Mustophoran^® (Powder) Instructions for Use

Marketing Authorization Holder

Les Laboratoires Servier (France)

Manufactured By

Cenexi-Laboratoires Thissen, S.A. (Belgium)

Manufactured By

EGIS Pharmaceuticals, PLC (Hungary)

Quality Control Release

CENEXI-LABORATOIRES THISSEN, S.A. (Belgium)

ATC Code

L01AD05 (Fotemustine)

Active Substance

Fotemustine (Rec.INN registered by WHO)

Dosage Form

Mustophoran®

Powder for solution for infusions 208 mg: vial 1 pc. in set with solvent (amp. 4 ml 1 pc.)

Dosage Form, Packaging, and Composition

Powder for solution for infusions light yellow in color; solvent – a transparent, colorless solution with a characteristic odor of ethanol.

Solvent ethanol 96% – 3.35 ml, water for injections – sufficient quantity to a volume of 4 ml.

Brown glass vials (1) in a set with solvent (amp. 4 ml 1 pc.) – plastic contour cell packaging (1) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Alkylating compound

Pharmacotherapeutic Group

Antineoplastic agent, alkylating compound

Pharmacological Action

Cytostatic antimitotic drug from the group of nitrosourea derivatives, possessing alkylating and carbamylating action. The pronounced antitumor activity of fotemustine has been confirmed experimentally.

The fotemustine molecule contains a bioisostere of alanine (amino-1-ethylphosphonic acid), which promotes the penetration of the drug into cells and passage through the blood-brain barrier.

Pharmacokinetics

Plasma protein binding is low (25-30%). Fotemustine penetrates through the blood-brain barrier.

The drug is almost completely metabolized.

After IV administration, the elimination pharmacokinetics of fotemustine from plasma is mono- or biexponential with a short T_1/2.

Indications

• Disseminated malignant melanoma (including brain metastases);
• Malignant brain tumors.

ICD codes

Dosage Regimen

To avoid extravasation, before administering fotemustine, it should be ensured that the IV needle is correctly inserted into the vein. In case of extravasation, it is necessary to stop the infusion, remove the extravasate contents as much as possible and fix the limb in an elevated position.

When used in monotherapy, the drug is used as induction therapy at a dose of 100 mg/m² on days 1, 8 and 15. Similar courses are repeated at intervals of 4-5 weeks.

As maintenance therapy, Mustophoran^® is administered at the same dose once every 3 weeks.

As part of combination chemotherapy, the drug is administered at a dose of 100 mg/m² on days 1 and 8.

In patients receiving Mustophoran^®, the platelet, leukocyte and granulocyte counts in the blood must be monitored before each administration. In case of hematological toxicity development, the dose of Mustophoran^® may be reduced, or the drug administration should be postponed according to the following scheme

Use in combination with dacarbazine

When fotemustine and dacarbazine were administered in high doses on the same day, cases of respiratory toxicity (adult respiratory distress syndrome) were noted. Simultaneous use of dacarbazine and fotemustine should be avoided (see section “Drug Interactions”). If combined use of these drugs is necessary, the following treatment regimen is recommended

• Induction therapy: Fotemustine at a dose of 100 mg/m² on days 1 and 8 of treatment; dacarbazine at a dose of 250 mg/m² on days 15, 16, 17 and 18 of treatment. Then a break – 5 weeks.
• Maintenance therapy: every 3 weeks Fotemustine at a dose of 100 mg/m² on day 1; dacarbazine at a dose of 250 mg/m² on days 2, 3, 4 and 5.

Rules for preparation and administration of the solution

The solution is prepared immediately before administration and used immediately after preparation.

The contents of the vial are dissolved in 4 ml of the supplied solvent and mixed for 2-3 minutes until the powder is completely dissolved. To prepare the infusion solution, the required dose is further diluted in 250 ml of 5% dextrose solution (in patients with diabetes mellitus, 0.9% sodium chloride solution can be used as a dilution solution).

The resulting solution is administered IV drip over 1 h, protected from light (the vial with the solution is placed in an opaque cover).

Adverse Reactions

The most common side effects in clinical studies were from the hematopoietic system. The delayed toxicity of fotemustine is manifested by anemia (14%), thrombocytopenia (40.3%) and leukopenia (46.3%) and reaches maximum severity at 4-5 and 5-6 weeks after the start of induction therapy. The development of pancytopenia is also possible.

