Melphalanum

General characteristics. Structure:

Active ingredient: 2 mg of Melphalanum in 1 tablet.

The drug rendering the antineoplastic, alkylating, cytostatic, immunodepressive actions.

Pharmacological properties:

Pharmacodynamics. Causes primary damage of macromolecules DNA and breaks its polymerization and reduplication, promotes formation of the DNA and RNA defective forms and stops protein synthesis. Cytotoxicity is caused by blockade of interchained cross reversible stitchings in molecule DNA owing to covalent linkng with guanine in 7 positions and interactions with phosphatic, sulphhydryl and other groups of nucleic acids and proteins. Thereby cellular replication is broken. It is active concerning the based and actively sharing tumor cells. The most sensitive phases of a mitotic cycle are the end of the phase G2  and transition of G2-M; at higher doses — transition of S-G2.

Activity is explained by formation of an unstable etilenimmoniyevy ion. A precursory symptom of damage of a tumor is disturbance of mitotic division of cells up to a full stop of mitoses. Causes permanent disturbances of glycolysis, decrease of the activity of phosphomonoesterases, acid phosphatase (activity of ShchF increases). Slows down phosphorylation of adenylic acid. Besides, as the structural analog of phenylalanine joins (together with products of its biotransformation) in metabolism of tumor cells. The earliest ultramicroscopic changes are found in mitochondrions.

At in introduction in standard doses approximately at 50% of patients with the progressing adenocarcinoma of ovaries the objective effect is observed, in high doses at in introduction at 50% of patients with a multiple myeloma full remission (regardless of that, it is applied or not protection by means of autologichesky marrow) is reached. In a prospective randomized research at children with the progressing neuroblastoma significant increase in survival was shown (in the absence of disease symptoms). It is characterized by sharp selectivity of specific action. At full death of tumoral fabric in vitals irreversible changes are not observed (excepting marrow).

Characteristic morphological feature is stimulation of proliferative processes in the connecting fabric surrounding a tumor and regeneration of nerve fibrils. Shifts of content of nucleic acids and disturbance of cytophysiological activity of fabrics most clearly are shown on 3–7 days after one-time introduction. To second day the number of leukocytes (granulocytes, lymphocytes) decreases, the maximum decrease is observed for the 5th day. Increases follicle-stimulating function of a hypophysis, strengthens corticosterone secretion. The most tolerable dose of Melphalanum makes 280 mg/sq.m.

Dozolimitiruyushchy complications at its use are mukozita and disturbances of TsNS. Dozozavisimo it is also irreversible (at long treatment) oppresses function of gonads, causing an amenorrhea or an azoospermism. Prolonged use can cause development of secondary malignant tumors (the remote effect).

Has cancerogenic, mutagen effect in bacterial systems, causes aberation chromosomes in cells of the person and animal in vitro and in vivo. At introduction to rats in doses of 6-18 mg/sq.m/days within 10 days teratogenic action was noted (formation of inborn defects of a brain at posterity, etc.).

Pharmacokinetics. Content in plasma at intake considerably varies and depends on intestinal absorption (it is soaked up from a GIT short) and effect of "the first passing" through a liver, expressiveness of hydrolysis. Use after food is followed by increase in time of achievement of Cmax  in plasma and decrease in AUC by 39–45%. Time of emergence of Melphalanum in plasma varies from 0 to 336 min., Cmax  in plasma makes from 70 to 630 ng/ml and is reached later 2 h. The average size of bioavailability makes 56±27%. Final T1/2  makes 90±57 min. of plasma; during 24 h in urine 11% of active agent are found. Later in/in introductions concentration in plasma quickly bieksponentsialno decreases:  Distribution phase T1/2 about 7,7±3,3 min., phases of terminal elimination — 108±20,8 min. Eliminiruyetsya from plasma is preferential by chemical hydrolysis to monogidroksi-and dihydroxymelphalanum.

After performing two-minute infusion of Melphalanum in doses of 5-23 mg/sq.m  at 10 patients with a carcinoma of ovaries or a multiple myeloma total initial and final T1/2 was made by 8,1±6,6 min. and 76,9±40,7 min. according to. Average sizes of volume of distribution of 29,1±13,6 l and 12,2±6,5 l, average Cl of 342,7±96,8 ml/min. At infusion of 2-20 min. in doses of 70-200 mg/sq.m  at 28 patients with various malignant tumors of T1/2 made 8,8±6,6 min. and 73,1±45,9 min. according to. Average sizes of volume of distribution of 40,2±18,3 l and 18,2±11,7 l, average Cl of 564,6±159,1 ml/min. After carrying out hyper thermal perfusion of the lower extremity to 11 patients with the progressing malignant melanoma of T1/2  made 3,6±1,5 min. and 46,5±17,2 min. according to. Average sizes of volume of distribution of 2,87±0,8 l and 1,01±0,28 l, average Cl of 55±9,4 ml/min.

