 161
- Company Medical Info Direct Line
- +44 (0)1304 616161
- Atc Code
- V03AF04
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Pfizer Limited
Ramsgate Road
Sandwich
Kent
CT13 9NJ
United Kingdom
- Authorisation Number
- PL 00057/1282
- Authorisation Date
- 17 Aug 2011
- Instruction Authorisation Holder
- Pfizer Limited
Ramsgate Road
Sandwich
Kent
CT13 9NJ
United Kingdom
- Instruction Authorisation Number
- PL 00057/1282
- Instruction Authorisation Date
- 17 Aug 2011
- Instruction Composition
- Calcium levofolinate equivalent to 1.00% w/v (10 mg/ml) of levoleucovorin (levofolinic acid).
Vials contain 25 mg, 50 mg or 175 mg of levofolinic acid (as calcium levofolinate) in 2.5 ml, 5 ml or 17.5 ml of solution respectively.
\*\*Excipient with known effect\*\*
Isovorin 25 mg/2.5 ml solution for injection contains 7.6 mg of sodium in each 2.5 ml of solution.
Isovorin 50 mg/5 ml solution for injection contains 15.2 mg of sodium in each 5 ml of solution.
Isovorin 175 mg/17.5 ml solution for injection contains 53.03 mg of sodium in each 17.5 ml of solution.
For the full list of excipients, see section 6.1
- Instruction Dosage Form
- Solution for injection.
Isovorin is a clear yellow solution.
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
\*\*Calcium Levofolinate Rescue\*\*
Calcium levofolinate is used to diminish the toxicity and counteract the action of folic acid antagonists such as methotrexate in cytotoxic therapy. This procedure is known as Calcium Levofolinate Rescue.
\*\*Advanced Colorectal Cancer - Enhancement of 5-Fluorouracil (5-FU) Cytotoxicity\*\*
Calcium levofolinate increases the thymine depleting effects of 5-FU resulting in enhanced cytotoxic activity. Combination regimens of 5-fluorouracil and levofolinate give greater efficacy compared to 5-FU given alone.4.2 Posology and method of administration
\*\*Posology\*\*
\*\*Calcium Levofolinate Rescue\*\*
\*\*Adults, Children and the Elderly:\*\*
Calcium Levofolinate Rescue therapy should commence 24 hours after the beginning of methotrexate infusion. Dosage regimes vary depending upon the dose of methotrexate administered. In general, the calcium levofolinate should be administered at a dose of 7.5 mg (approximately 5 mg/m2) every 6 hours for 10 doses by intramuscular injection, bolus intravenous injection or intravenous infusion, (see section below, for information concerning use of calcium levofolinate with infusion fluids). \*\*Do not administer calcium levofolinate intrathecally\*\* (see section 4.4).
Where overdose of methotrexate is suspected, the dose of calcium levofolinate should be at least 50% of the offending dose of methotrexate and should be administered in the first hour. In the case of intravenous administration, no more than 160 mg of calcium levofolinate should be injected per minute due to the calcium content of the solution.
In addition to calcium levofolinate administration, measures to ensure the prompt excretion of methotrexate are important as part of Calcium Levofolinate Rescue therapy. These measures include:
a. Alkalinisation of urine so that the urinary pH is greater than 7.0 before methotrexate infusion (to increase solubility of methotrexate and its metabolites). Foods, drinks and drugs that may increase urinary acidity should be avoided during the therapy.
b. Maintenance of urine output of 1800-2000 cc/m2/24 hr by increased oral or intravenous fluids on days 2, 3 and 4 following methotrexate therapy.
c. Plasma methotrexate concentration, BUN and creatinine should be measured on days 2, 3 and 4.
These measures must be continued until the plasma methotrexate level is less than 10-7 molar (0.1 μM).
Delayed methotrexate excretion may be seen in some patients. This may be caused by a third space accumulation (as seen in ascites or pleural effusion for example), renal insufficiency or inadequate hydration. Under such circumstances, higher doses of calcium levofolinate or prolonged administration may be indicated. Dosage and administration guidelines for these patients are given in Table 1. Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure.
TABLE 1:
Dosage and Administration Guidelines for Calcium Levofolinate Rescue
| | | |
| --- | --- | --- |
| \*\*Clinical Situation\*\* | \*\*Laboratory Findings\*\* | \*\*Calcium Levofolinate Dosage and Duration\*\* |
| Normal Methotrexate Elimination | Serum methotrexate level approximately 10 μM at 24 hours after administration, 1 μM at 48 hours and less than 0.2 μM at 72 hours. | 7.5 mg IM or IV every 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion). |
| Delayed Late Methotrexate Elimination | Serum methotrexate level remaining above 0.2 μM at 72 hours, and more than 0.05 μM at 96 hours after administration. | Continue 7.5 mg IM or IV every 6 hours, until methotrexate level is less than 0.05 μM. |
| Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Failure | Serum methotrexate level of 50 μM or more at 24 hours or 5 μM or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration. | 75 mg IV every 3 hours, until methotrexate level is less than 1 μM; then 7.5 mg IV every 3 hours until methotrexate level is less than 0.05 μM. |
IM – intramuscular administration
IV – intravenous administration
\*\*Colorectal Cancer: Enhancement of 5-FU Cytotoxicity\*\*
\*\*Adults and the Elderly:\*\*
\*\*Administration:\*\* The 175 mg in 17.5 ml vial of Calcium Levofolinate Solution for Injection should be used to administer the high doses of calcium levofolinate required in combination regimens.
