Cisplatin-Ebwee - instructions for use, doses, side effects, contraindications

Cisplatin is an antitumor drug containing a heavy metal platinum. Cisplatinum has properties similar to the properties of bifunctional alkylating agents that form inter-and intra-strand cross-links in DNA, thereby disrupting its functions, which leads to cell death. Wherein cisplatin does not have cyclic and phase specificity. Has immunosuppressive and radiosensitizing properties.

Pharmacokinetics:

After rapid intravenous infusion (15-60 minutes), the appearance of cisplatin in the blood plasma and the peak of its concentration is determined immediately after administration. With intravenous infusion for 6-24 hours, the concentration of the drug in the plasma increases gradually during the infusion, reaching a maximum at the end of the injection.

Cisplatin is characterized by extensive distribution in body fluids and in tissues; the highest concentrations are achieved in the kidneys, liver and prostate, slightly lower in the bladder, muscles, testicles, pancreas, and spleen. The lowest concentration of platinum is observed in the intestines, adrenal glands, heart, lungs, brain.2 hours after intravenous injection, more than 90% of the total amount of cisplatin binds to plasma proteins. With repeated courses of therapy, platinum accumulates in the tissues of the body, and platinum is found in some tissues for another six months after the last dose of the drug.

Biotransformation of cisplatin is carried out by rapid non-enzymatic transformation with formation of inactive metabolites. Cytotoxic effect has only cisplatin not bound to proteins, or its platinum-containing metabolites.

Following an injection or intravenous infusion of 2 to 7 hours in a dose range of 50 to 100 mg / m² the half-life of cisplatin from the blood plasma is approximately 30 minutes. After a dose of 100 mg / m² the ratio between cisplatin and total free (ultrafiltering) platinum in blood plasma is from 0.3 to 1.1.

The half-life of total platinum has a very wide individual variability and ranges between 2-72 hours in healthy people, and 1-240 hours with severe renal failure.1 hour after the administration of the drug, most of the cisplatin is excreted through the kidneys unchanged. The renal clearance of free (ultrafiltered) platinum also exceeds the creatinine clearance, is non-linear and depends on the dose, the rate of urine outflow and the individual features of tubular secretion and reabsorption in the patient. Strict correlation between renal clearance of free (ultrafiltered) platinum or cisplatin and creatinine clearance is not established. With daily administration of the drug, there is a danger of accumulation of free (ultrafiltered) platinum in the blood plasma. In other modes of administration, there is no such risk. After the administration of the drug, small concentrations of platinum are found in bile and in the large intestine, but the pathway for the removal of platinum through the gastrointestinal tract is negligible.

Cisplatin can be excreted from the systemic blood flow by dialysis, but only within the first 3 hours after drug administration.

Indications:

Cisplatin, usually as part of combined chemotherapy, is widely used in the treatment of the following solid tumors:

- germinogenous tumors of women and men;

- ovarian and testicular cancer;

- small cell and non-small cell lung cancer;

- squamous cell carcinoma of the head and neck;

- cancer of the bladder.

Besides, cisplatin has antitumor activity in the following types of tumors:

- cervical cancer;

- osteosarcoma;

- melanoma;

- neuroblastoma;

- esophageal carcinoma.

Contraindications:

- Hypersensitivity to cisplatin or other compounds containing platinum, as well as to any component of the drug;

- impaired renal function (serum creatinine level more than 115 μmol / liter);

- oppression of bone marrow hematopoiesis;

- hearing impairment;

- vaccination against yellow fever;

- pregnancy and the period of breastfeeding.

Carefully:

In patients with acute infectious diseases of the viral (chicken pox, including the recently transferred or recent contact with the patient, herpes zoster), fungal or bacterial genesis; Hyperuricemia (including manifested by gout and / or urate nephrourolythiasis), polyneuritis, nephrourolythiasis, radiation or chemotherapy in the anamnesis.

Pregnancy and lactation:

Contraindicated during pregnancy, because cisplatin can be toxic to the fetus when administered to a pregnant woman.