Melphalanum practically does not get into cerebrospinal liquid. Level of linkng with proteins of plasma (albumine and partially — about 20% — with an acid alfa1-glycoprotein) — 60–90%, about 30% communicates is irreversible. It is inactivated in liquids and body tissues and remains in blood in an active form about 6 h. The average volume of distribution — 0,5 l/kg. It is excreted by kidneys of 50% (10–15% in an invariable look) and with excrements of 20-50%. At introduction of high doses kumulirut, carrying out a hemodialysis is ineffective. At a renal failure decrease in clearance is noted.

Indications to use:

For intake: multiple myeloma, Osler's disease.

For injections: a multiple myeloma, a limfoepitelialny tumor of Shminke, a melanoma of extremities, the progressing neuroblastoma at children, sarcoma of soft tissues of extremities (including a gemangioendotelioma) — partial perfusion.

Intra arterial and intraperitoneal introduction of rather high doses: neuroblastoma, melanoma (late stages), cancer thick and rectum. Refractory malignant diseases of blood with the subsequent transplantation of autologous marrow.

Route of administration and doses:

Inside, in/in (within 15–20 min.), in / and, intraperitoneally, vnutriplevralno, hyper thermal partial perfusion. The dose is selected individually, adjusted on the basis of clinical effect and depending on expressiveness of gematotoksichesky action.

The adult, at a multiple myeloma: inside — 0,15 mg/kg/days, fractional doses in combination with 40 mg of Prednisolonum, within 4, repeatedly, bucketed days in 6 weeks; in/in — 8–30  bucketed mg/sq.m of 2-6 weeks (at a combination with cytostatics), or 16 mg/sq.m (0,4 mg/kg) of 1 times each 4 weeks at monotherapy, or once 100–200 mg/sq.m  (2,5–5 mg/kg). The average duration of treatment — 1 year.

At an Osler's disease for achievement of remission usually appoint in 6–10 mg/days within 5–10 days, a maintenance dose — 2–4 mg/days once a week.

At a melanoma hyper thermal partial perfusion is applied as adjuvant therapy at surgical interventions at an early stage of a malignant melanoma and as palliative treatment at the started, but localized disease forms.

At sarcoma of soft tissues partial perfusion is applied at treatment of all stages of the localized sarcoma of soft tissues, usually in combination with surgical treatment.

The progressing neuroblastoma at children — 100–240 mg/sq.m  within 3 days.

At a renal failure (Cl of 30-50 ml/min.) the dose should be reduced by 50%. The full dose can be applied only at the level of leukocytes not lower than 4·10 9/l and thrombocytes not lower than 100·10 9/l; at decrease to 3·10 9/l and 75·10
9/l respectively the dose makes 75%, to 2·10 9/l and 50·10 9/l — 50%. Decrease in number of leukocytes is lower 2·10 9/l and thrombocytes lower than 50·10 9/l treatment should be stopped.

Features of use:

Use at pregnancy and feeding by a breast. Contraindicated at pregnancy (especially in the I trimester). Category of action on a fruit on FDA — D. For the period of treatment it is necessary to stop breastfeeding.

Use is possible only under observation of the doctor having experience of chemotherapy. Prior to the beginning of and during treatment (with small intervals) determination of level of hemoglobin or a hematocrit, quantity of leukocytes (the general, differential), thrombocytes is necessary, for concentration of uric acid, an urea nitrogen, creatinine, control of body weight of patients. At emergence of the following symptoms: the fever, fever, cough or hoarseness, lower back pain or in a side, the painful or complicated urination, bleeding or hemorrhages, a black chair, blood in urine or Calais — immediately to consult with the doctor.

Miyelosupressiya is marked out during 2–3 weeks after an initiation of treatment (at some patients within 5 days), the lowest level — during 3–5 weeks, is normalized the level of uniform elements during 4–8 weeks (at development of signs of the expressed gematotoksichnost treatment should be stopped before elimination of symptoms).

The probability of a leykemization increases at increase in duration of treatment and size of a cumulative dose. For the purpose of elimination of a gematotoksichnost at polychemotherapy use of reinfusion of autologous cryotinned marrow right after high-dose therapy, or hemogenesis stimulators is possible (filgrasty, etc.).

When developing thrombocytopenia extreme care at implementation of invasive procedures, regular survey of places in/in introductions, skin and mucous membranes (for identification of signs of bleeding), restriction of frequency of venipunctures and refusal of injections in oil, control of content of blood in urine, emetic masses is recommended, to Calais. Such patients need to have a shave, do manicure with care, to brush teeth, to use dental flosses and toothpicks, to carry out dental interventions, it is necessary to carry out prevention of a lock, to avoid falling and other damages, alcohol intake and acetylsalicylic acid increasing risk of gastrointestinal bleedings.

For the purpose of prevention of the nephropathy caused by the increased formation of uric acid (most often arises during an initial stage of treatment), consumption of enough liquid, the subsequent strengthening of a diuresis, purpose of Allopyrinolum (in certain cases) and use of the means causing urine alkalifying is necessary. It is important not to accept bigger or smaller amount of drug; if reception was missed, the dose is not filled, and the subsequent does not double.