When used in combination regimens with 5-FU, calcium levofolinate should only be given by the intravenous route. The agents should not be mixed together. Each vial of calcium levofolinate 175 mg contains 0.7 mEq (0.35 mmol) of calcium per vial and it is recommended that the solution is administered over not less than 3 minutes.
For intravenous infusion, the 175 mg in 17.5 ml Solution for Injection may be diluted with any of the following infusion fluids before use: Sodium Chloride 0.9%; Glucose 5%; Glucose 10%; Glucose 10% and Sodium Chloride 0.9% Injection; Compound Sodium Lactate Injection (see section 6.6).
Calcium levofolinate should not be mixed together with 5-FU in the same infusion and, because of the risk of degradation, the giving set should be protected from light.
\*\*Dosage:\*\* Based on the available clinical evidence, the following regimen is effective in advanced colorectal carcinoma:
Calcium levofolinate given at a dose of 100 mg/m2 by slow intravenous injection, followed immediately by 5-FU at an initial dose of 370 mg/m2 by intravenous injection. The injection of levofolinate should not be given more rapidly than over 3 minutes because of the calcium content of the solution. This treatment is repeated daily for 5 consecutive days. Subsequent courses may be given after a treatment-free interval of 21-28 days.
For the above regimen, modification of the 5-FU dosage and the treatment-free interval may be necessary depending on patient condition, clinical response and dose limiting toxicity (see 5-FU labelling for specific information). A reduction of calcium levofolinate dosage is not required. The number of repeat cycles used is at the discretion of the clinician.
On the basis of the available data, no specific dosage modifications are recommended in the use of the combination regimen with 5-FU in the elderly. However, particular care should be taken when treating elderly or debilitated patients as these patients are at increased risk of severe toxicity with this therapy (see section 4.4).
\*\*\*Paediatric population\*\*\*
There are no data available on the use of this combination in children.
\*\*Method of administration\*\*
Solution for injection is for intravenous (as bolus injection or infusion) or intramuscular administration only.
For single use only.4.3 Contraindications
Hypersensitivity to calcium levofolinate or to any of the excipients listed in section 6.1.
Calcium levofolinate should not be used for the treatment of pernicious anaemia or other megaloblastic anaemias due to vitamin B12 deficiency.
Regarding the use of calcium levofolinate with methotrexate or 5-FU during pregnancy and lactation, see section 4.6 and the Summaries of Product Characteristics for methotrexate and 5-FU-containing medicinal products.4.4 Special warnings and precautions for use
Calcium levofolinate must not be administered intrathecally. When levofolinic acid has been administered intrathecally, following intrathecal overdose of methotrexate, death has been reported (see section 4.2).
\*General\*
Calcium levofolinate treatment may mask pernicious anaemia and other megaloblastic anaemias resulting from vitamin B12 deficiency.
Calcium levofolinate should only be used with 5-FU or methotrexate under the direct supervision of a clinician experienced in the use of cancer chemotherapeutic agents.
Many cytotoxic medicinal products – direct or indirect DNA synthesis inhibitors – lead to macrocytosis (hydroxycarbamide, cytarabine, mercaptopurine, thioguanine). Such macrocytosis should not be treated with folinic acid.
\*Calcium levofolinate / 5-FU\*
Calcium levofolinate may enhance the toxicity profile of 5-FU, particularly in elderly or debilitated patients. The most common manifestations are leucopoenia, mucositis, stomatitis and / or diarrhoea, which may be dose limiting.
Combined 5-FU / calcium levofolinate treatment should neither be initiated nor maintained in patients with symptoms of gastrointestinal toxicity, regardless of the severity, until all of these symptoms have completely disappeared.
Patients presenting with diarrhoea must be carefully monitored until the symptoms have resolved completely, since a rapid clinical deterioration leading to death can occur. If diarrhoea and / or stomatitis occur, it is advisable to reduce the dose of 5-FU until symptoms have fully resolved. The elderly and patients with a low physical performance due to their illness are especially prone to these toxicities. Therefore, particular care should be taken when treating these patients.
In elderly patients and patients who have undergone preliminary radiotherapy, it is recommended to begin with a reduced dosage of 5-FU.
Calcium levofolinate must not be mixed with 5-FU in the same IV injection or infusion.
\*Calcium levofolinate / methotrexate\*
An accidental overdose with a folate antagonist, such as methotrexate, should be treated quickly as a medical emergency. As the time interval between methotrexate administration and calcium levofolinate rescue increases, calcium levofolinate effectiveness in counteracting toxicity decreases.
