Melphalan - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Alkylating agents

Included in the formulation

Alkeran®

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Aspen Pharma Trading Limited

Melphalan-native

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NATIVA, LLC Russia

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.A.03 Melphalan

L.01.A.A Analogs of nitrogen mustard gas

Pharmacodynamics:

An antineoplastic agent of an alkylating type, a derivative of nitrogen mustard gas. The effect is due to the formation of the ethylenemonium ion, the alkylating link of many intracellular molecules, including nucleic acids (by binding to guanine in the 7th position), blocking their polymerization and reduplication, the formation of defective forms of DNA and the blockade of mitosis of rapidly dividing cells (including tumor). Active with respect to resting and actively dividing tumor cells. The action is phase-specific, but the cells that are at the end of phase G are most sensitive₂ and the transition G_2-1; when used in higher doses - in the S-G transition₂ and the phase of DNA synthesis. Has relatively high selectivity of action against cells of malignant tumors of lymph nodes. The greatest effectiveness is noted in the treatment of chronic lymphocytic leukemia, lymphogranulomatosis and lymphosarcoma. At the time of treatment, the number of pathological young cells produced by the bone marrow decreases.In the first place, granulocytopoiesis is disturbed, then lymphopoiesis and, to a lesser extent, erythro- and thrombocytopoiesis (as a rule, with prolonged use). After discontinuation of reception parameters of peripheral blood quickly normalize. The severity of the cytotoxic effect is dose-dependent. With complete destruction of tumor tissue in vital organs (excluding bone marrow), there are no irreversible changes. Stimulates proliferative processes in the connective tissue surrounding the tumor, and the regeneration of nerve fibers. Increases the follicle-stimulating function of the pituitary gland, increases the secretion of corticosterone. Mesositis and disturbances of CNS activity are considered to be dose-limiting complications.

Pharmacokinetics:

Absorption from the gastrointestinal tract is variable and incomplete. Relationship with plasma proteins 60-90% (moderate or high, mainly with albumin, α₁an acidic glycoprotein; 30% of the drug irreversibly binds to plasma proteins). Biotransformation in plasma by hydrolysis with formation of inactive metabolites. The elimination half-life is 160 hours. The distribution period is 10 minutes. The maximum concentration in the blood is reached after 2 hours.

Displayed mainly by chemical hydrolysis to monohydroxy- and dihydroxymethylphalan (no more than 10%), with oral administration by the kidneys (unchanged). It is not excreted by hemodialysis.

Indications:

- multiple myeloma;

- progressive ovarian adenocarcinoma;

- mammary cancer;

- form of malignant melanoma of the limbs;

- localized form of soft tissue sarcoma of the extremities;

- true polycythemia;

- neuroblastoma.

ICD-10

II.C00-C14.C09 Malignant neoplasm of tonsil

II.C00-C14.C11 Malignant neoplasm of nasopharynx

II.C15-C26.C20 Malignant neoplasm of rectum

II.C15-C26.C26 Malignant neoplasm of other and inaccurately indicated digestive organs

II.C43-C44.C43.9 Malignant melanoma of skin, unspecified

II.C45-C49.C49 Malignant neoplasm of other types of connective and soft tissue

II.C69-C72.C71 Malignant neoplasm of brain

II.C81-C96.C90 Multiple myeloma and malignant plasma cell neoplasms

II.C81-C96.C96 Other and unspecified malignant neoplasms of lymphoid, hematopoietic and related tissues

II.D37-D48.D45 Polycythemia true

Contraindications:

Individual intolerance, pregnancy and breastfeeding,oppression of bone marrow function (decrease in the number of leukocytes below 2×10⁹/ l and platelets below 50×10⁹/ l).

Carefully:

- Veterinary pox, shingles and other systemic infections;

- severe co-morbidities (parenchymal hepatitis, urolithiasis, hyperuricaemia, gouty arthritis);

- infiltration of bone marrow by tumor cells;

- previous cytotoxic or radiotherapy (interval not less than a month);

- terminal stage of the disease;

- impaired renal function;

- children and the elderly.

Pregnancy and lactation:

Action category for the fetus by FDA - D. It is forbidden to use during pregnancy and during breastfeeding.

Dosing and Administration:

The drug is administered orally, slowly intravenously for 20 minutes, intraarterially, intraperitoneal, intrapleural, hyperthermic regional perfusion. The dose is selected individually in each case, adjusted based on the effect of therapy and the manifestations of side effects.