Hematological toxicity while taking fotemustine may be enhanced in case of prior chemotherapy and/or combination therapy with other drugs that have a toxic effect on the hematopoietic system.

In elderly patients, more pronounced toxic effects on the hematopoietic system and gastrointestinal tract may be observed.

The frequency of adverse reactions that were noted during therapy with fotemustine is presented in the following gradation: 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), frequency not known (frequency cannot be calculated from available data).

From the hematopoietic organs very common – thrombocytopenia, leukopenia (grades 3-4), anemia (grades 3-4).

From the digestive system very common – nausea and vomiting developing within 2 h after the start of drug administration, transient moderate reversible increase in the activity of liver transaminases, alkaline phosphatase and serum bilirubin concentration; common – diarrhea, abdominal pain; frequency not known – hepatitis.

From the nervous system uncommon – transient neurological symptoms (impaired consciousness, paresthesia, loss of taste sensitivity).

From the urinary system uncommon – transient increase in serum urea concentration.

From the skin and subcutaneous tissues: uncommon – skin itching.

General disorders and administration site conditions common – fever, phlebitis (swelling, pain, redness over the damaged vein) at the injection site, in case of extravasation (see sections “Special Precautions” and “Dosage Regimen”).

From the respiratory system when administered simultaneously with dacarbazine, cases of pulmonary toxicity (adult respiratory distress syndrome) were noted (see section “Drug Interactions”). Toxicity of the respiratory system (interstitial pneumonia) has also been described with the use of fotemustine.

Benign, malignant and unspecified neoplasms (including polyps and cysts) the use of antitumor drugs, especially alkylating compounds, is associated with the risk of developing myelodysplastic syndrome and acute myeloid leukemia. Rare cases of such complications have been described with the use of fotemustine in high cumulative doses in monotherapy and in combination with other chemotherapeutic drugs, with and without radiation therapy.

Contraindications

• Combined use with yellow fever vaccine (see section “Drug Interactions”);
• Women of childbearing potential not using reliable contraception;
• Pregnancy;
• Lactation period (breastfeeding);
• Hypersensitivity to fotemustine, drugs of the nitrosourea group or to any of the excipients.

It is not recommended to use the drug in children and adolescents under 18 years of age, since efficacy and safety for this age group have not been established.

With caution the drug should be used in patients suffering from alcoholism, in patients with liver diseases and epilepsy.

Use in Pregnancy and Lactation

Pregnancy

Data on the use of Mustophoran^® in pregnant women are limited. Data from experimental animal studies are insufficient to assess reproductive toxicity.

Mustophoran^® is contraindicated during pregnancy, as well as in women of childbearing potential not using reliable contraception.

Lactation

It is not known whether Fotemustine or its metabolites are excreted in breast milk. Therefore, the risk of adverse effects on newborns/infants cannot be excluded.

Mustophoran^® is contraindicated during breastfeeding (see section “Contraindications”).

Fertility

Animal toxicity studies have revealed an effect of fotemustine on male fertility.

Use in Hepatic Impairment

With caution the drug should be used in patients with liver diseases.

Pediatric Use

Not recommended for use in children and adolescents under 18 years of age, since efficacy and safety for this age group have not been established.

Geriatric Use

Thrombocytopenia (grade 3), leukopenia (grade 3) and gastrointestinal toxic effects (grade 3) were significantly more common in patients over 60 years of age.

Special Precautions

Treatment with Mustophoran^® should be carried out only under the supervision of a physician experienced in antitumor therapy.

If less than 4 weeks have passed since previous treatment with cytostatic agents (and in case of treatment with nitrosourea drugs – 6 weeks), it is not recommended to prescribe the drug.

Treatment with Mustophoran^® can be prescribed only if the platelet count in peripheral blood is at least 100,000/µl and granulocytes – at least 2,000/µl.

Blood tests should be performed before each subsequent administration of the drug with appropriate dose adjustment depending on hematological parameters (see section “Dosage Regimen”).

An interval of 8 weeks is recommended between the start of induction therapy and the start of maintenance therapy. The recommended interval between two cycles of maintenance therapy is 3 weeks.