Calcium levofolinate has no effect on non-haematological toxicities of methotrexate such as the nephrotoxicity resulting from methotrexate and / or metabolite precipitation in the kidney. Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure and all toxicities associated with methotrexate. The presence of pre-existing or methotrexate-induced renal insufficiency is potentially associated with delayed excretion of methotrexate and may increase the need for higher doses or more prolonged use of calcium levofolinate.
The possibility that the patient is taking other medications that interact with methotrexate (e.g. medications which may interfere with methotrexate elimination or binding to serum albumin) should always be considered when laboratory abnormalities or clinical toxicities are observed.
Excessive calcium levofolinate doses must be avoided since this might impair the anti-tumour activity of methotrexate, especially in CNS tumours where calcium levofolinate accumulates after repeated courses.
Resistance to methotrexate as a result of decreased membrane transport implies also resistance to folinic acid rescue as both medicinal products share the same transport system.
\*\*Excipient Information:\*\*
Isovorin 25 mg/2.5 ml solution for injection contains 7.6 mg of sodium per 2.5 ml of solution, equivalent to 0.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Isovorin 50 mg/5 ml solution for injection contains 15.2 mg of sodium per 5 ml of solution, equivalent to 0.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Isovorin 175 mg/17. 5 ml solution for injection contains 53.03 mg of sodium per 17.5 ml of solution, equivalent to 2.65% of the WHO recommended maximum daily intake of 2 g sodium for an adult.4.5 Interaction with other medicinal products and other forms of interaction
When calcium levofolinate is given in conjunction with a folic acid antagonist (e.g. cotrimoxazole, pyrimethamine) the efficacy of the folic acid antagonist may either be reduced or completely neutralised.
Calcium levofolinate may diminish the antiepileptic effect of phenobarbital, phenytoin, primidone and succinimides, and may increase the frequency of seizures in susceptible patients. Clinical monitoring is therefore recommended.
Concurrent administration of chloramphenicol and folic acid in folate deficient patients may result in antagonism of haematopoietic response to folic acid.
Calcium levofolinate may enhance the toxicity of fluorouracil (see sections 4.2, 4.4 and 4.8).4.6 Fertility, pregnancy and lactation
\*\*Pregnancy\*\*
There are no adequate and well-controlled clinical studies conducted in pregnant or breast-feeding women.
No formal animal reproductive toxicity studies with calcium levofolinate have been conducted. Calcium levofolinate should only be used in pregnant women if the potential benefit justifies the potential risk to the foetus.
\*\*Breast-feeding\*\*
Calcium levofolinate may be excreted in human milk and should only be administered where the benefits of the drug to the mother outweigh possible hazards to the infant. Calcium levofolinate can be used during breast-feeding when considered necessary according to the therapeutic indications.
\*\*Fertility\*\*
No fertility studies have been conducted with calcium levofolinate in animals.4.7 Effects on ability to drive and use machines
There is no evidence that calcium levofolinate has an effect on the ability to drive or use machines.4.8 Undesirable effects
Within the organ system classes, adverse reactions are listed under the headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10,000, <1/1000); very rare (<1/10,000); not known (frequency cannot be estimated from the available data).
\*\*Immune system disorders:\*\*
| | |
| --- | --- |
| Very rare: | Anaphylactoid / anaphylactic reactions (including shock) |
| Not known: | Hypersensitivity |
\*\*Nervous system disorders:\*\*
| | |
| --- | --- |
| Rare: | Seizures and syncope |
\*\*Skin and subcutaneous tissue disorders:\*\*
| | |
| --- | --- |
| Not known: | Urticaria |
\*\*General disorders and administration site conditions:\*\*
| | |
| --- | --- |
| Not known: | Pyrexia |
Cases of Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), some fatal, have been reported in patients receiving calcium levofolinate in combination with other agents known to be associated with these disorders. A contributory role of calcium levofolinate in these cases cannot be excluded.
Calcium levofolinate may enhance 5-FU induced toxicities depending on the applied regimen.
\*\*Additional undesirable effects when used in combination with 5-FU:\*\*
\*\*Gastrointestinal disorders:\*\*
| | |
| --- | --- |
| Very common: | Nausea, vomiting, diarrhoea, stomatitis |
\*\*Metabolism and nutritional disorders:\*\*
| | |
| --- | --- |
| Not known: | Hyperammonaemia |
\*\*Blood and lymphatic system disorders:\*\*
| | |
| --- | --- |
| Very common: | Bone marrow failure, including fatal cases, leukopenia, neutropenia, thrombocytopenia, anaemia |
\*\*General disorders and administration site conditions:\*\*
| | |
| --- | --- |
| Very common: | Mucosal inflammation and chelitis. |
\*\*Skin and subcutaneous tissue disorders:\*\*
| | |
| --- | --- |
| Common: | Palmer-plantar erythrodysaesthesia syndrome |
Fatalities have occurred as a result of gastrointestinal toxicity (predominantly mucositis and diarrhoea) and myelosuppression.