Adults, with multiple myeloma prescribed by 0.15 mg / kg in day inside, in fractional doses in combination with 40 mg of prednisolone, for 4 days, repeatedly, at intervals of 6 weekspruce; intravenously - 8-30 mg / m² at intervals of 2-6 weeks (when combined with cytostatics), or 16 mg / m² (0.4 mg / kg) 1 time every 4 weeks with monotherapy, or once 100-200 mg / m² (2.5-5 mg / kg). The average duration of treatment is 1 year. With true polycythemia, to achieve remission, usually 6-10 mg day for 5-10 days, maintaining a dose of 2-4 mg in day 1 time a week. In melanoma hyperthermic regional perfusion is used as an adjuvant therapy for surgical interventions at an early stage of malignant melanoma and as a palliative treatment for advanced but localized forms of the disease. With soft tissue sarcoma, regional perfusion is used to treat all stages of localized soft tissue sarcoma, usually in combination with surgical treatment. Progressing neuroblastoma in children - 100-240 mg / m² within 3 days.

In case of impaired renal function (clearance 30-50 ml / min), the dose should be reduced by 50%. The total dose can be used only at a level of leukocytes not lower than 4×10⁹/ l and platelets not less than 100×10⁹/ l; at a decrease to 3×10⁹/ l and 75×10⁹/ l, respectively, the dose is 75%, up to 2×10⁹/ l and 50×10⁹/ l - 50%. Decrease in the number of leukocytes below 2×10⁹/ l and platelets below 50×10⁹/ l - treatment should be discontinued.

Side effects:

Blood: anemia, hemolytic anemia, neutropenia with or without infection, thrombocytopenia.

Respiratory system: pulmonary fibrosis.

Digestive system: nausea, vomiting, mucositis, stomatitis, stomach and duodenum ulcers, impaired liver function.

Urinary system: hyperuricemia or uracic nephropathy.

Leather: damage to the skin or soft tissues, severe recurrent vasculitis, alopecia, ulceration and necrosis of the skin during extravasation.

Allergy: anaphylaxis. Patients demonstrating hypersensitivity to chlorambucil (as skin rashes) may be hypersensitive to melphalan.

Reproductive system: gonadal suppression (amenorrhea or azoospermia), especially in combination with alkylating agents; effects depend on the dose and duration of treatment and can be irreversible.

Carcinogenicity (mutagenicity): secondary malignant tumors are a potential delayed side effect of many antitumor drugs. It is not known whether this is due to their mutagenic or immunosuppressive effect.It is unclear the effect of the dose and duration of treatment, but it is assumed that the risk increases with prolonged use. The 10-year risk of developing secondary acute leukemia or myeloproliferative syndrome is less than 2% with a cumulative dose of less than 600 mg, 19.5% at a cumulative dose of 730-9652 mg, which requires an individual assessment of the potential benefit and risk of induction of secondary malignant tumors .

Others: an increase in the concentration of 5-hydroxyindoleacetic acid in the urine (possibly due to the destruction of tumor cells and the release of metabolites), hepatitis.

Overdose:

Overdose develops anemia (unusual weakness or fatigue, bleeding or bruising), colitis (abdominal pain), severe mucositis (difficulty swallowing, diarrhea), nausea and vomiting, neutropenia, possibly with the attachment of infections (chills or fever, cough or coarsening of the voice, back pain, painful or difficult urination), stomatitis (painful ulcers on the oral mucosa), thrombocytopenia (unusual bleeding or bruising, black tarry stools, dotted red stems Effects on the skin), electrolyte disorders.

There is no specific antidote. Melphalan not removed during hemodialysis or hemoperfusion. Regular monitoring of peripheral blood levels is necessary for 3-6 weeks after an overdose. With the development of leukopenia, monitoring of infectious complications is necessary, antibiotic therapy may be required. The use of colony-stimulating factors can reduce the duration of pancytopenia. If natural food is not possible due to mucositis, parenteral nutrition is necessary.

Interaction:

Glucocorticoids - an increase in the antitumor effect of melphalan.

Interferon alfa - may increase the elimination of melphalan, probably due to fever induced by interferons alpha.

Carmustine - possible synergism with melphalan (with intravenous administration) with the development of pulmonary toxicity.

Metamizol sodium, chloramphenicol, chlorpromazine - increased myelosuppression.

Nalidixic acid - it is possible to develop severe (up to fatal) hemorrhagic enterocolitis in children when combined with high doses of melphalan.

Cyclosporine - increased risk of nephrotoxicity.

Cimetidine - reducing melphalan concentration in blood plasma, possibly due to reduction of absorption (to 30%).

Cisplatin - induction of renal dysfunction and changes in the clearance of melphalan.

Melphalan solution in 0.9% sodium chloride solution with concentration 0.1 mg / ml chemically compatible with infusion through the Y-shaped splitter with amphotericin B, daunorubicin, idarubicin, lorazepam, methylprednisolone, prochlorperazine and chlorpromazine.

Melphalan can not be diluted with dextrose solution.

Special instructions:

When preparing solutions melphalan should be guided by the rules for handling toxic and skin irritating substances.

Instructions

Melphalan (Melphalanum)