ISOVORIN SOLUTION FOR INJECTION 10 MG / ML - patient leaflet, side effects, dosage

Patient leaflet - ISOVORIN SOLUTION FOR INJECTION 10 MG / ML

1. what isovorin solution is and what it is used for

Isovorin Solution contains the active substance calcium levofolinate. Isovorin Solution for Injection 10 mg/ml may be used in combination with other medicines to treat cancer. In particular it may be used to reduce the harmful effects of an anti-cancer drug called methotrexate.

Isovorin Solution can be used to increase the effect of another drug, 5-fluorouracil (5FU) in treating some types of cancer such as cancer of the colon or rectum.

2. what you need to know before you use isovorin solution

Do not use Isovorin Solution if:

you are allergic to calcium levofolinate or any of the other ingredients of this medicine (listed in section 6)
you have a blood disease called anaemia caused by too little Vitamin B12
you are pregnant, think you might be pregnant or are breast- feeding

Warnings and precautions

Talk to your doctor, pharmacist or nurse before using Isovorin Solution if:

you have anaemia (megaloblastic or pernicious) caused by vitamin B12 deficiency __
you have blood problems caused by anti-cancer medicines
you are elderly or debilitated and being treated with 5-Fluorouracil
you are suffering from diarrhoea or stomach upset and receiving treatment along with 5-Flurouracil
you have undergone preliminary radiotherapy
you take an accidental overdose with methotrexate
you have taken an excessive dose of this as the activity of methotrexate may be impaired especially in anti-tumour therapy
you are resistant to methotrexate or folinic acid

3. how to use isovorin solution

Your doctor will give you Isovorin Solution by injecting it into one of your veins or muscle.

Isovorin Solution should not be injected into your spine

When used to reduce the harmful effects of methotrexate, your treatment will usually start about 24 hours after your methotrexate treatment starts. The usual dose of Isovorin Solution is 7.5 mg every 6 hours for 10 doses. However, the doctor may decide to change this, depending on your condition and the dose of methotrexate you have already received. During your treatment your doctor may also wish to give you other fluids and to take blood samples from you.

When used in combination with other drugs such as 5FU, the higher dose of 175 mg in 17.5 ml of Isovorin Solution will be given to you.

If you use more Isovorin Solution than you should

As this medicine will be given to you whilst you are in hospital it is unlikey that you will be given too little or too much however if you have any concerns then tell your doctor.

If you miss a dose of Isovorin Solution

If you think you have not been given a dose of Isovorin Solution, tell your doctor immediately.

If you think that you have missed a dose or have been given too much medicine, tell your doctor/nurse immediately.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If any of the following happen, tell your doctor immediately or go to your nearest hospital:

Severe allergic reactions such as breathing difficulties, swelling of the lips, face, neck and throat, and low blood pressure
Very severe skin reactions with reddening, blistering, severe inflammation and skin loss
Severe diarrhoea
Excessive bruising, shortness of breath, tiredness or repeated infections.

The side effects listed below are those that have been seen with the use of Isovorin Solution.

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

Fits; fainting

Not known: frequency cannot be estimated from available data.

Mild allergic reactions, such as skin rash and itching; fever

The side effects listed below are those that have also been seen when Isovorin Solution has been used in combination with 5FU.

Very common: may affect more than 1 in 10 people

Feeling or being sick; diarrhoea, inflammation of the lining of the intestine and mouth (including life-threatening conditions); reduction in the number of blood cells (including life-threating conditions)

Common: redness and swelling of the palms of the hands or the soles of the feet which may cause the skin to peel (hand-foot syndrome)
Not known: frequency cannot be estimated from available data.

Elevated levels of ammonia in the blood

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme website: or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

5. how to store isovorin solution

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and vial label after EXP. The expiry date refers to the last day of that month.