\*\*Reporting of suspected adverse reactions\*\*
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
There have been no reported sequelae in patients who have received significantly more calcium levofolinate than the recommended dosage. However, excessive amounts of calcium levofolinate may nullify the chemotherapeutic effect of folic acid antagonists.
Should overdose of the combination of 5-FU with calcium levofolinate occur, the overdose instructions for 5-FU should be followed.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment. ATC Code: V03AF04
Levofolinate is the pharmacologically active isomer of 5-formyltetrahydrofolic acid. Levofolinate does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilising folates as a source of "one carbon" moieties. Levofolinate is actively and passively transported across cell membranes.
Administration of levofolinate can "rescue" normal cells and thereby prevent toxicity of folic acid antagonists such as methotrexate which act by inhibiting dihydrofolate reductase. Levofolinate can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy such as 5-fluorouracil. 5-fluorouracil is metabolised to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FDUMP), which binds to and inhibits thymidylate synthase. Levofolinate is readily converted to another reduced folate, 5, 10-methylenetetrahydrofolate, which acts to stabilise the binding of FDUMP to thymidylate synthase and thereby enhances the inhibition of this enzyme.
Levofolinate is also effective in the treatment of megaloblastic anaemias due to folate deficiencies.5.2 Pharmacokinetic properties
\*\*Absorption\*\*
When levofolinate is injected intravenously it is 100% bioavailable.
The pharmacokinetics of levofolinate after intravenous administration of a 15 mg dose were studied in healthy male volunteers. After rapid intravenous administration, serum total tetrahydrofolate (total-THF) concentrations reached a mean peak of 1722 ng/ml. Serum levo-5-methyl-THF concentrations reached a mean peak of 275 ng/ml and the mean time to peak concentration was 0.9 hours. The mean half-life for total-THF and levo-5-methyl-THF was 5.1 and 6.8 hours respectively.
The plasma half-life of calcium levofolinate was 0.5 - 0.67 hours.
Peak serum levels of total tetrahydrofolate was reached at 0.2 hour after a dose of 15 mg intravenous administration. Area under the curve (AUC) for total tetrahydrofolate and 5-methyl-tetrahydrofolic acid (5-methyl-THF) were 3300±833 ng.hr/mL and 2135±400 ng.hr/mL, respectively.
\*\*Distribution\*\*
The distribution and plasma levels of levofolinate following intramuscular administration have not been established.
The distribution in tissue and body fluids and protein binding have not been determined.
\*\*Biotransformation\*\*
The major metabolic product of folinic acid is 5-methyl-THF which is predominantly produced in the liver and intestinal mucosa.
Peak levels of 5-methyl-THF are observed at 0.9 hours following intravenous administration.
\*In vivo\*, levofolinate is converted to levo-5-methyltetrahydrofolic acid (levo-5-methyl-THF), the primary circulating form of active reduced folate. Levofolinate and levo-5-methyl-THF are polyglutamated intracellularly by the enzyme folylpolyglutamate synthetase. Folylpolyglutamates are active and participate in biochemical pathways that require reduced folate.
\*\*Elimination\*\*
Levofolinate and levo-5-methyl-THF are excreted renally.
The elimination half-life is 32-35 minutes for the active L-form (calcium levofolinate) after dosed with calcium folinate. The total terminal half-life of the active metabolite is about 6 hours (after intravenous and intramuscular administration).
Due to the inherent lack of levofolinate toxicity, the influence of impaired renal or hepatic function on levofolinate disposition was not evaluated.5.3 Preclinical safety data
Genotoxicity, carcinogenicity and reproductive toxicity studies have not been conducted with calcium levofolinate.
.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
Sodium Chloride
Water for Injection
Hydrochloric Acid
Sodium Hydroxide6.2 Incompatibilities
Calcium levofolinate should not be mixed together with 5-FU in the same intravenous injection or infusion.
In addition to 5-FU, incompatibilities have also been reported between injectable forms of calcium levofolinate and injectable forms of droperidol, foscarnet and methotrexate.6.3 Shelf life
2 years.6.4 Special precautions for storage
Store and transport refrigerated (2°C – 8°C). Do not freeze.
Keep vial in the outer carton in order to protect from light.6.5 Nature and contents of container
Type I amber glass vials each containing the equivalent of 25 mg, 50 mg or 175 mg of calcium levofolinate in 2.5 ml, 5 ml or 17.5 ml of solution respectively. Isovorin Solution for Injection is packed in boxes of 1 vial.
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
For intravenous infusion, the 175 mg in 17.5 ml Solution for Injection may be diluted with any of the following infusion fluids before use: Sodium Chloride 0.9%; Glucose 5%; Glucose 10%; Glucose 10% and Sodium Chloride 0.9% Injection; Compound Sodium Lactate Injection.
When Isovorin Solution for Injection is diluted with the recommended infusion fluids, the resulting solutions are intended for immediate use but may be stored for up to 24 hours under refrigerated conditions (2 - 8°C). Because of the risk of degradation, reconstituted solutions should be protected from light prior to use if necessary.
