Cisplatinum

General characteristics. Structure:

Active ingredient: cisplatin;
1 ml of solution contains Cisplatinum, in terms of 100% substance - 0,5 mg;
excipients: sodium chloride, acid chlorohydrogen, sodium hydroxide, water for injections.

Pharmacological properties:

Pharmacodynamics. Cisplatinum – coordination compound of platinum - has biochemical properties, similar to properties of the alkylating bifunctional connections which selectively oppress synthesis of DNA by formation of mezhtyazhevy and vnutrityazhevy stitchings in DNA. Besides, Cisplatinum inhibits
embedding of predecessors in macromolecules DNA, RNA and proteins. Possibly, Cisplatinum gets into a cell by means of diffusion. Hydrolysis of chloride in its structure leads to formation of the activated drug form which reacts with nucleic acids and proteins. It is inefficient at intake.

Pharmacokinetics. After intravenous administration Cisplatinum is quickly redistributed in all fabrics, except for the central nervous system into which drug practically does not get. The highest concentration are reached in a liver, kidneys, a bladder, muscles, skin, testicles and a prostate. After intravenous administration drug is observed two-phase decrease in its concentration in a blood plasma. The instant reversible linkng with proteins of a blood plasma characteristic of some other medicines is not peculiar to Cisplatinum. However platinum as a part of Cisplatinum appears the plasma connected with proteins and in such look is slowly removed from an organism. The elimination half-life makes respectively 25-49 min. (a phase І) and 58-73 h (a phase ІІ). Cisplatinum is removed with urine (27–43% of the entered dose are allocated for the first five days after introduction). The most part is allocated with urine during 1 h after administration of drug in not changed look. Small concentration of platinum are present at bile and a large intestine (releases of platinum with a stake slightly).
Pharmaceutical characteristics. Main physical and chemical properties. Prozrachny, is more colourless solution.

Indications to use:

Small egg cancer, ovarian cancer, bladder cancer, planocellular cancer of the head and neck, lung cancer, cancer of a neck of uterus. Cisplatinum can be applied in the form of monotherapy, in a combination with other drugs and radiation therapy.

Route of administration and doses:

Cisplatinum dose when using in the form of monotherapy for adults and children makes 50-100 mg/sq.m of a body surface in the form of slow intravenous infusion for 6-8 h once each 3-4 weeks or 15-20 mg/sq.m every day for 5 days in 3-4 weeks. If Cisplatinum is used in the combined chemotherapy, its dose has to be reduced. The typical dose makes 20 mg/m ² or more once each 3-4 weeks.
Recommendations about administration of drug.
a) Hydration. For the purpose of stimulation of a diuresis for the maximum reduction of nefrotoksichny effect of drug it is necessary to provide sufficient hydration for
2 - 12 h before administration of drug and at least 6 h upon termination of infusion of Cisplatinum.
Hydration carry out by intravenous infusion 0,9% of solution of sodium chloride or mix of 5% of solution of glucose and 0,9% of solution of sodium of chloride (1:1). Hydration before treatment by Cisplatinum: one of the called solutions with a speed of 100-200 ml/h for 6-12 h is entered. Hydration after treatment by Cisplatinum: 2 l of one of the called solutions with a speed of 100-200 ml/h for 6-12 h are entered. If after hydration excretion of urine is less than 100-200 ml/h, it is possible to appoint osmotic diuretic, for example, attracts. For this purpose to the patient intravenously enter 375 ml of 10% of solution of a mannitol. Manitol or diuretics it is also necessary to appoint in cases when the dose of Cisplatinum exceeds 60 mg/sq.m of a body surface. It is necessary that patients used a large amount of liquid during 24 h after injection of Cisplatinum for providing dostatny excretion of urine.
b) Treatment. After hydration carry out slow intravenous infusion of Cisplatinum for 6-8 h, at the same time Cisplatinum dissolve in 1-2 liters 0,9% of solution of sodium of chloride for injections.

Features of use:

As aluminum reacts with Cisplatinum and inactivates it, it is important at preparation and at introduction not to use it needles and other equipment containing aluminum. At contact of aluminum with drug the deposit is formed that leads to reduction of its activity. 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 hit of drug on skin or mucous membranes it is necessary to wash away immediately and carefully solution from skin water and soap, and mucous to wash out water.

Features of use.
Precautionary actions in operating time with drug.
1. Cisplatinum needs to be applied under observation of the doctor who has experience of use of antineoplastic chemotherapeutic drugs.
2. Before introduction of repeated doses recovery of function of kidneys to normal level is necessary. Before therapy and before each following course of treatment it is necessary to determine the level of creatinine of serum, an urea nitrogen of blood, clearance of creatinine, and also concentration of magnesium, potassium and calcium in blood; for the maximum decrease in nephrotoxicity carrying out hydration is recommended.
3. Before an initiation of treatment and before each subsequent administration of drug it is necessary to conduct audiometric examination of the patient.
4. Repeated courses of therapy by Cisplatinum should not be conducted until the maintenance of thrombocytes in peripheral blood does not reach the level 100109/l, leukocytes - level not less than 4109/l. During therapy by Cisplatinum it is necessary to watch a picture of peripheral blood regularly.
5. At emergence of a face edema, a bronchospasm, tachycardia and arterial hypotension administration of adrenaline or corticosteroids and antihistaminic drugs is shown.
6. Control of level of electrolytes in blood is necessary for Prilecheniya Tsisplatinom.
7. At treatment by Cisplatinum it is necessary to conduct neurologic examination regularly.
8. It is recommended to control function of a liver periodically.
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:

