Lomustine - instructions for use, doses, side effects, contraindications

Clinical and pharmacological group: & nbsp

Antineoplastic agents

Included in the formulation

Lomustine medak

capsules inwards

medac GmbH Germany

Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

VED

ONLS

АТХ:

L.01.A.D Nitrosoureas derivatives

L.01.A.D.02 Lomustine

Pharmacodynamics:

In cells, it is cleaved to form methylcarbon ions acting on the nucleophilic centers of DNA, RNA, proteins (through carbamoylation of DNA polymerase and other DNA repair enzymes and damage to the DNA matrix) and alkylating molecules; blocks translation and transcription in tumor cells. Causes a significant number of chromosomal aberrations in tumor cells and bone marrow, the correction of which does not coincide in time in normal and tumor cells (the rate of reduction of chromosomal aberrations in tumor cells is much lower than in healthy cells, and the damage to the genetic apparatus is more significant, violations of kinetics and proliferation of cells are more pronounced in the tissues of the tumor). It slows down the passage of S-cells (at a time when there is significant inhibition of DNA synthesis) and G2 phases. The action is phase-specific, but most sensitive to lomustine cells in the stationary phase of growth (a factor determining activity in solid tumors with a low proliferative pool).

Pharmacokinetics:

Due to its high solubility in fats, it is quickly and almost completely absorbed from the gastrointestinal tract after ingestion. Penetrates through the blood-brain barrier and into breast milk. Relationship with plasma proteins 50% (moderate). It is subject to rapid and complete biotransformation in the liver with the formation of active metabolites - oxymethyldiazonium and isocyanate. Oxymethyldiazonium is ionized and converted to the methyl diazonium ion, which is transformed into a more stable tautomeric form (diazomethane), or decomposes into the methylcarbon ion and nitrogen. The half-life is biological - 94 minutes, chemical - 15 minutes (metabolites - 16-48 hours). TC_max 1-4 hours. Elimination in the form of metabolites is carried out by the kidneys (less than 5%) and lungs (10%); 50% - within 25 hours, 75% - within 4 days. Intestinal-hepatic recirculation is suggested.

Indications:

Lomustine is used in monotherapy and in combination therapy of the following diseases:

- primary and metastatic brain tumors after surgical treatment and / or radiotherapy;

- lymphogranulomatosis (Hodgkin's disease) as second-line therapy;

- cancer of the stomach and intestines, small cell lung cancer, kidney cancer, multiple myeloma, malignant melanoma.

ICD-10

II.C15-C26.C16 Malignant neoplasm of stomach

II.C15-C26.C17 Malignant neoplasm of small intestine

II.C15-C26.C18 Malignant neoplasm of colon

II.C15-C26.C20 Malignant neoplasm of rectum

XXI.Z80-Z99.Z85.1 In a personal history, a malignant neoplasm of the trachea, bronchi, and lung

II.C43-C44 Melanoma and other malignant neoplasms of the skin

II.C64-C68.C64 Malignant neoplasm of kidney, except for renal pelvis

II.C69-C72.C71 Malignant neoplasm of brain

II.C81-C96.C81 Hodgkin's disease [lymphogranulomatosis]

Contraindications:

Hypersensitivity, pregnancy, breast-feeding.

Carefully:

Inhibition of bone marrow function (including on the background of concomitant radiation or chemotherapy, intoxication), acute infectious diseases of viral, fungal or bacterial nature (including chicken pox, shingles), cachexia, renal and / or hepatic insufficiency, respiratory failure.

Pregnancy and lactation:

In view of the potential threat to the fetus for women of childbearing age during the treatment with lomustine, the use of contraceptives is recommended.Controlled studies in humans are not conducted. Possible development of fetal side effects observed in adults. Lomustine embryotoxic in experiments on rabbits and rats when administered at doses equivalent to those recommended for humans. It should avoid the use of antitumor, especially combined chemotherapy in pregnancy, especially in the first trimester. It is necessary to relate the risk and benefit and take into account the mutagenic, carcinogenic and teratogenic potential of these agents. Lomustine excreted by breast milk. In view of the potential risk of adverse effects on the child (side effects, carcinogenicity, mutagenicity) during lomustine treatment, breast-feeding should be discontinued.

Category of recommendations FDA - D.

Dosing and Administration:

Lomustine should be taken orally in the evening, before going to bed or 3 hours after eating. The recommended dose of lomustine in adults and children is 130 mg / m² with a single oral intake every 6 weeks.

