Etopozid

General characteristics. Structure:

Active ingredient: etoposide;
1 ml of solution contains an etopozid, in terms of 100% substance - 20 mg;
excipients: benzyl alcohol, ethanol anhydrous, polyethyleneglycol 300, polysorbate 80, citric acid, monohydrate, sodium citrate.

Pharmacological properties:

Pharmacodynamics. Etopozid is a semi-synthetic derivative of podophyllotoxin and has property to rummage a cellular cycle on a premitotic phase that leads to accumulation of cells on the late phases S and G2. Though the exact mechanism of action of an etopozid obscure, seemingly, that its cytotoxic effect leads to single and double ruptures of chains of DNA and connections between proteins and DNA. The cytotoxic effect of an etopozid consists in disturbance of process of cutting stitching of DNA under the influence of topoisomerase II enzyme. Enzyme covalently contacts DNA, forming proteinassotsiirovanny gaps. Etopozid also oppresses penetration of nucleosides through a plasma membrane which interferes with synthesis and recovery of DNA.

Pharmacokinetics. After intravenous administration of an etopozid peak concentration in plasma makes 30 mkg/ml. Etopozid is actively metabolized in an organism. Drug is removed dvukhfazno: at adults with normal function of kidneys and a liver the elimination half-life averages about 1,5 hours with the period of final removal 3 - 11 hour. The maximum levels of concentration in plasma and the area under a curve which describes change of concentration in plasma increase directly eventually
in proportion with doses it is higher than 100 - 600 mg/sq.m. Etopozid does not collect in plasma at daily use in a dose of 100 mg/sq.m within 5 days. Removal of drug from a blood plasma and renal clearance do not depend on a dose. Linkng with proteins of plasma makes 94%. Drug is found in pleural liquid, in saliva, liver tissue, a spleen, kidneys, myometriums, brain tissues. Level of removal of an etopozid with urine varies ranging from 5,1 to 14,6 ml/min./sq.m that makes about 36% of full distribution of drug.
Pharmaceutical characteristics.
Main physical and chemical properties. Prozrachny, honor more colourlessly till poorly yellow color solution. Incompatibility. Etopozid it is not necessary to dilute with buffered solutions with рН> 8 as in this case formation of a deposit is possible.

Indications to use:

Germinogenny tumors of a small egg, small-celled tumors of lungs.

Route of administration and doses:

Etopozid (it is applied mainly in a combination with other chemotherapeutic means) enter intravenously in a dose 50 - 100 mg/sq.m a day. The course of treatment makes 3-5 days. Repeated courses are conducted in 10-20 days only after normalization of indicators of peripheral blood. In the presence at the patient of renal failures of a dose of an etopozid it is necessary to reduce. The corresponding recommendations are provided in table 1.
Table 1
Clearance of creatinine                       of the Dose of an etopozid
51                          ml/min. 50-100 mg/sq.m of a body surface
15 - 50 ml/min.                      of 75% of an initial dose
less than 15 ml/min.                 drug is contraindicated
At the choice of a dose it is necessary to consider miyelosupressorny effect of other drugs at use in a combination with Etopozid, and also side effects of the previous radiation therapy and chemotherapy.
Before introduction Etopozid part 0,9% with solution of chloride sodium or 5% dextrose solution to final concentration of 0,2 - 0,4 mg/ml. Solution which was prepared thus is entered by intravenous injection for 30 - 60 min.

Features of use:

At preparation and administration of solutions of drug, as well as during the work with other antineoplastic means, it is necessary to be careful and to use gloves. In case of drug solution hit on skin or mucous membranes it is necessary to wash away immediately carefully solution from skin water with soap, and mucous to wash out clear water.
Features of use.
1. Etopozid it is necessary to apply under observation of the doctor who has experience of use of antineoplastic chemotherapeutic drugs.
2. Oppression of function of marrow is toxic effect which limits Etopozid's dose. During treatment it is regularly necessary to determine by drug structure of uniform elements of blood – at the beginning of therapy, in a break and before each following course of treatment Etopozid. In case of decrease in quantity of thrombocytes is lower 50 x 109/l and/or absolute quantity of neutrophils to 0,5 x 109/l therapy it is necessary to stop.
3. In case of the symptoms reminding anaphylactic such as fever, fever, tachycardia, a bronchospasm, an asthma, administration of drug it is necessary to stop and begin therapy with use of corticosteroids and/or antihistamines.
4. With restriction apply at patients who accepted beam and chemotherapy, the patient with chicken pox surrounding with herpes at infectious damages of mucous membranes, at disturbances of a cordial rhythm, at the increased risk of development of a myocardial infarction, abnormal liver functions, diseases of a nervous system (epilepsy), an alcoholism earlier. Ability to influence speed of response at control of motor transport or other mechanisms. During treatment it is necessary to avoid occupations which require special attention and bystry psychomotor reactions.

