Doxorubicine

General characteristics. Structure:

Active ingredient: 2 mg of doxorubicine in 1 ml of solution.

Antineoplastic drug.

Pharmacological properties:

Pharmacodynamics. Suppresses synthesis of DNA and RNA: interkalirut in a double helix of DNA between base pairs (the matrix is broken and the space structure changes) and causes splitting of DNA owing to education of free radicals. In addition antineoplastic action is perhaps caused by change of cellular functions as a result of linkng with lipids of cellular membranes and interaction with topoisomerase II.

Has high antineoplastic and antileukemic activity at low selectivity of action. A hemopoiesis oppresses, has immunosuppressive and cardiotoxic effect. Can cause the remote effects in the form of development of secondary malignant tumors (the risk increases at prolonged use). Has cancerogenic effect at animals and it is potentially cancerogenic for the person. Influences sexual function, but at the person this action is weaker, than the action revealed in experiences on mice. In experiments on animals shows embriotoksichesky and teratogenic effect, causes abortions.

Pharmacokinetics. Later in/in introductions it is quickly distributed in plasma and fabrics, being found in a liver, lungs, heart and kidneys through 30 villages of Obyem distributions (at stable concentration) — more than 20-30 l/kg,  distribution phase T1/2 — about 5 min. Cmax  in blood decreases by 50% the first 30 min. after an injection, but significant level remains to 20 h. Reduction of concentration of doxorubicine in plasma has three-phase character: initial T1/2  — 10 min., T1/2  of the second phase — 1–3 h, final T1/2  — 30–40 h. Does not get through GEB and does not reach the measured concentration in TsNS; can pass through a placenta at the person. Quickly (during 1 h) it biotransformirutsya in a liver with formation of an active metabolite of a doksorubitsinol.

Partial recovery by enzymes of a liver is followed by formation of the free radicals promoting cardiotoxicity. It is excreted in not changed look and in the form of metabolites with bile (40–50%) and urine (5–12%) within 5 days.  Removal phase T1/2 — 20–48 h. The abnormal liver function leads to delay of removal and cumulation in plasma and fabrics.

Indications to use:

Sarcoma of soft tissues, osteosarcoma, Ewing's sarcoma, breast cancer, small-celled cancer of a lung, cancer of a thyroid gland, malignant thymoma, gullet cancer, hepatoblastoma, primary hepatocellular cancer, carcinoma of the stomach, pancreatic cancer, carcinoid, bladder cancer (treatment and prevention of a recurrence after an operative measure), a germinogenny tumor of a small egg, ovarian cancer, a neuroblastoma, trophoblastic tumors, Vilms's tumor, endometrial cancer, cancer of a neck of uterus, a prostate cancer, an acute lymphoblastoid leukosis, an acute miyeloblastny leukosis, a chronic lymphoid leukosis, a multiple myeloma, a lymphogranulomatosis, a nekhodzhkinsky lymphoma, Kaposha's sarcoma at AIDS, cancer of adrenal glands, a retinoblastoma.

Route of administration and doses:

In/in slowly, vnutripuzyrno. The mode of dosing is set individually, depending on indications, by conditions of the patient and the applied scheme of treatment.

The adult, in/in — on 60–75 mg/sq.m  of 1 times in 3–4 weeks, or on 25–30 mg/sq.m/days within 2–3 days in a row each 3–4 weeks or on 20 mg/sq.m/days once a week in the 1, 8 and 15 days of a course. A break between courses — 3–4 weeks.

To children — in/in in a dose of 30 mg/sq.m/days within 3 days each 4 weeks. Enter 30–50 mg into a bladder with an interval of 1 week up to 1 month once a week. At a combination therapy — 25–50 mg/sq.m  each 3–4 weeks. The course dose should not exceed 500–550 mg/sq.m.

At number of leukocytes less than 3,3-3,5·10 9/l and thrombocytes less than 100-149·10 9/l dose is reduced by 50 and 75% respectively. At the level of bilirubin of 12-30 mg/ml and higher than 30 mg/l the dose is reduced by 50 and 75% respectively.

Features of use:

During treatment strict control of indicators of blood (at least 2 weekly) is necessary, for action of the heart and a liver (oppression of a marrowy hemopoiesis and cardiotoxicity are dozolimitiruyushchy factors). The repeated course can be begun only after complete elimination of signs of a gematotoksichnost.

With care apply at patients with the insufficient reserve of marrow caused by age, the previous use of cytotoxic means or radiation therapy.

Dental interventions should be completed whenever possible prior to therapy or to postpone until normalization of a picture of blood (possibly increase in risk of microbic infections, delay of processes of healing, bleeding of gums).

At the slightest signs of hit under skin injection should be stopped and chosen immediately for an injection other vein.

It is not necessary to apply earlier than in 1 month after the previous chemotherapy.