Isovorin Solution for Injection 10 mg/ml should be kept in a refrigerator (2–8°C) in the original container to protect from light.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

6. contents of the pack and other information

What Isovorin Solution contains

The active substance is calcium levofolinate. Each vial contains 10mg per ml of calcium levofolinate.
The other ingredients are sodium chloride, water for injection, hydrochloric acid and sodium hydroxide. Excipients containing sodium (see section 2 ‘Isovorin solution contains sodium’).

What Isovorin Solution looks like and contents of the pack

Isovorin Solution is a clear yellow solution. It is supplied in small amber glass bottles (called vials). Each vial contains 25 mg, 50 mg or 175 mg of the active ingredient calcium levofolinate in 2.5 ml, 5 ml and 17.5 ml respectively.

Isovorin Solution for Injection 10mg/ml is supplied in a carton containing one vial. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

The marketing authorisation holder is: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom

The manufacturer of this medicine is: Wyeth Lederle S.p.A, Via Franco Gorgone, Zona Industriale, Catania, Italy

The information in this leaflet applies only to Isovorin Solution. If you would like more information about Isovorin Solution for Injection 10 mg/ml, have any questions or you are not sure about anything, you should ask your doctor.

This leaflet was last revised in 02/2021

Ref: IO 7_1 UK

HEALTH PROFESSIONALS’ USER LEAFLET

1. NAME OF THE MEDICINAL PRODUCT

Isovorin Solution for Injection 10 mg/ml

2. QUALITATIVE AND QUANTITATIVE 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.

Excipients 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

3. PHARMACEUTICAL FORM

Solution for injection.

Isovorin Solution is a clear yellow solution.

4. 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.

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).
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 pM).

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	Levofolinate Dosage and Duration
Normal Methotrexate Elimination	Serum methotrexate level approximately 10 pM at 24 hours after administration, 1 pM at 48 hours and less than 0.2 pM 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 pM at 72 hours, and more than 0.05 pM at 96 hours after administration.	Continue 7.5 mg IM or IV every 6 hours, until methotrexate level is less than 0.05 pM.
Delayed Early Methotrexate Elimination and/ or Evidence of Acute Renal Injury	Serum methotrexate level of 50 pM or more at 24 hours or 5 pM 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 pM; then 7.5 mg IV every 3 hours until methotrexate level is less than 0.05 pM.

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.

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. 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 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, (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.

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 GI 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 disappeared 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. 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 antitumour 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.

4.6. Fertility, pregnancy and lactation

Pregnancy and breast-feeding

There are no adequate and well-controlled clinical studies conducted in pregnant or breast-feeding women.

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.

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: Allergic reactions, urticaria

Nervous system disorders:

Rare: Seizures and syncope

General disorders and administration site conditions:

Not known: Fever

Cases of Stevens Johnson Sydrome (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

Metabolism and nutritional disorders:

Not known: Hyperammonaemia

Blood and lymphatic system disorders:

Very common: bone marrow failure, including fatal cases

General disorders and administration site conditions:

Very common: Mucositis, including stomatitis and chelitis.

Fatalities have occurred as a result of mucositis.

Skin and subcutaneous tissue disorders:

Common: Palmar-Plantar Erythrodysaesthesia

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:

or search for MHRA Yellow Card in the Google Play or Apple App Store.

By reporting side effects you can help provide more information on the safety of this medicine.

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.

5. 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

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 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. 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.

Levofolinate and levo-5-methyl-THF are excreted renally.

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

The pre-clinical data raises no concerns for the clinical uses indicated.

6. PHARMACEUTICAL PARTICULARS
- 6.1. List of excipients

Sodium Chloride

Water for Injection Hydrochloric Acid Sodium Hydroxide

6.2. 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).

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

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.

7. MARKETING AUTHORISATION HOLDER

Pfizer Limited

Ramsgate Road Sandwich

Kent

CT13 9NJ

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S) PL 00057/1282
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 17 Aug 2011
10. DATE OF REVISION OF THE TEXT 04/2021