Lomustine medac (Capsules) Instructions for Use

Marketing Authorization Holder

Medac, GmbH (Germany)

Manufactured By

Haupt Pharma Amareg, GmbH (Germany)

Packaging and Quality Control Release

Medac, GmbH (Germany)

ATC Code

L01AD02 (Lomustine)

Active Substance

Lomustine (Rec.INN registered by WHO)

Dosage Form

Lomustine medac

Capsules 40 mg: 20 pcs.

Dosage Form, Packaging, and Composition

Capsules are hard gelatin, size No. 3, with a blue body and cap; the capsule contents are a powder from white to light yellow in color, possibly with yellow inclusions.

Excipients: lactose monohydrate – 100 mg, wheat starch – 40 mg, talc – 16 mg, magnesium stearate – 4 mg.

Capsule shell composition: gelatin – 49 mg, titanium dioxide (E171) – 0.5 mg, indigo carmine (E132) – 0.06 mg.

20 pcs. – plastic jars (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agents; alkylating agents; nitrosourea derivatives

Pharmacological Action

Lomustine is an antineoplastic drug with an alkylating action from the nitrosourea group.

The mechanism of action involves the alkylation of DNA and RNA. Inhibition of DNA synthesis is due to the carbamoylation of DNA polymerase and other DNA repair enzymes, and damage to the DNA template. The drug may also inhibit key enzymatic processes by altering the structure and function of many proteins and enzymes. Lomustine acts in the late G1 and early S-phase of the cell cycle. Cells in the stationary growth phase are most sensitive to lomustine (a factor determining activity in solid tumors with a low proliferative pool).

Pharmacokinetics

After oral administration, it is rapidly and almost completely absorbed from the gastrointestinal tract. C_max of the drug in blood plasma is reached in 1-4 hours. Plasma protein binding is 50%. It penetrates the blood-brain barrier and into breast milk. More than 50% of the plasma concentration is detected in the cerebrospinal fluid.

It is metabolized in the liver to form active metabolites (hydroxymethyldiazonium and isocyanate). Hydroxymethyldiazonium ionizes and turns into a methyldiazonium ion, which transforms into a more stable tautomeric form (diazomethane), or decomposes into a methylcarbonium ion and nitrogen. T_1/2 of active metabolites ranges from 16 to 48 hours. It is excreted mainly by the kidneys in the form of metabolites, less than 5% through the intestines.

Indications

Lomustine is used in monotherapy and in combination therapy for the following diseases

• Primary and metastatic brain tumors after surgical treatment and/or radiotherapy;
• Hodgkin’s disease [lymphogranulomatosis] as a second-line therapy;
• Gastric and intestinal cancer, small cell lung cancer, kidney cancer, multiple myeloma, malignant melanoma.

ICD codes

Dosage Regimen

Lomustine should be taken orally in the evening, before bedtime or 3 hours after a meal. The recommended dose of lomustine for adults and children is 130 mg/m² as a single oral dose every 6 weeks.

In patients with impaired bone marrow function, the dose can be reduced to 100 mg/m² while maintaining the six-week interval between doses.

In case of combination therapy, the drug is used at a dose of 70-100 mg/m².

Repeat courses should not be prescribed if the platelet count is less than 100,000/µl and leukocytes are less than 4000/µl.

The total dose for all treatment courses should not exceed 1000 mg/m².

Subsequent doses of the drug should be selected depending on the patient’s hematological response to the previous dose. The following scheme can be used for dose selection

Adverse Reactions

From the hematopoietic system: thrombocytopenia develops after 4 weeks, leukocytopenia after 5-6 weeks of drug use and may last for 1-2 weeks. Usually, thrombocytopenia is more severe than leukocytopenia. Anemia and granulocytopenia are observed less frequently.

Lomustine can cause cumulative myelosuppression, and after repeated doses, more pronounced bone marrow suppression may be noted, or the duration of myelosuppression may be longer.