Increase in concentration of uric acid in blood and risk of development of a nephropathy can demand correction of doses of uricosuric antigouty means. In the course of treatment it is necessary to provide sufficient consumption of liquid with the subsequent strengthening of a diuresis for ensuring removal of uric acid.

Use has to be made by specially trained medical personnel with observance of the established precautionary measures at preparation, dilution of injection solutions (in the sterile cabinet with use of one-time surgical gloves and masks) and destruction of needles, syringes, bottles, ampoules and the rest of unused drug.

It is not necessary to mix in one syringe with other antineoplastic drugs.

Contraindicated at pregnancy. Category of action on a fruit on FDA — D. For the period of treatment it is necessary to stop breastfeeding.

Side effects:

From cardiovascular system and blood (a hemopoiesis, a hemostasis): ≤10% (at the general total dose more than 550 mg/sq.m) — the congestive heart failure which is shown an asthma, puffiness of feet and anklebones, the speeded-up or spasmodic heartbeat and demanding the immediate termination of treatment since development irreversible and eventually a lethal cardiomyopathy (depending on a dose is possible or duration of treatment it can develop also in several weeks after drug withdrawal); acute atrial and ventricular arrhythmia (preferential during the first hours after introduction); seldom, within several days or weeks after introduction — toxic myocarditis or a syndrome of a pericardis myocarditis (tachycardia, heart failure, a pericardis); thrombocytopenia, the leukopenia reaching peak cherez10-15 days after an initiation of treatment (the picture of blood is recovered usually for 21 days after the introduction termination); phlebosclerosis (at introduction to small veins or repeated introduction to the same vein), rush of blood to the person and a hyperemia on the vein course (at too bystry introduction).

From bodies of a GIT: nausea, vomiting, stomatitis or an esophagitis (can arise cherez5-10 days, in particular at introduction within 3 consecutive days, and to lead to development of heavy infections), an ulceration in a GIT; seldom — anorexia, diarrhea.

From urinogenital system: a hyperuricemia, a nephropathy (it is connected with the increased formation of uric acid), reddish coloring of urine (disappears during 48 h). At intravesical introduction — burning in a bladder and an urethra, frustration of an urination (morbidity, a zatrudnennost, etc.), cystitis, a hamaturia.

From integuments: alopecia (full and reversible), darkening of soles, palms and nails, recurrence of a beam erythema.

Allergic reactions: skin rash, an itch, the increased body temperature, a fever, an anaphylaxis.

Others: extravasate, cellulitis, a necrosis (at hit in surrounding fabrics), it is rare — conjunctivitis, dacryagogue.

Interaction with other medicines:

Pharmaceutical it is incompatible with solutions of heparin, dexamethasone, a ftoruratsil, hydrocortisone of sodium of succinate, Aminophyllinum, cefalotin (formation of a deposit is possible).

Streptozotsin increases  doxorubicine T1/2.

Strengthens toxic action of other antineoplastic means (an exacerbation of the hemorrhagic cystitis caused by cyclophosphamide, increase in a hepatotoxic action 6 Mercaptopurinums, etc.) and radiation therapy (on function of marrow, a myocardium, mucous membranes, skin and a liver).

Weakens action of the inactivated and live virus vaccines. Can strengthen side effects of live virus vaccines.

Contraindications:

Hypersensitivity to hydroxybenzoates, the expressed oppression of function of marrow owing to reception of other chemotherapeutic drugs or radiation therapy, the previous treatment by anthracyclines in limit total doses, a leukopenia, thrombocytopenia, anemia, heavy abnormal liver functions, an acute hepatitis, a serious illness of heart (myocarditis, the expressed disturbances of a rhythm, an acute phase of a myocardial infarction), pregnancy, feeding by a breast. At intravesical introduction (in addition): invasive tumors with a penetration in a wall of a bladder, an infection and an inflammation of a bladder and urinary tract.

Restrictions to use. A peptic ulcer of a stomach and duodenum, a bilirubinemia, gout (including in the anamnesis), uratny нефроуролитиаз (including in the anamnesis), parasitic and infectious diseases of the virus, fungal or bacterial nature (now or recently postponed, including recent contact with the patient), including the herpes simplex surrounding herpes (a viremichesky phase), the chicken pox, measles, the amebiasis, a strongyloidosis (established or suspected) — risk of development of a serious generalized illness; age to 2 and after 70 years (increase in frequency of cardiotoxic action), organic lesions of heart (risk of development of cardiotoxic action is possible at low doses).

Overdose:

Symptoms: strengthening of toxic effects (inflammation of mucous membranes, leukopenia, thrombocytopenia).

Treatment: therapy by antibiotics, transfusion of granulotsitarny weight, symptomatic treatment of an inflammation of mucous membranes.

Storage conditions:

To store at a temperature of 2-8 °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:

Solution for injections of 2 mg/ml, on 5 ml in each bottle. On 1 or on 5 bottles, together with the application instruction in cardboard packaging.