Because the cisplatin penetrates into breast milk, then during treatment should stop breastfeeding the baby.

Dosing and Administration:

Cisplatin can be used as a monotherapy or in combination with other cytostatics in different doses depending on the therapy scheme. For individual dose selection, reference should be made to the literature.

Cisplatin is administered intravenously or with indications (intraperitoneal tumors) in the abdominal cavity.

Cisplatinum in monotherapy and in combination with other chemotherapeutics is usually administered at a dose of 50-120 mg / m as an intravenous infusion every 3-4 weeks or 15-20 mg / m² intravenously daily for 5 days every 3-4 weeks.

The dose should be reduced in patients with oppression of bone marrow function or in the development of renal dysfunction.

Recommendations for the preparation and administration of a solution of cisplatin for intravenous infusions

In order to stimulate diuresis and to minimize the nephrotoxic effect of the drug, hydration is performed. For 2-12 hours (preferably 2-3 hours) before the introduction of cisplatin, it is necessary to inject 0.5-1.5 (-2.0) l / m intravenously to the patient² physiological solution.

Within 6-24 hours after cisplatin administration, sufficient fluid support (2-3 l / m² solution of sodium chloride with 5% glucose in a ratio of 1: 1.5). Diuresis should be 100-200 ml per hour. If necessary, you can assign D-mannitol. "Loop" diuretics should not be used.

When using cisplatin with a fluid retention in the body more than 1 L in a dose of less than 60 mg / m², with the condition of normal renal function, it is possible to use D-mannitol under the control of weight and fluid balance.

When using cisplatin in a dose of more than 60 mg / m, it is necessary to apply D-mannitol in a dose of 8 g / m immediately before the introduction of cisplatin. Cisplatinum can be administered only with a minimal diuresis in 250 ml for 30 minutes.

Cisplatin is administered intravenously drip at a rate of no more than 1 mg / minute.

Short-term infusions in low doses (up to 20 mg / m²) are held for 30-60 minutes. Dilution of cisplatin should be carried out D-mannitol 62.5 ml of a 20% solution.

Prolonged infusions in high doses of cisplatin are carried out within 6-8-24 hours, provided sufficient diuresis before and during the administration of the drug. The required dose of cisplatin should be diluted in 1-2 liters of sodium chloride solution.One liter of the solution can also contain 50 g of glucose and 18.75 grams D-mannitol.

In patients with moderate impairment of renal function (creatinine clearance to 115 μmol / L), a standard dose reduction of 50% is recommended.

Cisplatin is diluted in one of the following infusion solutions: 0.9% solution of sodium chloride, to a concentration of 1 mg / ml. Do not use dextrose solutions for dilution.

Infusion solution prepared 0.9% sodium chloride at a concentration of 1 mg / ml stable for 6-8 hours at a temperature of no higher than 25 ° C in a dark place.

Since aluminum reacts with cisplatin and inactivates it, and also causes the formation of a precipitate, it is very important in the preparation and administration of cisplatin Do not use needles or other equipment containing aluminum.

Side effects:

The incidence of side effects is described in accordance with the following gradation: very frequent - ≥ 1/10 appointments; frequent - ≥ 1/100 of appointments, infrequent - ≥ 1/1000 appointments, rare - ≥ 1/10000 prescriptions, very rare - <1/10000 prescriptions.

From the side of the neutral nervous system

rare: peripheral neuropathy, convulsions, leukoencephalopathy;

frequency is unknown: stroke (hemorrhagic, ischemic), loss of taste, a symptom of Lermitt (a piercing pain resembling an electric shock, passing down the arms or trunk with the bending of the neck), myelopathy, autonomic neuropathy, cerebral arteritis.

From the sense organs

infrequent: unilateral or bilateral tinnitus, ototoxicity;

frequency is unknown: change in the perception of colors, especially in the yellow-blue part of the spectrum, optic neuritis, optic nerve papilloma, cortical blindness, irregular retinal pigmentation in the area of the yellow spot, deafness. These side effects are dose-dependent, cumulative and reversible.