Prior to administration, calcium levofolinate should be inspected visually. The solution for injection or infusion should be a clear and yellowish solution. If cloudy in appearance, or if particles are observed, the solution should be discarded. Calcium levofolinate solution for injection or infusion is intended only for single use.
Any unused product or waste material should be disposed of in accordance with local requirements.
- Instruction Content
- ## Composition
Calcium levofolinate equivalent to 1.00% w/v (10 mg/ml) of levoleucovorin (levofolinic acid).
Vials contain 25 mg, 50 mg or 175 mg of levofolinic acid (as calcium levofolinate) in 2.5 ml, 5 ml or 17.5 ml of solution respectively.
\*\*Excipient with known effect\*\*
Isovorin 25 mg/2.5 ml solution for injection contains 7.6 mg of sodium in each 2.5 ml of solution.
Isovorin 50 mg/5 ml solution for injection contains 15.2 mg of sodium in each 5 ml of solution.
Isovorin 175 mg/17.5 ml solution for injection contains 53.03 mg of sodium in each 17.5 ml of solution.
For the full list of excipients, see section 6.1
## Pharmaceutical Form
Solution for injection.
Isovorin is a clear yellow solution.
## Clinical Particulars
4.1 Therapeutic indications
\*\*Calcium Levofolinate Rescue\*\*
Calcium levofolinate is used to diminish the toxicity and counteract the action of folic acid antagonists such as methotrexate in cytotoxic therapy. This procedure is known as Calcium Levofolinate Rescue.
\*\*Advanced Colorectal Cancer - Enhancement of 5-Fluorouracil (5-FU) Cytotoxicity\*\*
Calcium levofolinate increases the thymine depleting effects of 5-FU resulting in enhanced cytotoxic activity. Combination regimens of 5-fluorouracil and levofolinate give greater efficacy compared to 5-FU given alone.4.2 Posology and method of administration
\*\*Posology\*\*
\*\*Calcium Levofolinate Rescue\*\*
\*\*Adults, Children and the Elderly:\*\*
Calcium Levofolinate Rescue therapy should commence 24 hours after the beginning of methotrexate infusion. Dosage regimes vary depending upon the dose of methotrexate administered. In general, the calcium levofolinate should be administered at a dose of 7.5 mg (approximately 5 mg/m2) every 6 hours for 10 doses by intramuscular injection, bolus intravenous injection or intravenous infusion, (see section below, for information concerning use of calcium levofolinate with infusion fluids). \*\*Do not administer calcium levofolinate intrathecally\*\* (see section 4.4).
Where overdose of methotrexate is suspected, the dose of calcium levofolinate should be at least 50% of the offending dose of methotrexate and should be administered in the first hour. In the case of intravenous administration, no more than 160 mg of calcium levofolinate should be injected per minute due to the calcium content of the solution.
In addition to calcium levofolinate administration, measures to ensure the prompt excretion of methotrexate are important as part of Calcium Levofolinate Rescue therapy. These measures include:
a. Alkalinisation of urine so that the urinary pH is greater than 7.0 before methotrexate infusion (to increase solubility of methotrexate and its metabolites). Foods, drinks and drugs that may increase urinary acidity should be avoided during the therapy.
b. Maintenance of urine output of 1800-2000 cc/m2/24 hr by increased oral or intravenous fluids on days 2, 3 and 4 following methotrexate therapy.
c. Plasma methotrexate concentration, BUN and creatinine should be measured on days 2, 3 and 4.
These measures must be continued until the plasma methotrexate level is less than 10-7 molar (0.1 μM).
Delayed methotrexate excretion may be seen in some patients. This may be caused by a third space accumulation (as seen in ascites or pleural effusion for example), renal insufficiency or inadequate hydration. Under such circumstances, higher doses of calcium levofolinate or prolonged administration may be indicated. Dosage and administration guidelines for these patients are given in Table 1. Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure.
TABLE 1:
Dosage and Administration Guidelines for Calcium Levofolinate Rescue
| | | |
| --- | --- | --- |
| \*\*Clinical Situation\*\* | \*\*Laboratory Findings\*\* | \*\*Calcium Levofolinate Dosage and Duration\*\* |
| Normal Methotrexate Elimination | Serum methotrexate level approximately 10 μM at 24 hours after administration, 1 μM at 48 hours and less than 0.2 μM at 72 hours. | 7.5 mg IM or IV every 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion). |
| Delayed Late Methotrexate Elimination | Serum methotrexate level remaining above 0.2 μM at 72 hours, and more than 0.05 μM at 96 hours after administration. | Continue 7.5 mg IM or IV every 6 hours, until methotrexate level is less than 0.05 μM. |
| Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Failure | Serum methotrexate level of 50 μM or more at 24 hours or 5 μM or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration. | 75 mg IV every 3 hours, until methotrexate level is less than 1 μM; then 7.5 mg IV every 3 hours until methotrexate level is less than 0.05 μM. |
IM – intramuscular administration
IV – intravenous administration
\*\*Colorectal Cancer: Enhancement of 5-FU Cytotoxicity\*\*
\*\*Adults and the Elderly:\*\*
\*\*Administration:\*\* The 175 mg in 17.5 ml vial of Calcium Levofolinate Solution for Injection should be used to administer the high doses of calcium levofolinate required in combination regimens.