Side effects:

From system of a hemopoiesis. Decrease in quantity of leukocytes, thrombocytes and neutrophils (leukopenia) depends on a dose which is entered, and is the main indicator limiting Etopozid's dose. Anemia, a miyelosupressiya is dozozavisimy and dozolimitiruyushchy effect. Recovery of indicators of blood happens usually for the 20th day after introduction of a standard dose of drug. Exceptional cases of an acute leukosis (both with a preleukemic phase, and without it) at the patients receiving этопозид in monotherapy or in combination with others antineoplastic were celebrated
drugs.
From a digestive tract. Nausea and vomiting arise at 30-40% of patients and are more often observed at oral administration, than at intravenous. As a rule, these phenomena are moderate or moderately severe, it is necessary to stop treatment because of gastrointestinal by-effects seldom. The abdominal pain, anorexia, a diarrhea, stomatitis are also possible. At use of high doses - toxic reactions from a liver (an easy temporary hyperbilirubinemia and increase in level of transaminases).
From cardiovascular system. At bystry intravenous administration at 1 - 2% of patients the temporary lowering of arterial pressure which is usually recovered at the termination of infusion of drug and use of means of symptomatic therapy was noted. In need of resuming of introduction of Etopozid the speed of infusion needs to be reduced.
From TsNS and peripheral nervous system. Drowsiness, increased fatigue, is in certain cases possible peripheral neuropathy.
From a metabolism. A hyperuricemia, when using high doses - a metabolic acidosis.
From reproductive system. Azoospermism, amenorrhea. Hypersensitivity reactions. Symptoms which remind anaphylactic, such
as temperature increase, tachycardia, a bronchospasm, an asthma noted 0,7 - 2% of patients.
These reactions are usually observed in time or right after Etopozid's introduction. In such cases it is recommended to stop administration of drug and to appoint symptomatic therapy. It was reported also about cases of hypertensia and/or rushes of blood to the person. Normalization of the ABP usually happens within several hours after the termination of infusion of an etopozid. Sometimes there were a puffiness of the person or language, cough, plentiful sweating, cyanosis, feeling of squeezing in a throat, a laryngospasm, a dorsodynia, a loss of consciousness. About developing of the apnoea connected with hypersensitivity it was reported seldom. In rare instances the anaphylaxis can lead to a lethal outcome. Dermatological reactions. The reversible alopecia, in certain cases total, arises, at least, at 66% of patients. Emergence of pigmentation, an itch is seldom noted. In one case the recurrence of beam dermatitis was observed. When using an etopozid in the doses which are in a research stage it was reported about development of the generalized pruritic erythematic spotty and papular rashes which are followed by a perivasculitis. Other toxic manifestations. Peripheral нейротоксичнисть (1–2%). Are occasionally noted: residual smack in a mouth, fever, pigmentation, a dysphagy, a blindness of cortical genesis; the recurrence of beam dermatitis (1 case), a metabolic acidosis, toxic action on TsNS (unusual fatigue, the complicated walking, feeling of numbness or a pricking in fingers of hands and legs, weakness), muscular spasms, a hyperuricemia, phlebitis (pain in the place of an injection) was observed, at hit under skin – local irritative action is expressed.

Interaction with other medicines:

At the accompanying radiation therapy or therapy by other drugs which suppress function of marrow cytotoxic and myelosuppressive action of an etopozid can amplify.
The Sinergichny antineoplastic effect is shown at use of an etopozid together with Cisplatinum, karboplatiny, mitomitsiny With, cyclophosphamide, BCNU, Vincristinum, Dactinomycinum and tsitozinarabinozidy. Phenylbutazone, sodium salicylate and acetylsalicylic acid can force out етопозид, connected with proteins of plasma. Cross resistance between anthracyclines and etopozidy is experimentally found. The undiluted concentrate should not contact to acrylic polymers (which can be a part of syringes and infusional systems) or polymers on the basis of an akrilnitril, butadiene and styrene as it can entail damage or course of systems. When using weak solutions of it it is not observed.

Contraindications:

The expressed miyelodepresiya, the expressed abnormal liver functions and kidneys (the clearance of creatinine is less than 15 ml/min.), pregnancy, feeding by a breast, children's age, increase in sensitivity to Podophyllinum and its derivatives.

Use during pregnancy or feeding by a breast. Etopozid is contraindicated at pregnancy. In need of use in the period of a lactation it is necessary to stop feeding by a breast. During treatment and for 3 months after its termination patients of childbearing age need to use effective methods of contraception. By pilot studies it is established that Etopozid has teratogenic and embriotoksichny action.
Children. Drug is contraindicated to children.

Overdose:

The general doses of 2,4 - 3,5 g/m2 entered intravenously for three days led to a heavy inflammation of mucous membranes and toxic damage of marrow. At patients who received higher in comparison with recommended, doses of an etopozid, the metabolic acidosis was noted and cases of toxic influence on a liver were observed. There is no antidote for use in case of drug overdose Etopozid. Patients with signs of overdose need to cancel immediately Etopozid and to appoint detoksikatsikatsionny and symptomatic therapy. In case of overdose such measures can be taken:
at nausea, vomiting – antiemetics;
at allergic reactions – drug withdrawal, corticosteroids, antihistaminic
drugs, plasma substitutes;
at a bronchospasm – aminophylline, corticosteroids;
at hypotension – drug withdrawal, plasma substitutes;
at a hyperuricemia – Allopyrinolum.

Storage conditions:

Period of validity. 2 years from the date of production of in bulk. To store in original packaging at a temperature not above 25 °C. To avoid freezing. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

On 5 ml (100 mg) in bottles, 1 bottle in a pack.