Oksaliplatin

General characteristics. Structure:

Active ingredient: 50 mg or 100 mg of an oksaliplatin.

Pharmacological properties:

Pharmacokinetics. In vivo оксалиплатин is exposed to active biotransformation and does not come to light in plasma by the end of 2 h after introduction in a dose of 130 mg/sq.m, at the same time 15% of the entered platinum are in blood, and other 85% are quickly distributed on fabrics or removed by kidneys. Platinum contacts albumine of plasma and is removed with urine within the first 48 hours. By 5th day about 54% of all dose are found in urine and less than 3% - in Calais. At a renal failure considerable decrease in clearance of an oksaliplatin from 17,6 l/hour to 9,95 l/hour is observed. Influence of a heavy renal failure on clearance of platinum is not studied.

Pharmacodynamics. Oksaliplatin is the antineoplastic drug belonging to the new class of derivatives of platinum in which atom of platinum forms a complex with oxalate and 1,2 diaminocyclohexane. Oksaliplatin shows a wide range of cytotoxic action. He also shows activity of in vitro and in vivo on various models of the tumors steady against Cisplatinum.

In a combination with 5-ftoruratsily synergy cytotoxic action is observed. Studying of the mechanism of action of an oksaliplatin confirms a hypothesis that the biotransformed derivatives of an oksaliplatin interacting with DNA by formation of boundaries - and vnutrityazhevy bridges suppress DNA synthesis that leads to cytotoxicity and antineoplastic effect.

Indications to use:

- adjuvant therapy of a colorectal cancer of the III stage (With across Dyyuk) after a radical resection of primary tumor in a combination with 5-ftoruratsily and folic acid;

- the disseminated colorectal cancer (as monotherapy or a combination therapy in a combination with 5-ftoruratsily and folic acid).

Route of administration and doses:

Intravenously in the form of 2-6 h infusions. The overhydratation at use of an oksaliplatin is not required. It is applied only at adults. Drug has to be used at once after solution preparation. At a combination with 5-ftoruratsily infusion of an oksaliplatin has to precede introduction of a 5-ftoruratsil.

Adjuvant therapy of a colorectal cancer: on 85 mg/sq.m of 1 times in 2 weeks during 12 cycles (6 months).

The disseminated colorectal cancer: on 85 mg/sq.m of 1 times in 2 weeks as monotherapy or in a combination with 5-ftoruratsily. Repeated introduction of an oksaliplatin is made only at quantity of neutrophils more 1500/mkl and thrombocytes more 50000/mkl.

Recommendations about dose adjustment and mode of introduction of an oksaliplatin.

In case of hematologic disturbances (quantity of neutrophils <1500/mkl and/or thrombocytes <50000/mkl) purpose of the following course is postponed until recovery of laboratory indicators.

At development of diarrhea 4 degrees of toxicity (on a scale of WHO), neutropenias 3-4 degrees (quantity of neutrophils <1000/mkl), thrombocytopenia 3-4 degrees (quantity of thrombocytes <50000/mkl) the dose of an oksaliplatin at the subsequent introductions has to be lowered from 85 mg/sq.m to 65 mg/sq.m at therapy of the disseminated colorectal cancer and to 75 mg/sq.m at adjuvant therapy in addition to a usual dose decline of a 5-ftoruratsil in case of their combined use.

The patient, at which during infusions or within several hours after 2-hour. infusions acute laryngopharyngeal paresthesia develops, the following infusion of an oksaliplatin should be carried out within 6 hours.

Recommendations about correction of a dose of an oksaliplatin at development of a neurotoxicity:

- at the symptoms of a neurotoxicity causing pain lasting more, than 7 days, the subsequent dose of an oksaliplatin has to be lowered from 85 mg/sq.m to 65 mg/sq.m at therapy of the disseminated colorectal cancer and to 75 mg/sq.m at adjuvant therapy;

- at the paresthesia without functional disturbances remaining to the following cycle, the subsequent dose of an oksaliplatin has to be lowered from 85 mg/sq.m to 65 mg/sq.m at therapy of the metastasizing colorectal cancer and to 75 mg/sq.m at adjuvant therapy;

- at the paresthesia with functional disturbances remaining to the following cycle оксалиплатин it has to be cancelled;

- at reduction of expressiveness of symptoms of a neurotoxicity after cancellation of an oksaliplatin, it is possible to consider a question of treatment resuming.

At development of stomatitis and/or mukozit of the 2nd and more degree of toxicity, treatment oksaliplatiny has to be suspended before their stopping or decrease in manifestations of toxicity to 1 degree.