When used in combination regimens with 5-FU, calcium levofolinate should only be given by the intravenous route. The agents should not be mixed together. Each vial of calcium levofolinate 175 mg contains 0.7 mEq (0.35 mmol) of calcium per vial and it is recommended that the solution is administered over not less than 3 minutes.
For intravenous infusion, the 175 mg in 17.5 ml Solution for Injection may be diluted with any of the following infusion fluids before use: Sodium Chloride 0.9%; Glucose 5%; Glucose 10%; Glucose 10% and Sodium Chloride 0.9% Injection; Compound Sodium Lactate Injection (see section 6.6).
Calcium levofolinate should not be mixed together with 5-FU in the same infusion and, because of the risk of degradation, the giving set should be protected from light.
\*\*Dosage:\*\* Based on the available clinical evidence, the following regimen is effective in advanced colorectal carcinoma:
Calcium levofolinate given at a dose of 100 mg/m2 by slow intravenous injection, followed immediately by 5-FU at an initial dose of 370 mg/m2 by intravenous injection. The injection of levofolinate should not be given more rapidly than over 3 minutes because of the calcium content of the solution. This treatment is repeated daily for 5 consecutive days. Subsequent courses may be given after a treatment-free interval of 21-28 days.
For the above regimen, modification of the 5-FU dosage and the treatment-free interval may be necessary depending on patient condition, clinical response and dose limiting toxicity (see 5-FU labelling for specific information). A reduction of calcium levofolinate dosage is not required. The number of repeat cycles used is at the discretion of the clinician.
On the basis of the available data, no specific dosage modifications are recommended in the use of the combination regimen with 5-FU in the elderly. However, particular care should be taken when treating elderly or debilitated patients as these patients are at increased risk of severe toxicity with this therapy (see section 4.4).
\*\*\*Paediatric population\*\*\*
There are no data available on the use of this combination in children.
\*\*Method of administration\*\*
Solution for injection is for intravenous (as bolus injection or infusion) or intramuscular administration only.
For single use only.4.3 Contraindications
Hypersensitivity to calcium levofolinate or to any of the excipients listed in section 6.1.
Calcium levofolinate should not be used for the treatment of pernicious anaemia or other megaloblastic anaemias due to vitamin B12 deficiency.
Regarding the use of calcium levofolinate with methotrexate or 5-FU during pregnancy and lactation, see section 4.6 and the Summaries of Product Characteristics for methotrexate and 5-FU-containing medicinal products.4.4 Special warnings and precautions for use
Calcium levofolinate must not be administered intrathecally. When levofolinic acid has been administered intrathecally, following intrathecal overdose of methotrexate, death has been reported (see section 4.2).
\*General\*
Calcium levofolinate treatment may mask pernicious anaemia and other megaloblastic anaemias resulting from vitamin B12 deficiency.
Calcium levofolinate should only be used with 5-FU or methotrexate under the direct supervision of a clinician experienced in the use of cancer chemotherapeutic agents.
Many cytotoxic medicinal products – direct or indirect DNA synthesis inhibitors – lead to macrocytosis (hydroxycarbamide, cytarabine, mercaptopurine, thioguanine). Such macrocytosis should not be treated with folinic acid.
\*Calcium levofolinate / 5-FU\*
Calcium levofolinate may enhance the toxicity profile of 5-FU, particularly in elderly or debilitated patients. The most common manifestations are leucopoenia, mucositis, stomatitis and / or diarrhoea, which may be dose limiting.
Combined 5-FU / calcium levofolinate treatment should neither be initiated nor maintained in patients with symptoms of gastrointestinal toxicity, regardless of the severity, until all of these symptoms have completely disappeared.
Patients presenting with diarrhoea must be carefully monitored until the symptoms have resolved completely, since a rapid clinical deterioration leading to death can occur. If diarrhoea and / or stomatitis occur, it is advisable to reduce the dose of 5-FU until symptoms have fully resolved. The elderly and patients with a low physical performance due to their illness are especially prone to these toxicities. Therefore, particular care should be taken when treating these patients.
In elderly patients and patients who have undergone preliminary radiotherapy, it is recommended to begin with a reduced dosage of 5-FU.
Calcium levofolinate must not be mixed with 5-FU in the same IV injection or infusion.
\*Calcium levofolinate / methotrexate\*
An accidental overdose with a folate antagonist, such as methotrexate, should be treated quickly as a medical emergency. As the time interval between methotrexate administration and calcium levofolinate rescue increases, calcium levofolinate effectiveness in counteracting toxicity decreases.
Calcium levofolinate has no effect on non-haematological toxicities of methotrexate such as the nephrotoxicity resulting from methotrexate and / or metabolite precipitation in the kidney. Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure and all toxicities associated with methotrexate. The presence of pre-existing or methotrexate-induced renal insufficiency is potentially associated with delayed excretion of methotrexate and may increase the need for higher doses or more prolonged use of calcium levofolinate.