From the gastrointestinal tract

rare: inflammation of the mucous membranes of the mouth;

frequency unknown: nausea, hiccups, vomiting, diarrhea, anorexia, increased concentration of "liver" enzymes and bilirubin in blood plasma.

From the side of the cardiovascular system

Frequent: arrhythmia, bradycardia, tachycardia;

rare: myocardial infarction; very rare: heart failure;

frequency is unknown: thrombolytic microangiopathy, cerebral arteritis, Raynaud's disease.

From the genitourinary system

infrequent: impaired spermatogenesis;

frequency is unknown: acute renal failure, toxic kidney damage (including tubular), manifested by an increase in the concentration of urea, uric acid, creatinine in the blood plasma and / or a decrease in the clearance of creatinine.

From the side of water-electrolyte exchange

very frequent: hyponatremia (may be due to the syndrome of inappropriate production of antidiuretic hormone);

infrequent: hypomagnesemia;

frequency is unknown: dehydration, hypocalcemia, hypokalemia, hypophosphatemia, hyperuricemia.

On the part of the organs of hematopoiesis

Often: thrombocytopenia, leukopenia, anemia, myelosuppression. After cisplatin administration in high doses, severe bone marrow depression (including agranulocytosis and / or aplastic anemia) is possible;

frequency unknown: kumbs-positive hemolytic anemia.

Allergic reactions

infrequent: anaphylactic reactions (redness and swelling of the face, bronchospasm, wheezing in the lungs, tachycardia, lowering of blood pressure);

very rare: urticaria, spottypapular skin rash.

Other

very frequent: fever; Frequent: sepsis; infrequent: acute leukemia;

frequency is unknown: infection (including fatal), increased serum amylase concentration, alopecia, asthenia, malaise, platinum gum line, pulmonary embolism, extravasation at the injection site (accompanied by local toxicity of soft tissues: redness, swelling, pain, cellulite, fibrosis, necrosis).

Overdose:

Symptoms: there is an increase in the severity of side effects, indicated in the section "Side effect." The main complications are manifested mainly in the form of impaired renal function, liver function, vision (including retinal detachment) and hearing (deafness), severe myelosuppression, uncontrollable nausea and vomiting and / or neuritis. A lethal outcome is possible.

Treatment: antidote is unknown. It is necessary to use symptomatic therapy with constant monitoring of the patient and vital functions. The effect, at least partial, is achieved only by hemodialysis if it is used within the first three hours after an overdose, as platinum quickly binds to plasma proteins.

Interaction:

Simultaneous or sequential use of cisplatin with nephrotoxic drugs (eg, cephalosporins, aminoglycosides, amphotericin B, contrast agents) can potentiate its nephrotoxic and ototoxic effect.

With simultaneous application of cisplatin and ifosfamide, nephrotoxicity of the latter may be increased.

"Loop" diuretics (furosemide, clopamide, ethacrynic acid), aminoglycosides, ifosfamide can enhance the ototoxicity of cisplatin. Cisplatinum can disrupt the excretion via the kidneys of bleomycin and methotrexate (possibly due to a cisplatin-induced nephrotoxic effect) and increase the toxicity of these drugs.

With the simultaneous use of cisplatin, hexamethylmelamine and pyridoxine in the treatment of ovarian cancer, the duration of remission has been reduced.

In patients receiving cisplatin and anticonvulsants, the concentration of the latter in the serum can be reduced to subtherapeutic values.

Cisplatin may cause an increase in the concentration of uric acid in the blood. Therefore, patients who simultaneously take medicines to treat gout, such as allopurinol, colchicine, probenecid or sulfinpyrazone, it may be necessary to adjust the dosage of these drugs to control hyperuricemia and gout attacks.

When cisplatin interacts with aluminum, a precipitate forms.

In the case of administration of paclitaxel after cisplatin, clearance of paclitaxel may decrease by 70-75%.

In a combination of cisplatin, bleomycin and etoposide, a decrease in the concentration of lithium in the blood was recorded in several cases. Therefore, during the treatment it is recommended to control the levels of lithium.

