Procarbazinum

General characteristics. Structure:

Active ingredient: 50 mg of Procarbazinum in 1 capsule.

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

Pharmacological properties:

Pharmacodynamics. Derivative a methylhydrazine, breaks transmethylation processes — transfer of methyl radicals from methionine on acceptor RNA (TRNK). Lack of normally functioning TRNK causes disturbance of synthesis of DNA, RNA and proteins (treats S-fazospetsifichnym to means). Important component in the mechanism of action is formation of peroxide of hydrogen as a result of an autooksigenation. Hydrogen peroxide, interacting with sulphhydryl groups of fabric proteins, promotes more dense spiralling of molecule DNA and difficulty of processes of a transcription. Blocks activity of MAO that causes accumulation of tyramine and, as a result, increase in maintenance of noradrenaline in the terminations of a sympathetic nervous system and increase in the ABP. Frequency of remission and five-year survival are increased by a combination therapy with use of other cytostatic drugs. At prolonged use manifestation of the remote effect — development of secondary malignant tumors is possible; renders strong cancerogenic, mutagen, teratogenic action (it was observed at appointment to rats in doses, v4-13raz exceeding most recommended for the person — 6 mg/kg/days). In laboratory researches the lethal dose made at rabbits 150 mg/kg, at mice of 1300 mg/kg. Causes degenerative changes of gonads, premature abortion, breaks a spermatogenesis.

Pharmacokinetics. It is quickly and completely soaked up from a GIT, passes through GEB and a placental barrier, it is found in cerebrospinal liquid, cosecretes in breast milk. Cmax  in plasma is reached in 30–60 min. after intake. The main active metabolite — N-izopropiltereftalevaya acid is exposed to biotransformation in a liver and kidneys. T1/2  — 10 min.

It is removed preferential by kidneys (70% are excreted with urine for 24 h, mainly in the form of N-izopropiltereftalevoy of acid, less than 5% — in not changed look) and lungs in the form of methane and carbon dioxide. At a renal failure cumulative action, at patients with an anury is observed, dose adjustment is required by a serious illness of a liver (risk of development of a hepatic prekoma).

Indications to use:

Lymphogranulomatosis, malignant reticulosis, histiocytic lymphoma, Valdenstrem's macroglobulinemia, lymphocytic lymphoma, Brilla-Simmers's disease, nekhodzhkinsky lymphoma, primary tumors of a brain, lung cancer, melanoma, multiple myeloma, Osler's disease, chronic lymphoid leukosis.

Route of administration and doses:

Inside. The dose is selected individually, adjusted on the basis of clinical effect, severity of toxic action.

Adult: at monotherapy the initial dose makes 50 mg with the subsequent daily increase by 50 mg to a daily dose of 250-300 mg. Appoint in 1–3 receptions daily in techeniye15-20dny or before development of a leukopenia and thrombocytopenia. With approach of therapeutic effect the dose is gradually reduced to supporting, usually by 150–50 mg/days. The general dose on a course of treatment most often makes 4–7 g.

Features of use:

Restrictions to use. Ratio assessment risk advantage is necessary at appointment in the following cases: arrhythmia and other cardiovascular diseases, a diabetes mellitus, a hyperthyroidism, the vascular diseases of a brain, paranoid schizophrenia and other states which are followed by a hyperexcitability, epilepsy, alcoholism, parkinsonism, chicken pox, shingles and other system infections, chronic viral diseases, the previous cytotoxic or radiation therapy, a sympathectomy in the anamnesis, advanced age.

Use at pregnancy and feeding by a breast. Contraindicated at pregnancy. 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) definition of hemoglobin or a hematocrit, quantity of leukocytes (the general, differential), thrombocytes is necessary, for activity of nuclear heating plant, ALT, LDG, level of creatinine, glucose (at patients with a diabetes mellitus), bilirubin and an urea nitrogen, and also a research of punctates of marrow.

The dose needs to be reduced at the combined or radiation therapy, advanced age.

At emergence of allergic reaction, the diarrhea expressed to a leukopenia, thrombocytopenia (the lowest level is observed in 4 weeks, is recovered approximately in 6 weeks), stomatitis treatment should be stopped.

At the patients who were earlier receiving cytotoxic drugs or completed a course of radiation therapy (in order to avoid risk of increase in toxic action on marrow), it is possible to carry out treatment by Procarbazinum not earlier than in 1 month. At the planned spinal anesthesia cancellation of Procarbazinum not less than in 10 days prior to carrying out surgical intervention is recommended.

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; it is necessary to carry out prevention of a lock, to avoid falling and other damages, and also the alcohol intake and acetylsalicylic acid increasing risk of gastrointestinal bleedings.