The possibility that the patient is taking other medications that interact with methotrexate (e.g. medications which may interfere with methotrexate elimination or binding to serum albumin) should always be considered when laboratory abnormalities or clinical toxicities are observed.
Excessive calcium levofolinate doses must be avoided since this might impair the anti-tumour activity of methotrexate, especially in CNS tumours where calcium levofolinate accumulates after repeated courses.
Resistance to methotrexate as a result of decreased membrane transport implies also resistance to folinic acid rescue as both medicinal products share the same transport system.
\*\*Excipient Information:\*\*
Isovorin 25 mg/2.5 ml solution for injection contains 7.6 mg of sodium per 2.5 ml of solution, equivalent to 0.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Isovorin 50 mg/5 ml solution for injection contains 15.2 mg of sodium per 5 ml of solution, equivalent to 0.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Isovorin 175 mg/17. 5 ml solution for injection contains 53.03 mg of sodium per 17.5 ml of solution, equivalent to 2.65% of the WHO recommended maximum daily intake of 2 g sodium for an adult.4.5 Interaction with other medicinal products and other forms of interaction
When calcium levofolinate is given in conjunction with a folic acid antagonist (e.g. cotrimoxazole, pyrimethamine) the efficacy of the folic acid antagonist may either be reduced or completely neutralised.
Calcium levofolinate may diminish the antiepileptic effect of phenobarbital, phenytoin, primidone and succinimides, and may increase the frequency of seizures in susceptible patients. Clinical monitoring is therefore recommended.
Concurrent administration of chloramphenicol and folic acid in folate deficient patients may result in antagonism of haematopoietic response to folic acid.
Calcium levofolinate may enhance the toxicity of fluorouracil (see sections 4.2, 4.4 and 4.8).4.6 Fertility, pregnancy and lactation
\*\*Pregnancy\*\*
There are no adequate and well-controlled clinical studies conducted in pregnant or breast-feeding women.
No formal animal reproductive toxicity studies with calcium levofolinate have been conducted. Calcium levofolinate should only be used in pregnant women if the potential benefit justifies the potential risk to the foetus.
\*\*Breast-feeding\*\*
Calcium levofolinate may be excreted in human milk and should only be administered where the benefits of the drug to the mother outweigh possible hazards to the infant. Calcium levofolinate can be used during breast-feeding when considered necessary according to the therapeutic indications.
\*\*Fertility\*\*
No fertility studies have been conducted with calcium levofolinate in animals.4.7 Effects on ability to drive and use machines
There is no evidence that calcium levofolinate has an effect on the ability to drive or use machines.4.8 Undesirable effects
Within the organ system classes, adverse reactions are listed under the headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10,000, <1/1000); very rare (<1/10,000); not known (frequency cannot be estimated from the available data).
\*\*Immune system disorders:\*\*
| | |
| --- | --- |
| Very rare: | Anaphylactoid / anaphylactic reactions (including shock) |
| Not known: | Hypersensitivity |
\*\*Nervous system disorders:\*\*
| | |
| --- | --- |
| Rare: | Seizures and syncope |
\*\*Skin and subcutaneous tissue disorders:\*\*
| | |
| --- | --- |
| Not known: | Urticaria |
\*\*General disorders and administration site conditions:\*\*
| | |
| --- | --- |
| Not known: | Pyrexia |
Cases of Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), some fatal, have been reported in patients receiving calcium levofolinate in combination with other agents known to be associated with these disorders. A contributory role of calcium levofolinate in these cases cannot be excluded.
Calcium levofolinate may enhance 5-FU induced toxicities depending on the applied regimen.
\*\*Additional undesirable effects when used in combination with 5-FU:\*\*
\*\*Gastrointestinal disorders:\*\*
| | |
| --- | --- |
| Very common: | Nausea, vomiting, diarrhoea, stomatitis |
\*\*Metabolism and nutritional disorders:\*\*
| | |
| --- | --- |
| Not known: | Hyperammonaemia |
\*\*Blood and lymphatic system disorders:\*\*
| | |
| --- | --- |
| Very common: | Bone marrow failure, including fatal cases, leukopenia, neutropenia, thrombocytopenia, anaemia |
\*\*General disorders and administration site conditions:\*\*
| | |
| --- | --- |
| Very common: | Mucosal inflammation and chelitis. |
\*\*Skin and subcutaneous tissue disorders:\*\*
| | |
| --- | --- |
| Common: | Palmer-plantar erythrodysaesthesia syndrome |
Fatalities have occurred as a result of gastrointestinal toxicity (predominantly mucositis and diarrhoea) and myelosuppression.
\*\*Reporting of suspected adverse reactions\*\*
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
There have been no reported sequelae in patients who have received significantly more calcium levofolinate than the recommended dosage. However, excessive amounts of calcium levofolinate may nullify the chemotherapeutic effect of folic acid antagonists.
