Cisoter - instructions for use, doses, side effects, contraindications

Cisplatin (cis-diamine-dichloroplatinum) is an antitumor drug containing a heavy metal platinum. Cisplatinum possesses properties similar to the properties of bifunctional alkylating agents forming interstitial and interstitial crosslinks in DNA, thereby disrupting its functions, which leads to cell death, with the preparation having no cyclic and phase specificity. Has immunosuppressive and radiosensitizing properties.

Pharmacokinetics:

The drug binds to blood proteins (albumins, gamma globulin, transferrin) on 90% and with cellular elements of plasma (including with erythrocytes). Fast metabolized by non-enzymatic conversion into inactive metabolites. Cytotoxic effect has only cisplatin, not associated with proteins, or its platinum-containing metabolites.

After rapid intravenous (IV) infusion (15 minutes - 1 hour), the appearance of cisplatin in the blood plasma and the maximum concentration of cisplatin is achieved immediately after administration. With intravenous infusion for 6-24 hours, the concentration of the drug in the plasma increases gradually, reaching a maximum at the end of the injection.

Cisplatin is characterized by extensive distribution in body fluids and in tissues; while the highest concentrations are achieved in the kidneys, liver and the prostate gland. Biotransformation of cisplatin is carried out by rapid non-enzymatic transformation with formation of inactive metabolites.

After an inkjet or intravenous infusion of 2 to 7 hours in the dose range from 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. Three hours after the bolus and two hours after the end of the three-hour infusion, 90% of the total free platinum in plasma appears in protein-bound state. 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. 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 nonlinear 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 digestive tract is negligible.

Cisplatin can be excreted from the systemic circulation by dialysis, but only in during the first 3 hours after the administration of the drug.

Indications:

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

- germinogenous tumors of women and men;

- ovarian and testicular cancer;

- cancer of the bladder;

- squamous cell carcinoma of the head and neck.

- lung cancer;

- cervical cancer (including in combination with radiotherapy)

Besides, cisplatin has antitumor activity in the following species tumors:

- 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 / l);

- severe oppression of bone marrow hematopoiesis;

- Hearing impairment;

- vaccination with live antiviral vaccines, including yellow fever vaccine;

- pregnancy and the period of breastfeeding;

- dehydration;

- simultaneous use of phenytoin, for the prevention of seizures.

Carefully:

Acute infectious diseases of the virus (including herpes zoster, chicken pox), fungal and bacterial etiology; hyperuricemia (including manifested by gout and / or urate nephrolithiasis); nefrourolitiaz, oppression of bone marrow hematopoiesis (including on the background of radiation and chemotherapy); polyneuritis.

Dosing and Administration:

Cisoter is administered as an intravenous infusion at a rate of no more than 1 mg / min.

Prolonged infusions are carried out within 6-8-24 hours provided sufficient diuresis before and during administration of the drug.

Cisoter can be used as a monotherapy or in combination with other cytostatics in different doses depending on the therapy scheme. Cisoter is administered intravenously, and also, with indications, into the pleural and abdominal cavities.

To stimulate diuresis (up to 100 ml / h) and to minimize the nephrotoxic effect of the drug, hydration is performed. 8-12 hours before the application of cisplatin in the form of IV infusion, inject up to 2 liters of fluid (0.9 % solution of sodium chloride or 5% solution of dextrose). After the administration of cisplatin, 400 ml of a 0.9% solution of sodium chloride or a 5% solution of dextrose are additionally administered. Fluid intake and maintenance of diuresis must be observed within 24 hours. If intensive hydration is not sufficient to maintain adequate diuresis, osmotic diuretics (including mannitol) are recommended.

Usually Cisoter for children and adults in monotherapy and in combination with other chemotherapy drugs is administered in a dose of 50-120 mg / m² in the form of intravenous infusion every 3-4 weeks or at a dose of 15-20 mg / m² intravenously drip daily for 5 days, every 3 to 4 weeks.

For treatment of cervical cancer in combination with radiation therapy, the recommended dose of cisplatin is 40 mg / m² Once a week for 6 weeks.

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

In patients with moderate renal failure (creatinine clearance up to 115 μmol / L), the standard dose should be reduced by 50%.

Repeated courses are conducted at a concentration in the serum of creatinine of less than 130 μmol / L (<1.5 mg / dl), urea less than 9 mmol / L (urea nitrogen <25 mg / dl) and peripheral blood platelet count more than 100,000 / neutrophils - more than 1500 / mkl.

Recommendations for the preparation and administration of solutions for intravenous infusion

The required amount of Cisoter is diluted in 1-2 liters of 0.9 % solution of sodium chloride.

Do not use a dextrose solution to dilute the Cisoter preparation.

Since aluminum reacts with cisplatin and inactivates it, and also precipitates, when preparing and injecting Tsisoter, do not use needles and other equipment containing aluminum.

Begin the introduction of the solution immediately after its preparation.