In case of manifestation of a gematotoksichnost the subsequent course of treatment is possible if quantity of leukocytes not less than 3·10 9/l and thrombocytes more than 80·10 9/l. 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 alcohol intake, hypnotic drugs (barbiturates, benzodiazepines) and other symptomatic means without appointments of the doctor is contraindicated. With care to apply in operating time to drivers of vehicles and people whose profession is connected with the increased concentration of attention.

Men and women of childbearing age during treatment by Procarbazinum and at least within 3 months later should apply reliable measures of contraception. The products rich with tyramine or other amines with high vasoconstrictive activity are excluded from a diet (the matured cheese; beer, including low alcohol or nonalcoholic; wine — red and white, Sherry, liqueurs; barmy/proteinaceous extracts, yogurt, bananas, haricot or green beans, meat and other products), caffeine (chocolate, coffee), Coca, tea and other tonics.

In case of contact of drug with skin or mucous membranes careful washing by water (mucous membranes) or water with soap is necessary (skin).

Side effects:

From bodies of a GIT: anorexia, a dysphagy, dryness in a mouth, nausea, vomiting, a diarrhea/lock, an abdominal pain, stomatitis, caries and other diseases of peridental fabrics, oral cavity candidiasis, damage of a liver, cholestatic jaundice, intestinal impassability, bleedings.

From a nervous system and sense bodys: headache, paresthesia, peripheral neuropathy, ataxy (seldom), excitement TsNS, hypomaniacal and maniacal states, spasms, hallucinations, nightmares, fatigue, adynamy, confusion of consciousness, lump, weakness, fatigue; diplopia, nystagmus, photophobia, hypostasis of an optic nerve, intraocular hemorrhage, hearing easing.

From cardiovascular system and blood (a hemopoiesis, a hemostasis): hypertensive crisis, orthostatic hypotension, leukopenia, thrombocytopenia, eosinophilia, hemolitic anemia, bleedings and hemorrhages.

From bodies of respiratory system: pneumonitis, pleurisy, cough (seldom).

From urinogenital system: a renal failure, the painful and complicated urination, a hamaturia, an amenorrhea, an azoospermism.

From integuments: allergic reactions (dermatitis, itch, rash, urticaria, etc.), alopecia, hyperpegmentation, caumesthesia or face reddening, пруриго.

Others: a pain syndrome (a dorsodynia, in a side, muscles and joints), immunosuppression (development of infections), temperature increase, a gynecomastia, risk of development of malignant tumors.

Interaction with other medicines:

Care at Procarbazinum combination to barbiturates is necessary for minimization of oppression of TsNS and possible potentiation, narcotic, antihistaminic, antihypertensives, fenotiazina. Procarbazinum is incompatible with alcohol (disulfiramopodobny reaction is possible).

As Procarbazinum exerts the weak inhibiting impact on activity of MAO, it is necessary to avoid use with sympathomimetics (strengthens the cardiostimulating and vasoconstrictive action of sympathomimetics — it is not necessary to appoint at the same time and during 2 weeks after cancellation of Procarbazinum), tricyclic antidepressants (including with amitriptyline, Imipraminum).

Simultaneous use with carbamazepine, Maprotilinum and MAO inhibitors, including furasolidone and паргилин is not recommended (the interval between the termination of reception of the last and the beginning of therapy by Procarbazinum has to make not less than 2 weeks). NPVS increase risk of development of bleedings.

At simultaneous use of other miyelotoksichny drugs, radiation therapy the perhaps additive oppression of function of marrow.

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

Contraindications:

Hypersensitivity, heart failure, liver and/or renal failure, marrow hypoplasia, pheochromocytoma, pregnancy, lactation period.

Overdose:

Symptoms: are minimum during 12 h after administration of drug, reach a maximum in 24–48 h (remain within several days) — nausea, vomiting, dizziness, hallucinations, a depression, spasms, arterial hypotension, tachycardia, the expressed marrow depression, fever, bleedings.

Treatment: induction of vomiting or a gastric lavage with the subsequent use of suspension of absorbent carbon (at the first symptoms), symptomatic therapy, monitoring of the vital functions, carrying out artificial ventilation of the lungs, an oxygen therapy, slow in/in administration of diazepam (at signs of stimulation of TsNS), in/in introduction of weak solution of vasoconstrictive drug (at hypotension and vascular insufficiency), stopping of symptoms of a hyper metabolic state.

At hypertensive crises — phase-out of Procarbazinum, in/in slow administration of phentolamine in a dose of 5 mg (for immediate decrease in the ABP), decrease in body temperature by outside cooling. If necessary — transfusion of components of blood, prescription of antibiotics of a broad spectrum of activity.

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:

Capsules of 50 mg. On 10 capsules in each blister, on one, two or three blisters together with the application instruction in cardboard packaging.