Hlorambutsil

General characteristics. Structure:

Active ingredient: 2 mg of a hlorambutsil in 1 tablet.

The drug rendering the antineoplastic, alkylating, cytostatic and immunodepressive effect.

Pharmacological properties:

Pharmacodynamics. Contacts nucleoproteids of cellular kernels. The etilenimoniya influences DNA chains by alkylation by means of education of highly active radicals, causes a stitching or ruptures of DNA threads and breaks their replication. To a lesser extent changes RNA synthesis. Exerts toxic impact both on sharing, and on not sharing cells. Depressing influences tumoral and hemopoietic fabric. Affects an adenoid tissue more selectively, than granulotsitarny elements. The clinical effect is shown in 3–4 weeks.

At a part of patients at treatment within the first 2 years total number of leukocytes of blood is normalized, the relative maintenance of lymphocytes in marrow makes 20%, the splenomegaly is eliminated and the increased lymph nodes are reduced. The most tolerable dose — 400 mg/m
2. Dozozavisimo it is also irreversible (at long treatment, and also when using at prepubertatny age) oppresses function of gonads, causing an amenorrhea or an azoospermism.

Prolonged use can cause development of secondary malignant tumors (the remote effect). Has teratogenic effect: in experiences on rats formation of inborn defects of urinogenital system is noted (including lack of a kidney). Causes chromatid and aberation chromosomes in cells of the person and animal in vitro and in vivo. In experiences on mice showed cancerogenic properties. At patients development of an acute leukosis and formation of other miyelodisplastichesky processes was noted.

Pharmacokinetics. It is quickly and completely absorbed from a GIT. Contacts proteins of plasma for 99%, it is preferential with albumine. Breaks up to the feniluksusnokisly yperite (the main metabolite) keeping antineoplastic activity and circulating in blood by 1,6 times longer than hlorambutsit. Cmax  is reached during 0,25–2 p. T1/2  makes 1,5 h (hlorambutsit) and 2,5 h (an active metabolite). Passes gistogematichesky barriers, including placental. Hlorambutsil and his active metabolite (AUC of the last exceeds in 1,33 AUC hlorambutsil) spontaneously almost completely pass in mono - and dihydroxylic derivatives and in insignificant quantity (less than 1%) are excreted with urine.

Indications to use:

Lymphogranulomatosis, nekhodzhkinsky lymphoma (lympho-and reticulosarcoma), chronic lymphoid leukosis, hairy cell leukosis, multiple myeloma, Valdenstrem's macroglobulinemia, disease to Letterera-Siwa, cancer of an ovary, mammary gland, horionepiteliom of a uterus, nephrotic syndrome.

Route of administration and doses:

Inside. The dose is selected individually, adjusted on the basis of clinical effect and depending on expressiveness of gematotoksichesky action.

Features of use:

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 carrying out chemotherapy. Before, in time and after treatment (not less than 3 weekly) definition of hemoglobin or a hematocrit, quantity of leukocytes (the general, differential), thrombocytes is necessary, for activity of nuclear heating plant, ALT, LDG, ShchF, concentration of uric acid. At development of toxic action on lungs or emergence of the expressed skin reactions drug should be cancelled.

For prevention of development of an irreversible miyelosupressiya the dose needs to be reduced at decrease in quantity of leukocytes or thrombocytes and to completely cancel drug at more expressed pancytopenia.

At initially reduced level of leukocytes and thrombocytes treatment has to is carried out by low doses. After a single dose in a high dose the lowest level of leukocytes and thrombocytes is possible in 1–2 weeks of treatment with the subsequent recovery during 2–3 weeks; at a short course the miyelodepressiya can not be noted (up to 3 weeks).

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.

Nausea and vomiting arise at a single dose (inside in doses of 20 mg and from above), less than 24 p proceed and becomes more rare at further treatment. At children with a nephrotic syndrome and at the patients receiving high doses in the pulsterapiya mode the risk of development of a generalized convulsive syndrome is high.

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).

During the work with drug the medical personnel have to be guided by the safety rules accepted for the toxic and irritating skin substances.

Side effects:

From bodies of a GIT: gastrointestinal bleedings, aphthous stomatitis, nausea, vomiting, diarrhea, abnormal liver function (necrosis, cirrhosis), jaundice.

From cardiovascular system and blood (a hemopoiesis, a hemostasis): a miyelodepressiya — a leukopenia, thrombocytopenia, anemia, a lymphopenia, an acute leukosis, bleedings and hemorrhages.

From respiratory system: cough, short wind, pneumosclerosis, intersticial pneumonia.

From urinogenital system: the painful, complicated urination, a hamaturia, a hyperuricemia, aseptic cystitis, hypostases, an amenorrhea, an azoospermism.

From a nervous system and sense bodys: tremor, muscular shiver, excitement, consciousness disturbance, ataxy, peripheral neuropathy, sluggish paralyzes, hallucinations, partial and/or system epileptic seizures (neurotoxic action).

From integuments: a mnogoformny erythema, a toxic epidermal necrosis, Stephens's syndrome — Johnson, rash, dermatitis and other skin allergic reactions.

Others: pain syndrome (dorsodynia, joints), development of infections, fervescence, fever, secondary malignancy.

Interaction with other medicines:

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.

Against the background of reception of tricyclic antidepressants, a haloperidol, Maprotilinum, MAO inhibitors (including furasolidone, Procarbazinum, селегилин), fenotiazin or thioxanthenes the risk of development of convulsive attacks increases (reduce a convulsive threshold).

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.

At simultaneous use with other immunodepressants (Azathioprinum, glucocorticoids, corticotropin, cyclophosphamide, cyclosporine, Cytarabinum, etc.) the risk of development of an infection and secondary tumors increases.

At simultaneous use with lovastatiny (at transplantation of heart) the risk of an acute necrosis of skeletal muscles and an acute renal failure increases.

Other miyelotoksichny drugs, radiation therapy can exponentiate development of a miyelodepressiya (a neutropenia, thrombocytopenia).

Let's combine with other cytostatic drugs in the combined chemotherapy (the methotrexate, ftoruratsit), and also with Prednisolonum.

Contraindications:

Hypersensitivity, including to other alkylating drugs, a marrow hypoplasia (the expressed leukopenia, thrombocytopenia), epilepsy, a renal failure, heavy abnormal liver functions.

Restrictions to use. Ratio assessment risk advantage is necessary at appointment in the following cases: chicken pox, shingles and other system infections, oppression of function of marrow, infiltration of marrow tumor cells, the previous cytotoxic or radiation therapy (the interval has to make 4–6 weeks), gout, an urolithiasis, a hyperuricemia, an abnormal liver function and kidneys, a head injury, convulsive frustration (including in the anamnesis), children's and advanced age.

Overdose:

Symptoms: a pancytopenia, disturbances of the TsNS functions (from inadequate behavioural reactions in the form of agitation to big epipripadok), strengthening of other collateral symptoms.

Treatment: hospitalization, monitoring and maintenance of the vital functions, gastric lavage, symptomatic therapy, prescription of antibiotics of a broad spectrum of activity. Gemodaliz 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.