It is necessary to delay the schedule of vaccination (to carry out not earlier than in 3 months till 1 year after end of a last year of chemotherapy) to the patient and other family members living with it (it is necessary to refuse immunization by a peroral vaccine against poliomyelitis). To exclude contact with infectious patients or to use nonspecific actions for prevention (a protective mask, etc.).

During treatment it is necessary to use adequate measures of contraception. In case of contact of drug with skin or mucous membranes — carefully to wash out water (mucous membranes) or water with soap (skin).

Special instructions. At preparation of solutions of Melphalanum it is necessary to be guided by rules of the treatment of the toxic and irritating skin substances. For in/in introductions solution is prepared by ex tempore: the lyophilized powder is dissolved in 10 ml of the enclosed solvent (it is necessary to add quickly) and intensively stir up a bottle. The received solution is immediately connected to normal saline solution (concentration for in/in infusion should not exceed 0,45 mg/ml) and at once begin introduction.

Side effects:

From bodies of a GIT: anorexia, gastrointestinal bleedings, stomach ulcers and a duodenum (the risk of development of these side effects considerably amplifies when performing the combined cytostatic therapy), stomatitis, nausea, vomiting (30%), an esophagitis, diarrhea.

From cardiovascular system and blood (a hemopoiesis, a hemostasis):

miyelodepressiya (leukopenia, thrombocytopenia, anemia), hemolitic anemia, bleedings and hemorrhages, vasculitis, venookklyuzionny defeats, cardiac standstill.

From respiratory system: cough, bronchospasm, fibrosis of pulmonary fabric, intersticial pneumonitis.

From urinogenital system: the painful, complicated urination, a hamaturia, a hyperuricemia, a nephropathy, hypostases, a proteinuria, a hypo-ovaria (especially during the period before a menopause), an amenorrhea, an azoospermism.

Allergic reactions: anaphylaxis (2%), acute anaphylaxis, Quincke's edema, small tortoiseshell, skin rash, itch.

Others: disturbance of the TsNS functions, a pain syndrome (a dorsodynia, a side), development of infections, fervescence, a fever, an alopecia, increase in concentration of 5-hydroxyindolacetic acid, a necrosis of okolososudisty space, feeling of heat and/or a pricking in an injection site.

Interaction with other medicines:

Weakens efficiency of immunization by the inactivated vaccines; when using the vaccines containing live viruses strengthens replication of a virus and side effects of vaccination.

Aminazine, levomycetinum, pyrazolon derivatives, radiation therapy and other miyelotoksichny drugs exponentiate a miyelodepressiya (a neutropenia, thrombocytopenia).

Cyclosporine against the background of in/in introductions of Melphalanum can cause a heavy renal failure, Acidum nalidixicum — a hemorrhagic necrotic coloenteritis (in children).

Cisplatinum induces a renal failure. The effect strengthens Prednisolonum.

Increasing concentration of uric acid, reduces effect of antigouty drugs (Allopyrinolum, colchicine, a probenetsid or Sulfinpyrazonum) at treatment of a hyperuricemia and gout (correction of doses of the last is necessary).

Uricosuric means increase risk of a nephropathy.

Cross hypersensitivity to a hlorambutsil is observed.

It is incompatible with the infusion solutions containing a dextrose; perhaps combined use from 0,9% (in a mass ratio) chloride sodium solution for infusions.

Contraindications:

Hypersensitivity, oppression of function of marrow (decrease in number of leukocytes is lower 2·10 9/l and thrombocytes lower than 50·10 9/l).

Restrictions to use. Ratio assessment risk advantage is necessary at appointment in the following cases: chicken pox, shingles and other system infections, serious associated diseases, parenchymatous hepatitis, an urolithiasis, a hyperuricemia, gouty arthritis, infiltration of marrow tumor cells, the previous cytotoxic or radiation therapy (it is necessary to appoint not earlier than in 3–4 weeks), a disease end-stage, a renal failure, children's and advanced age (safety and efficiency were not studied).

Overdose:

Symptoms: the miyelosupressiya, nausea and vomiting, disturbance of consciousness, a spasm, muscular paralysis, cholinomimetic effects, mukozit, stomatitis, colitis, diarrhea, hemorrhagic damages of a GIT, a hyponatremia, nephrotoxicity, a respiratory distress syndrome of adults.

Treatment: hospitalization, monitoring of the vital functions; symptomatic therapy; if necessary — transfusion of components of blood (at a pancytopenia), platelet and leukocytic concentrate, bone marrow transplantation, prescription of antibiotics of a broad spectrum of activity is possible. The hemodialysis is inefficient.

Storage conditions:

To store at a temperature of 15-25 °C, in dry, protected from light and the place, unavailable to children. Period of validity 3 years. Not to use after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets of 2 mg, 20 tablets in each blister, on one, two or three blisters together with the application instruction in cardboard packaging.