From the digestive system: nausea and vomiting (3-6 hours after taking lomustine, usually lasting up to 24 hours), anorexia. The frequency and duration of these side effects can be reduced by prophylactic use of antiemetic drugs, as well as by prescribing lomustine to patients on an empty stomach. Rarely – diarrhea, stomatitis, increased activity of liver enzymes and bilirubin concentration.

From the respiratory system: rarely – cough, respiratory failure, accompanying the appearance of infiltrates and/or pulmonary fibrosis (noted after 6 months or later after the start of treatment with total drug doses of more than 1100 mg/m². One case of pulmonary toxicity was reported at a cumulative dose of 600 mg/m²).

From the nervous system: disorientation, lethargy, ataxia, speech articulation disorder, increased fatigue.

From the urinary system: urinary retention, swelling of the feet or lower extremities, azotemia, reduction in kidney size (usually with high cumulative doses of the drug during prolonged treatment with lomustine and other nitrosourea drugs).

From the reproductive system: azoospermia (in some cases irreversible), amenorrhea.

Other: rarely – alopecia, irreversible damage to the optic nerves leading to blindness (when combined with brain radiation therapy). Acute leukemias and bone marrow dysplasias have been reported as a result of treatment with nitrosourea drugs.

Contraindications

• Hypersensitivity to lomustine, other nitrosourea derivatives, or components of the drug;
• Pregnancy and breastfeeding period.

With caution: myelosuppression (including against the background of concomitant radiation or chemotherapy, intoxication); chickenpox (including recently contracted or after contact with sick individuals), herpes zoster and other acute infectious diseases of viral, fungal or bacterial nature; cachexia, intoxication, renal and/or hepatic insufficiency, respiratory failure, history of treatment with cytostatics and radiation therapy.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and breastfeeding.

Use in Hepatic Impairment

With caution: hepatic insufficiency.

Use in Renal Impairment

With caution: renal insufficiency.

Pediatric Use

Use is possible according to the dosage regimen.

Special Precautions

Lomustine should be used under the supervision of physicians experienced in working with antineoplastic drugs.

Systematic (at least once a week) monitoring of the peripheral blood picture is necessary during therapy and for 6 weeks after the end of treatment, as well as periodic monitoring of laboratory parameters of liver and kidney function.

Against the background of thrombocytopenia and leukocytopenia, bleeding and severe infections may occur in debilitated patients.

Lung function should be assessed before starting therapy and during treatment. Patients with initially reduced lung vital capacity are more susceptible to the pulmonary toxicity of lomustine. It is not recommended to use the drug more often than once every 6 weeks.

Men and women of childbearing potential should use reliable methods of contraception during treatment and for at least 6 months after.

Do not open the capsules (the powder has an irritant effect), avoid getting the powder on the skin and mucous membranes.

Overdose

In case of overdose, an increase in the severity of side effects should be expected – suppression of bone marrow hematopoiesis, gastrointestinal disorders and deterioration of liver function, and neurological disorders. An antidote is not known. Treatment is symptomatic.

Drug Interactions

Drugs that cause myelosuppression, as well as other cytostatics and radiotherapy, may enhance the leukocytopenia and thrombocytopenia caused by lomustine. Concomitant use of lomustine with amphotericin B increases the risk of nephrotoxic effects, decreased blood pressure, and bronchospasm.

A case of significant enhancement of leukocytopenia and neutropenia with the combined use of lomustine and cimetidine has been described.

Increased toxicity may be observed with simultaneous administration of lomustine and theophylline. Phenobarbital, which activates microsomal enzymes, may enhance the metabolism of lomustine. In patients receiving Lomustine, a weakening of the body’s defense mechanisms may occur, which may cause a reduction in antibody formation upon administration of antiviral vaccines. This condition lasts from 3 months to 1 year after the last course of chemotherapy. Particular caution should be exercised in the case of using vaccines containing live viruses.

Storage Conditions

List B. Store at a temperature not exceeding 25°C (77°F) in a place inaccessible to children.

Shelf Life

Shelf life – 3 years. Do not use after the expiration date printed on the package.

Dispensing Status

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.