Cisplatin can reduce the absorption of phenytoin and thus reduce the effectiveness of antiepileptic therapy.

Chelating agents, in particular penicillamine, can reduce the effectiveness of cisplatin treatment.

The simultaneous use of antihistamines, phenothiazides, thioxanthins can mask the symptoms of ototoxicity (such as dizziness, ringing (noise) in the ears).

Special instructions:

The use of Cisplatin-Ebove should be carried out under the supervision of a qualified physician with experience in working with antitumor chemotherapeutic drugs.

The dose and scheme of taking the drug is selected individually.

Care should be taken when working with Cisplatin-Ebove. Dilute the drug in aseptic conditions in a specially designated room. This should be handled by trained personnel. It is necessary to take all measures to prevent the solution of cisplatin from getting on the skin and mucous membranes, in particular to use protective clothing (gown, cap, mask, glasses and disposable gloves). If cisplatin hits the skin or mucous membranes, rinse thoroughly with soap and water or (eyes) with plenty of water.

Men and women of childbearing age should use reliable contraceptive methods during and for 6 months after the end of Cisplatin-Ebove therapy. Since in the process of treatment possible the development of irreversible infertility, men should consider the possibility of cryo-preservation of sperm in the bank before the treatment. Patients on the background of Cisplatin-Ebove treatment should periodically be examined by a neurologist. With obvious symptoms of toxic effects on the central nervous system, cisplatin therapy should be discontinued.

Before the start of therapy, audiometry should be performed, and in cases where there are symptoms of hearing damage or clinical hearing impairments, repeated audiometry is indicated. In clinically significant hearing disorders, dosage adjustment or cancellation of therapy may be required.

During the treatment with Cisplatin-Ebev, regular monitoring of the clinical blood test, renal and hepatic functional tests, as well as the level of electrolytes in blood serum is necessary.

Occurrence of nausea and vomiting in patients usually occurs during the first hour of therapy and lasts for 24 hours or more. These side effects are only partially eliminated with the use of standard antiemetic drugs. The severity of these symptoms can be reduced by dividing the total dose calculated for the therapy cycle into smaller doses that are administered once a day for five days.

Repeatedly, the drug should not be administered until the serum creatinine level is raised to 15-20 mg / L; the content of platelets in the blood will not be 100,000 / mm³, leukocytes - not less than 4000 / mm³. The lowest content of leukocytes and platelets in the blood is usually observed from the 18th to the 23rd day after the administration of cisplatin. In most patients, these rates are restored by the 39th day.

With the development of allergic reactions in the form of edema of the face, bronchospasm, tachycardia and hypotension, adrenaline, corticosteroids and antihistamines should be used.

Special precautions for the destruction of unused medications

The remnants of the preparation and all tools and materials used for the preparation of Cisplatin-Ebove infusion solutions must be disposed of in accordance with the standard hospital procedure for the disposal of cytotoxic substances, taking into account existing regulations on hazardous waste disposal.

Effect on the ability to drive transp. cf. and fur:

Because of the likelihood of side effects, such as visual impairment, convulsions, caution should be exercised when engaging in potentially dangerous activities requiring increased concentration and speed of psychomotor reactions.

Form release / dosage:

Concentrate for solution for infusion, 0.5 mg / ml.

Packaging:

For 10 mg / 20 ml, 25 mg / 50 ml or 50 mg / 100 ml in brown glass bottles, type 1, Hept. F, sealed with rubber stoppers, coated with fluoropolymer film underneath (Al. closed with a protective Teflon cap.

One bottle with the drug, along with instructions for use, is placed in a cardboard box.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Do not freeze.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use the product after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:P N015106 / 01-2003

Date of registration:09.06.2008

The owner of the registration certificate:Ebewe Pharma Gesmb.b. Nfg. KGEbewe Pharma Gesmb.b. Nfg. KG Austria

Manufacturer: & nbsp

EBEWE PHARMA, Ges.m.b.H.Nfg.KG Austria

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp27.09.2015

Illustrated instructions

Instructions

Cisplatin-Ebove (Cisplatin-Ebewe)