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

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

Repeated courses should not be administered with platelet counts less than 100,000 / mm3 and leukocytes less than 4000 / mm3.

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

Side effects:

Hematological: anemia, immunosuppression, leukopenia (usually asymptomatic) or infection, thrombocytopenia.

From the digestive tract: nausea, vomiting, stomatitis, diarrhea, loss of appetite.

From the respiratory system: infiltrates and / or pulmonary fibrosis.

From the nervous system: neurotoxicity.

From the urinary system: nephrotoxicity and acute renal failure.

Dermatological: alopecia, skin pigmentation.

Hypersensitivity: skin itch, rashes.

On the part of the reproductive system: suppression of gonads (azoospermia, amenorrhea), which can be irreversible. The frequency and severity increase with combination with alkylating agents. In experiments on male rats lomustine reduces fertility in doses exceeding the equivalent for humans.

Carcinogenicity (mutagenicity): Lumustine carcinogenicity studies have not been carried out, but secondary malignant tumors are a potential delayed side effect of taking many antitumor drugs.It is unclear whether this is due to their mutagenic or immunosuppressive effect. Also, the effect of the dose and duration of treatment is not determined, but it assumes an increased risk with prolonged use. With prolonged treatment with nitrosourea derivatives, the development of secondary malignant tumors (acute leukemia) and bone marrow dysplasia is described. Lomustine is carcinogenic when administered to mice and rats at doses approximately equivalent to that for humans, and, like other alkylating agents, is possibly carcinogenic to humans.

Other: hepatotoxicity, transient and transient increase in hepatic transaminase activity, an increase in bilirubin concentration in the blood.

Overdose:

Increased severity of side effects. The specific antidote is unknown. The cases of pancytopenia and subsequent polyorganic (hepatic and pulmonary) insufficiency (tachypnea, hypoxemia, abdominal pain) and central neurotoxicity (confusion and disorientation) after taking lomustine at a dose of 200 mg for 7 days (instead of a single dose) are described.Despite the restoration of the number of leukocytes (regress of other types of toxicity is not noted), fever and hypotension developed, after which the patient died on the 59th day after the first admission. In another case, a patient with 30 years after receiving lomustine at a dose of 28 mg / kg for 7 days or more developed severe myelosuppression, lasting 50 days. The patient received colony-stimulating factors, antibacterial drugs, norethisterone (to prevent menstruation) and acetylcysteine (for the prevention of organ failure). Gastrointestinal necrosis and increased activity of hepatic enzymes were noted even after the overdose was stopped, but the patient survived, and her tumor regressed without subsequent chemotherapy.

Treatment is symptomatic (colony-stimulating factors, antimicrobial agents, blood transfusion and transfusion of platelet mass).

Interaction:

Theophylline - described the development of leukopenia and thrombocytopenia in a patient 45 years after receiving a combination of theophylline and lomustine.

A case of significant enhancement of leukopenia and neutropenia in the joint use of lomustine and cimetidine is described.

Special instructions:

Monitoring of hematocrit or hemoglobin content, number of leukocytes, platelets (before treatment, periodically during and 6 weeks after administration), activity of hepatic transaminases, lactate dehydrogenase, the concentration of bilirubin, urea, creatinine, lung function (before treatment and periodically during it, depending on the patient's condition, doses of lomustine and other combination drugs).

Distinctive characteristics

Lomustine treatment is advisable to carry out in the presence of an objective effect. If there is no tumor response after 1-2 treatment cycles, then the effectiveness of subsequent treatment is unlikely.

Cross-resistance between lomustine and carmustine is described.

The subsequent course of treatment with lomustine should be performed only after restoration of blood to acceptable levels (leukocytes - more than 4 × 109 / l, platelets - more than 100 × 109 / l).

With initial myelosuppression, the dose of lomustine is reduced to 100 mg / m² every 6 weeks. In subsequent (after the first) cycles, it needs to be adjusted based on the number of leukocytes and platelets in the nadir period: more than 3 × 109 / L and 50 × 109 / L - 100% of the previous dose; 2.9-3 × 109 / L and 25-74 × 109 / L, respectively - 70% of the previous dose; less than 2 × 109 / L and 25 × 109 / L, respectively - 50% of the previous dose.

In view of the possibility of delayed and cumulative myelosuppression, the next course of treatment with lomustine should be performed no more often than every 6 weeks.

The package can contain capsules of several kinds with different doses, which are necessary for the collection of the desired dose.

Instructions

Lomustine (Lomustinum)