Should overdose of the combination of 5-FU with calcium levofolinate occur, the overdose instructions for 5-FU should be followed.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment. ATC Code: V03AF04
Levofolinate is the pharmacologically active isomer of 5-formyltetrahydrofolic acid. Levofolinate does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilising folates as a source of "one carbon" moieties. Levofolinate is actively and passively transported across cell membranes.
Administration of levofolinate can "rescue" normal cells and thereby prevent toxicity of folic acid antagonists such as methotrexate which act by inhibiting dihydrofolate reductase. Levofolinate can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy such as 5-fluorouracil. 5-fluorouracil is metabolised to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FDUMP), which binds to and inhibits thymidylate synthase. Levofolinate is readily converted to another reduced folate, 5, 10-methylenetetrahydrofolate, which acts to stabilise the binding of FDUMP to thymidylate synthase and thereby enhances the inhibition of this enzyme.
Levofolinate is also effective in the treatment of megaloblastic anaemias due to folate deficiencies.5.2 Pharmacokinetic properties
\*\*Absorption\*\*
When levofolinate is injected intravenously it is 100% bioavailable.
The pharmacokinetics of levofolinate after intravenous administration of a 15 mg dose were studied in healthy male volunteers. After rapid intravenous administration, serum total tetrahydrofolate (total-THF) concentrations reached a mean peak of 1722 ng/ml. Serum levo-5-methyl-THF concentrations reached a mean peak of 275 ng/ml and the mean time to peak concentration was 0.9 hours. The mean half-life for total-THF and levo-5-methyl-THF was 5.1 and 6.8 hours respectively.
The plasma half-life of calcium levofolinate was 0.5 - 0.67 hours.
Peak serum levels of total tetrahydrofolate was reached at 0.2 hour after a dose of 15 mg intravenous administration. Area under the curve (AUC) for total tetrahydrofolate and 5-methyl-tetrahydrofolic acid (5-methyl-THF) were 3300±833 ng.hr/mL and 2135±400 ng.hr/mL, respectively.
\*\*Distribution\*\*
The distribution and plasma levels of levofolinate following intramuscular administration have not been established.
The distribution in tissue and body fluids and protein binding have not been determined.
\*\*Biotransformation\*\*
The major metabolic product of folinic acid is 5-methyl-THF which is predominantly produced in the liver and intestinal mucosa.
Peak levels of 5-methyl-THF are observed at 0.9 hours following intravenous administration.
\*In vivo\*, levofolinate is converted to levo-5-methyltetrahydrofolic acid (levo-5-methyl-THF), the primary circulating form of active reduced folate. Levofolinate and levo-5-methyl-THF are polyglutamated intracellularly by the enzyme folylpolyglutamate synthetase. Folylpolyglutamates are active and participate in biochemical pathways that require reduced folate.
\*\*Elimination\*\*
Levofolinate and levo-5-methyl-THF are excreted renally.
The elimination half-life is 32-35 minutes for the active L-form (calcium levofolinate) after dosed with calcium folinate. The total terminal half-life of the active metabolite is about 6 hours (after intravenous and intramuscular administration).
Due to the inherent lack of levofolinate toxicity, the influence of impaired renal or hepatic function on levofolinate disposition was not evaluated.5.3 Preclinical safety data
Genotoxicity, carcinogenicity and reproductive toxicity studies have not been conducted with calcium levofolinate.
.
## Pharmaceutical Particulars
6.1 List of excipients
Sodium Chloride
Water for Injection
Hydrochloric Acid
Sodium Hydroxide6.2 Incompatibilities
Calcium levofolinate should not be mixed together with 5-FU in the same intravenous injection or infusion.
In addition to 5-FU, incompatibilities have also been reported between injectable forms of calcium levofolinate and injectable forms of droperidol, foscarnet and methotrexate.6.3 Shelf life
2 years.6.4 Special precautions for storage
Store and transport refrigerated (2°C – 8°C). Do not freeze.
Keep vial in the outer carton in order to protect from light.6.5 Nature and contents of container
Type I amber glass vials each containing the equivalent of 25 mg, 50 mg or 175 mg of calcium levofolinate in 2.5 ml, 5 ml or 17.5 ml of solution respectively. Isovorin Solution for Injection is packed in boxes of 1 vial.
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
For intravenous infusion, the 175 mg in 17.5 ml Solution for Injection may be diluted with any of the following infusion fluids before use: Sodium Chloride 0.9%; Glucose 5%; Glucose 10%; Glucose 10% and Sodium Chloride 0.9% Injection; Compound Sodium Lactate Injection.
When Isovorin Solution for Injection is diluted with the recommended infusion fluids, the resulting solutions are intended for immediate use but may be stored for up to 24 hours under refrigerated conditions (2 - 8°C). Because of the risk of degradation, reconstituted solutions should be protected from light prior to use if necessary.
Prior to administration, calcium levofolinate should be inspected visually. The solution for injection or infusion should be a clear and yellowish solution. If cloudy in appearance, or if particles are observed, the solution should be discarded. Calcium levofolinate solution for injection or infusion is intended only for single use.
Any unused product or waste material should be disposed of in accordance with local requirements.
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