The clinical use of Cisplatinum can be limited owing to the toxic reactions caused by its use, at the same time duration and frequency of toxic reactions usually depend on the scheme and a way of administration of drug. With care patients need to appoint Cisplatinum with clinical manifestations of a hyperuricemia and proteinemia. Nephrotoxicity. The side effect of drug demands dose adjustment. Renal toxicity was observed at 28–36% of patients after one-time introduction of 50 mg/sq.m of drug. Renal toxicity can be divided into two phases – acute and chronic. Acute phase: it is usually observed for the first 24-48 h, is more often at patients who did not receive sufficient hydration before therapy. It is characterized by disturbance of electrolytic balance (gipomagneimiya), considerable decrease in glomerular filtering, in certain cases tranzitorny increase in level of nitrogen of urine, blood and creatinine in serum. Chronic phase: it is characterized by stable decrease in clearance of creatinine that can be followed by increase in level of creatinine in serum. Renal toxicity can amplify at simultaneous administration of other nefrotoksichny drugs, including aminoglikozidny antibiotics. Renal toxicity gains longer and difficult character at repeated
courses of treatment drug. Before introduction of the following dose of drug it is necessary to voostanovit function of kidneys to the level of normal indicators. It is recommended to apply to decrease in frequency and reduction of manifestations of nephrotoxicity schemes of intravenous hydration, a mannite diuresis and infusions of Cisplatinum during 6-8 h.
Neurotoxicity. The neurotoxicity is usually shown by paresthesias, hearing disorder (ototoxicity) and disturbances of perception of color (when using drug in high doses). In certain cases the cortical blindness, a papilledema and retrobulbar neuritis took place.
Ototoxicity. 31% of patients after one-time introduction of 50 mg/sq.m of Cisplatinum had such manifestations of ototoxicity (tinit and/or loss of auditory acuity in the high-frequency range - higher than 2000 Hz), at 10–15% of patients it was noted decline in the ability to hear sounds and the normal speech in the range of 250-2000 Hz. Ototoxicity depends on a dose. More expressed manifestations at children during treatment by drug. The hearing loss can be unilateral or bilateral in case of carrying out repeated courses; however about development of deafness after introduction of an initial dose of drug it was reported only occasionally. Before an initiation of treatment, and also before introduction of each following dose of drug it is necessary to do
careful audiometric inspection.
From system of a hemopoiesis. As a result of use of drug for 25–30% of patients oppression of a marrowy hemopoiesis develops, however it usually is not heavy. The greatest decrease in levels of leukocytes and thrombocytes in peripheral blood is observed from the 18th to the 23rd day, but indicators are recovered for the 39th day. The leukopenia and thrombocytopenia are more expressed if apply the raised doses (> 50 mg/sq.m) Cisplatinum, can be followed by anemia. Digestive tract. Nausea and vomiting, a loss of appetite, increase in activity "hepatic" трансминаз take place. Nausea and vomiting are usually observed in 1-4 h after administration of drug, proceed during 24 h, up to one week after administration of drug. It is possible that use of antiemetics and administration of drug within several hours will help to reduce weight of the specified manifestations.
From a nervous system. Dizziness, a peripheral neuropathy, a myasthenic syndrome, spasms (at manifestation of such reactions drug should be cancelled). Disturbances of electrolytic balance. The hypomagnesiemia and a hypocalcemia can take place. Regular control of level of electrolytes in serum and their completion is recommended (if necessary). Anaphylactoid reactions. At patients who were treated the drugs containing platinum earlier tachycardia and arterial hypotension were sometimes noted a face edema, диспноэ. Such reactions can be reduced by intravenous administration of adrenaline, corticosteroids and antihistamines. Cardiovascular system. In isolated cases bradycardia, interventricular blockade, congestive heart failure and Reynaud's phenomenon are observed.
The increased concentration of uric acid (hyperuricemia). The increased content of uric acid in blood is observed at use of doses which exceed 50 mg/sq.m. The maximum concentration of uric acid usually take place during the period from the 3rd to the 5th day after administration of drug. Uses of Allopyrinolum effectively reduces concentration of uric acid.
Other toxic effects. Seldom cytogenetic changes of peripheral blood lymphocytes connected with treatment of a leukosis, the acute ischemic phenomena, a local neurotoxicity after intra-arterial administration of drug, damage of tissues of brain, pancreatitis.

Interaction with other medicines:

Potentially nefrotoksichny and ototoksichny medicines, such as aminoglikozidny antibiotics and loopback diuretics, can strengthen nefrotoksichny and ototoksichny effects of Cisplatinum. It is necessary to avoid simultaneous use of such drugs and Cisplatinum.

Contraindications:

- Hypersensitivity to active agent or other drugs which contain platinum;
- renal failure;
- the dehydrated state;
- oppression of function of marrow;
- hearing disorder;
- the neuropathy caused by Cisplatinum;
- period of pregnancy and feeding by a breast.

Use during pregnancy and feeding by a breast. At pregnancy it is contraindicated. Women of childbearing age need to recommend to avoid approach of pregnancy during administration of drug. As Cisplatinum gets to milk, during treatment by drug it is necessary to stop nursing the child.
Children. Drug is used at children.

Overdose:

The overdose of drug can lead to development of a renal failure, insufficient function of the liver, deafness, toxic influence on sight (including peeling of a retina) expressed to a miyelosupressiya, nausea and vomiting and/or neuritis. Antidotes are unknown. Treatment has to include actions of the symptomatic and supporting therapies directed to removal of the patient from a toxic state.

Storage conditions:

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

Issue conditions:

According to the recipe

Packaging:

On 20 ml (10 mg) or 100 ml (50 mg) in bottles, 1 bottle in a pack.