Maintenance therapy can be prescribed if the platelet count in peripheral blood is at least 100,000/µl and granulocytes – at least 2,000/µl.

It is recommended to regularly assess liver function parameters during and after induction chemotherapy.

Mustophoran^® is contraindicated during pregnancy, as well as in women of childbearing potential not using reliable contraception (see section “Contraindications”).

Men and women of childbearing potential should use reliable contraception during and for at least 6 months after the end of treatment with fotemustine.

When working with Mustophoran^®, the necessary rules for the use and disposal of cytotoxic drugs should be observed. Pregnant women are prohibited from working with Mustophoran^®. When working with the drug, the use of latex gloves and masks is recommended. If the solution gets on the skin or mucous membranes, these areas should be thoroughly washed with water and soap. If the drug gets into the eyes, they should be rinsed with plenty of water. Inhalation of the drug should be avoided.

The drug contains an 80% ethanol solution, i.e. 1.3 g of ethanol per 100 mg of fotemustine, which is equivalent to 32 ml of beer, 13.3 ml of wine. This amount of ethanol can be dangerous for patients suffering from alcoholism. When prescribing the drug to patients at risk (for example, with liver diseases or epilepsy), it should also be remembered that it contains ethanol.

Elderly patients: the toxicity of fotemustine was compared in patients under and over 60 years of age. Thrombocytopenia (grade 3), leukopenia (grade 3) and gastrointestinal toxic effects (grade 3) were significantly more common in patients over 60 years of age.

To avoid extravasation, before administering fotemustine, it must be ensured that the IV needle is correctly inserted into the vein. In case of extravasation, the infusion should be stopped, the extravasate contents should be removed as much as possible and the limb should be fixed in an elevated position.

Effect on ability to drive vehicles and mechanisms

No studies have been conducted to assess the effect on the ability to drive a car. Nevertheless, it is not recommended to drive a car and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions immediately after the administration of fotemustine.

Overdose

Specific antidotes for overdose of Mustophoran^® are not known.

Treatment: discontinuation of drug administration and supportive therapy with enhanced monitoring of hematological parameters.

Drug Interactions

No studies of the interaction of Mustophoran^® with other drugs have been conducted.

Interaction characteristic of cytotoxic drugs

Patients with malignant neoplasms have an increased risk of thrombosis, so they are often prescribed anticoagulants. Against the background of taking anticoagulants, the INR indicator should be monitored more often, since such patients have variability in blood coagulation parameters, which is complicated by the risk of interaction between oral anticoagulants and antitumor agents.

Drug combinations that are contraindicated

When used in combination with yellow fever vaccine, there is a risk of fatal systemic post-vaccination complications (see section “Contraindications”).

Undesirable drug combinations

Phenytoin (and presumably fosphenytoin): risk of seizures, because with simultaneous use, due to decreased absorption at the level of the digestive tract, the serum concentration of phenytoin/fosphenytoin may decrease. There is a risk of increased toxicity or decreased efficacy of fotemustine, due to increased activity of its metabolism in the liver caused by phenytoin/fosphenytoin.

Live and attenuated vaccines (except yellow fever vaccine): risk of developing systemic diseases induced by vaccines, with possible fatal outcome. The risk is higher in patients with immunosuppressive conditions caused by existing diseases. For vaccination of such patients, inactivated vaccines should be used, if available, (for example, polio vaccine).

Drug combinations that require caution

When used simultaneously with immunosuppressants, pronounced suppression of the immune system and the risk of lymphoproliferation are observed.

Interaction specific to fotemustine

Drug combinations that require caution

When fotemustine and dacarbazine were administered in high doses on the same day, cases of respiratory toxicity (adult respiratory distress syndrome) were noted. Simultaneous use of dacarbazine and fotemustine should be avoided. The recommended interval between the last dose of fotemustine and the first dose of dacarbazine is 1 week.

Storage Conditions

The drug should be stored out of the reach of children, protected from light at a temperature from 2°C (35.6°F) to 8°C (46.4°F).

Shelf Life

The shelf life of the powder for solution for infusions is 2 years; the shelf life of the solvent is 3 years. Do not use after the expiration date stated on the package.

The prepared solution should be used immediately after preparation.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.