Cisoter solution should not be mixed with other solutions and medications.

Infusion should be completed within 24 hours after the preparation of the solution.

Pregnant women should not work with cisoter.

Side effects:

According to the World Health Organization (WHO), adverse reactions are classified according to their developmental frequency as follows: very often (≥1/10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, < 1/100), rarely (≥1 / 10000, <1/1000) and very rarely (<1/10000); frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.

Disturbances from the nervous system

rarely: peripheral neuropathy, convulsions, leukoencephalopathy (including the syndrome of posterior reversible leukoencephalopathy);

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

Disturbances on the part of the organ of sight

frequency is unknown: blurred vision, change in the perception of colors, especially in the yellow-yellow part of the spectrum, acquired color blindness, optic neuritis, optic disc edema, cortical blindness, irregular retinal pigmentation in the area of the macula.

Hearing disorders and labyrinthine disorders

infrequently: one-sided or bilateral tinnitus, hearing loss, especially in the high-frequency range (4000-8000 Hz) (ototoxicity is dose-dependent and cumulative, but it is unknown if it is reversible);

frequency is unknown: deafness.

Disorders from the gastrointestinal tract

rarely: inflammation of the oral mucosa;

frequency unknown: nausea, hiccough, vomiting, diarrhea, anorexia.

Disorders from the cardiovascular system

often: arrhythmia, bradycardia, tachycardia;

rarely: myocardial infarction;

rarely: heart failure;

frequency is unknown: thrombolytic microangiopathy (hemolytic-uremic syndrome), cerebral arteritis, Raynaud phenomenon, pulmonary embolism.

Disorders from the kidneys and urinary tract, genital organs and mammary gland

infrequently: 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.

Violations of the blood and lymphatic system

Often: thrombocytopenia, leukopenia, anemia, myelosuppression.

After using cisplatin in high doses, severe bone marrow depression (including agranulocytosis and / or aplastic anemia) is possible;

infrequently: acute leukemia;

frequency is unknown: coombs-positive hemolytic anemia.

Immune system disorders

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

rarely: urticaria, maculopapular skin rash.

Infectious and parasitic diseases

often: sepsis;

frequency is unknown: infection (including fatal).

Laboratory and instrumental data

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

infrequently: hypomagnesemia;

rarely: hypercholesterolemia;

rarely: increased serum iron levels;

frequency is unknown: an increase in the activity of amylase in the blood serum, an increase in the activity of "hepatic" enzymes and bilirubin concentration in the blood plasma, hypocalcemia, hypokalemia, hypophosphatemia, hyperuricemia.

General disorders and disorders at the site of administration

Often: fever;

frequency is unknown: alopecia, asthenia, malaise, dehydration, muscle spasm, platinum gum line, extravasation at the injection site (accompanied by local toxicity of soft tissues: redness, swelling, pain, cellulitis, fibrosis, necrosis).

Overdose:

The main anticipated complications of overdose are renal, hepatic, visual impairment (including retinal detachment) and hearing (deafness), severe myelosuppression, indomitable vomiting and / or severe neuritis. In case of an overdose, a lethal outcome is possible.

Antidote to cisplatinum is not known. Treatment is symptomatic. A partial effect can be achieved with hemodialysis performed within the first three hours after an overdose.

Interaction:

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

With simultaneous or preliminary use of cisplatin and ifosfamide it is possible to increase nephrotoxicity of the latter and increase protein excretion. The nephrotoxic effect of cisplatin may be enhanced by concomitant treatment with antihypertensive drugs such as furosemide, hydralazine, diazoxide and propranolol.

Cisplatin may impair renal excretion bleomycin and methotrexate (possibly due to a cisplatin-induced nephrotoxic effect) and to increase the toxicity of these drugs.

Loop diuretics (furosemide, clopamide, ethacrynic acid), aminoglycosides, ifosfamide can enhance the ototoxicity of cisplatin.

With the simultaneous use of cisplatin and hexamethylmelamine and pyridoxine In the treatment of ovarian cancer, there was a reduction in the duration of remission.

In patients receiving cisplatin and anticonvulsants, the concentration of the latter in the serum can be reduced to subtherapeutic values. Cisplatinum can reduce absorption phenytoin and thus reduce the effectiveness of antiepileptic therapy. During the period of using cisplatin, treatment with phenytoin for the first time is contraindicated.

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, can there is a need to adjust the dose of these drugs to control hyperuricemia and gout attacks.

In the interaction of cisplatin with aluminum a precipitate is formed.

In the case of administration paclitaxel after cisplatin, clearance of paclitaxel can be reduced to 33% and neurotoxicity - increased.

Clinical studies have shown that patients with advanced cancer or metastases docetaxel in combination with cisplatin causes more pronounced manifestations of neurotoxic effect (dose-dependent effect) than these drugs when applied separately in identical doses.