Patients with a renal failure. There are no data on use of an oksaliplatin for patients with heavy degree of a renal failure. Due to the limitation of data concerning safety and portability of drug at patients with moderate degree of a renal failure, before use of drug it is necessary to weigh the relation advantage/risk for the patient. Therapy at this category of patients can be begun with the recommended dose, under careful control of function of kidneys. At easy degree of a renal failure dose adjustment of an oksaliplatin is not required.

Patients with insufficiency of function of a liver. Change of a dosage with a weak or moderate form of insufficiency of function of a liver is not required from patients. There are no data on use of an oksaliplatin for patients with heavy abnormal liver functions.

Elderly patients. The profile of safety of an oksaliplatin as means of monotherapy or at a combination with 5-ftoruratsily at patients is similar the senior 65 years that it is observed at patients up to 65 years.

Features of use:

Treatment oksaliplatiny should be performed under control of the doctor having experience of use of cytotoxic drugs. Constant control behind possible toxic effects at therapy oksaliplatiny is obligatory. Regularly (weekly), and also before each administration of drug оксалиплатин it is necessary to carry out control of uniform elements of peripheral blood and indicators of function of kidneys and a liver. Before each cycle of therapy by drug оксалиплатин it is necessary to conduct neurologic examination regarding identification of signs of a neurotoxicity.

Patients should be informed on a possibility of steady symptoms of peripheral touch neuropathy after the termination of a course of treatment. The localized moderate paresthesias with functional disturbances can keep to 3 years after the end of treatment according to the scheme of adjuvant use of drug. At emergence of such symptoms as dry cough, диспноэ, rattles or identification of pulmonary infiltrates at X-ray inspection, treatment by drug окслиплатин it is necessary to suspend to an exception of existence of an intersticial pneumonitis.

Such symptoms as dehydration, paralytic Ilheus, impassability of intestines, a hypopotassemia, a metabolic acidosis and a renal failure can be caused by the expressed diarrhea or vomiting, especially at drug use оксалиплатин in a combination with 5-ftoruratsily.

Patients with allergic reactions to other compounds of platinum in the anamnesis should be controlled on existence of allergic symptoms. In case of reaction on оксалиплатин, similar anaphylactic, infusion it is necessary to interrupt and appoint the corresponding symptomatic treatment immediately. Further use of drug оксалиплатин in case of development of allergic reactions contraindicated. At the emergence of an abnormal liver function or portal hypertensia which is not caused by metastasises in a liver the question of possible existence of the gepatovaskulyarny disturbances caused by drug which are observed very seldom has to be considered.

In case of an ekstravazation infusion it is necessary to stop and begin a topical symptomatic treatment immediately. The remained dose of drug should be entered into other vein.

Side effects:

Reactions from digestive tract (diarrhea, nausea, vomiting, mukozit), hematologic reactions (a neutropenia, thrombocytopenia) and neurologic reactions (acute and cumulative dozozavisimy peripheral touch neuropathy) were the most frequent side effects observed at use of an oksaliplatin including in a combination with 5-ftoruratsilom/folic acid. In general, these side effects were more frequent and heavy at a combination of an oksaliplatin with 5-ftoruratsilom/folic acid, in comparison with use only 5-ftoruratsit also folic acid. Frequency of the side reactions given below is stated according to the following gradation: very often (> 1/10), it is frequent (> 1/100, <1/10); infrequently (> 1/1000, <1/100); seldom> 1/10000, <1/1000); very seldom (<1/10000), including separate messages.

From system of a hemopoiesis: very often - anemia, a leukopenia, a neutropenia, thrombocytopenia, a lymphopenia; often - a febrile neutropenia (including 3-4 degree), sepsis against the background of a neutropenia; seldom — hemolitic anemia, immune thrombocytopenia.

From system of digestion: very often - nausea, vomiting, diarrhea, stomatitis, mukozit, pains in a stomach, a lock, appetite loss; often — dyspepsia, a gastro-ezofagalny reflux, a hiccups; infrequently - intestinal impassability; seldom - colitis, including cases of pseudomembranous colitis.

From the central and peripheral nervous system: very often - peripheral neurosensory neuropathy, sensitivity disturbances, a headache, an adynamy; often - dizziness, a meningism, a depression, sleeplessness; infrequently - the increased nervousness; seldom - a dysarthtia.