The simultaneous use of cisplatin and other drugs, oppressive function of red bone marrow, or radiotherapy enhances myelosuppressive effect. The interaction of cisplatin and cyclosporine enhances the immunosuppressive effect and can lead to the development of lymphoproliferative diseases.

Cisplatin combined with bleomycin and vinblastine can contribute to the development of the Raynaud phenomenon.

With combined therapy with cisplatin, bleomycin and etoposide in a few cases, there was a decrease in the concentration of lithium in the blood. Therefore, during the treatment it is recommended to monitor the concentration of lithium.

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

Simultaneous application antihistamines, phenothiazines, thioxanthins can mask symptoms of otogoksichnosti (such as dizziness, ringing (noise) in the ears).

Live attenuated yellow fever vaccine is strictly contraindicated for administration in connection with the possible risk of developing lethal systemic reactions to the vaccine. If necessary, use an inactivated vaccine.

Live viral vaccines it is recommended to use no earlier than 3 months after the end of treatment.

Special instructions:

The use of the drug Tsisoter should be carried out under the supervision of a qualified doctor who has experience with antitumor chemotherapeutic drugs.

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

Care should be taken when working with Cisoter. Dilute the drug should be in aseptic conditions in a specially designated room. This should be handled by trained personnel. You must take all measures for Cisoter solution on the skin and mucous membranes, in particular to wear protective clothing (gown, cap, mask, goggles and disposable gloves). If the product gets on the skin or mucous membranes, rinse thoroughly with soap and water or (eyes) with plenty of water. Cisplatinum should be administered intravenously. When extravasation is necessary to carefully monitor the place of administration. At the present time, there is no specific treatment for the drug in the surrounding tissues.

Cisplatin chemically interacts with aluminum, forming black precipitates of platinum, so all devices that contain aluminum, as well as catheters, syringes are not recommended for use in these patients.

Men and women of childbearing age should use reliable methods of contraception during and for 6 months after the end of therapy with Cisoter. Since in the process of treatment possible the development of irreversible infertility, men should consider the possibility of cryopreservation of sperm in the bank before the treatment.

Patients on the background of treatment with Cisoter should periodically be examined by a neurologist. With obvious symptoms of toxic effects on the central nervous system, therapy with Cisoter 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. Ototoxicity can be more pronounced in children. In clinically significant hearing disorders, dose adjustment or treatment can be required.

Before, during and after treatment with Cisoter, a weekly monitoring of the clinical blood test, renal and hepatic functional tests, as well as the concentration of electrolytes in the blood serum is required.

Repeat the drug should not be used until the serum creatinine concentration has decreased ≤130 μmol / l, urea <250 mg / l; the content of platelets in the blood does not become >100x10⁹/ l, white blood cells> 4.0 x10⁹/ l. The lowest content of white blood cells and platelets in the blood is usually observed from the 18th to the 23rd day after the administration of the drug Cisoter. In most patients, these rates are restored by the 39th day.

After the introduction of cisplatin, nausea, vomiting, and diarrhea often occur, which most patients go through 24 hours. Slight nausea and lack of appetite can last for 7 days after treatment. The prophylactic use of antiemetics can reduce or prevent unwanted reactions. With intensive nausea and vomiting, antiemetic therapy is required and, if necessary, replenishment of fluid loss. When developing allergic reactions in the form of edema of the face, bronchospasm,tachycardia and lowering blood pressure should be applied epinephrine, glucocorticosteroids and antihistamines.

The level of diuresis of 100 ml / h and above contributes to a decrease in nephrotoxicity in the treatment of cisplatin. It is recommended to pre-hydrate (colloidal solutions, 2 l intravenously) followed by hydration of 2500 ml / m for 24 hours. If possible, forced diuresis (using, for example, mannitol).

In rare cases, with the treatment of cisplatinum and the presence of other leukemogenic factors, acute leukemia develops.

With the simultaneous use of oral anticoagulants, careful monitoring of INR is required.

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

Given that when using Cisoter, dizziness, visual impairment and color perception may appear in patients, during the introduction of the drug should refrain from controlling vehicles and mechanisms and performing other works that require concentration and speed of psychomotor reactions.

Form release / dosage:

Concentrate for the preparation of a solution for infusions 1 mg / ml.

Packaging:

For 50 ml of the drug (50 mg of cisplatin) in a bottle of amber glass (type I), sealed with bromobutyl stopper and aluminum cap.

1 bottle with instructions for use in a pack of cardboard.

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:

2 years. Do not use after the expiry date printed on the package.

Ready the solution should be used immediately after preparation.

Terms of leave from pharmacies:On prescription

Registration number:LP-004140

Date of registration:13.02.2017

Expiration Date:13.02.2022

The owner of the registration certificate:ARS, LLC ARS, LLC Russia

Manufacturer: & nbsp

TerDoz Pharma Private, Limited India

Representation: & nbspARS, LLCARS, LLC

Information update date: & nbsp22.03.2017

Illustrated instructions

Instructions

Tsissoter (Cisoter)