The neurotoxicity is the by-effect limiting a dose. Often symptoms of touch neuropathy are provoked by cold. Duration of these symptoms which are usually stopped in an interval between courses increases depending on a total dose of an oksaliplatin. Functional disturbances which are expressed by difficulty of performance of exact movements are possible effects of touch damage. The risk of functional disturbances for a total dose about 850 mg/sq.m (10 cycles) makes about 10%, reaching 20% in case of a total dose of 1020 mg/sq.m (12 cycles). In most cases neurologic symptoms improve or absolutely pass after the treatment termination. However at 3% of patients in 3 years after the end of treatment were observed or the steady localized paresthesias of moderate intensity (2,3%) or the paresthesias influencing functional activity (0,5%).

Against the background of treatment oksaliplatiny acute neurosensory manifestations which usually arose within several hours after administration of drug and were most often provoked by cold are noted. They were characterized by passing paresthesia, a dizesteziya or a giposteziya, is rare (1-2%) an acute syndrome of a laryngopharyngeal dizesteziya. The last was shown by subjective feeling of a dysphagy and asthma without objective signs respiratory a distress syndrome (cyanosis or a hypoxia), either a spasm of a throat or a bronchospasm (without stridor or goose breathing). Also such phenomena as a jaw spasm, a language dizesteziya, a dysarthtia and feeling of pressure in a thorax were observed. Usually these symptoms were quickly stopped both without use of medicamentous therapy, and at introduction of antihistaminic and bronchodilatory means. Increase in time of infusion at the subsequent cycles of therapy oksaliplatiny allow to reduce the frequency of this syndrome.

From a musculoskeletal system: very often - dorsodynias; often - an arthralgia, ostealgias.

From the party of a respiratory organs: very often - cough, short wind; often - rhinitis, upper respiratory tract infections; seldom - a pneumosclerosis.

From cardiovascular system: often - pains behind a breast, thrombophlebitis of deep veins, a thromboembolism of pulmonary arteries.

From an urinary system: often - a hamaturia, a dysuria.

From skin and skin appendages: very often - an alopecia, skin rashes; often — a peeling of skin of palms and stop, erythematic rashes, the increased perspiration, disturbances from nails.

From organs of sight and hearing: often - conjunctivitis, vision disorders; seldom - tranzitorny decrease in visual acuity, loss of fields of vision, decrease in hearing, neuritis of an acoustical nerve.

Allergic reactions: seldom (at monotherapy use) or often (in a combination with 5-ftoruratsily +/-calcium фолинат) the bronchospasm, a Quincke's disease, hypotension and an acute anaphylaxis can be observed. Cases of such allergic manifestations as rash (in particular a small tortoiseshell), conjunctivitis or rhinitis were often noted.

Local reactions: at a drug ekstravazation - pain and inflammatory reactions in an injection site.

From laboratory indicators: very often - increase in level of an alkaline phosphatase, activity of "hepatic" enzymes, contents of bilirubin, a lactate dehydrogenase, a hypopotassemia, disturbances of content of sodium and glucose in blood serum; often - increase in level of creatinine.

Others: very often - fervescence, the increased fatigue, increase in body weight, taste disturbance.

Interaction with other medicines:

Pharmaceutical it is incompatible with the alkaline solutions and solutions containing chlorine.

In cases of introduction by the patient of a single dose of 85 mg/sq.m of an oksaliplatin just before purpose of a 5-ftoruratsil change of level of a 5-ftoruratsil was not noted. Noticeable change of linkng of an oksaliplatin with proteins of plasma in joint experiences of in vitro with erythromycin, salicylates, granisetrony, paklitaksely and sodium Valproatum was not observed.

Incompatibility:

• not to apply together with alkaline drugs or solutions (in particular, 5-ftoruratsily, alkaline solutions, trometamoly and the drugs of folic acid containing трометамол as excipient),

• not to use for dissolution of drug or cultivation of solution of drug (for preparation of infusion solution) saline solutions, not to mix with other drugs in one capacity or in infusional system

• not to use the equipment for introduction containing aluminum (formation of a deposit and decrease of the activity of an oksaliplatin is possible).

Contraindications:

• hypersensitivity to an oksaliplatin or other components of drug;

• a miyelosupressiya (number of neutrophils less 2000/mkl and/or thrombocytes less 100000/mkl) prior to the beginning of the first course of treatment;

• peripheral touch neuropathy with functional disturbances prior to the beginning of the first course of treatment;

• heavy renal failures (clearance of creatinine less than 30 ml/min.);

• pregnancy;

• feeding period breast.

Overdose:

Symptoms: strengthening of the described side effects.

Treatment: There is no specific antidote. Hematologic control and symptomatic therapy.

Issue conditions:

According to the recipe

Packaging:

The lyophilized powder for preparation of solution for infusions on 50 or 100 mg in bottles in packaging No. 1, No. 12 and No. 24.