Cisplatin-RONC - instructions for use, dose, 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) by 90% and with cellular elements of the plasma (including with erythrocytes). Rapidly 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.

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 / m, the ratio between cisplatin and total free (ultrafiltered) platinum in blood plasma is 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 accumulation of free (ultrafiltered) platinum in 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 blood flow by dialysis, but only within the first 3 hours after drug administration.

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;

- cancer of the cervix (including in combination with radiation therapy).

Besides, cisplatin has antitumor activity in the following types of 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;

- pregnancy and the period of breastfeeding.

Carefully:

- Acute infectious diseases of the viral (including herpes zoster, chicken pox), fungal and bacterial etiology;

- hyperuricemia (including manifested by gout and / or urate nephrolithiasis), nephrourolythiasis;

- oppression of bone marrow hematopoiesis (including on the background of radiation and chemotherapy);

- polyneuritis.

Dosing and Administration:

Cisplatin-RONTS® is administered as an intravenous infusion at a rate of no more than 1 mg / min. Long-term infusions are carried out during 6-8-24 hours under condition of sufficient diuresis prior to administration and during the administration of the drug.

Cisplatin-RONTS® can be used as a monotherapy or in combination with other cytostatics in different doses depending on the therapy scheme. Cisplatin-RONTS® 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 Cisplatin-RONTS® for children and adults in monotherapy and in combination with other chemotherapy drugs is administered at a dose of 50-100 mg /m² in the form of intravenous infusion every 3-4 weeks or at a dose of 15-20 mg /m²intravenously drip daily for 5 days, every 3-4 weeks.

For the 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.

Recommendations for the preparation and administration of solutions for intravenous infusion

The necessary amount of the drug Cisplatin-RONTS® is diluted in 1-2 liters of 0.9% sodium chloride solution.

Do not use a solution of Cisplatin-RONT® solution of dextrose for dilution.

Since aluminum reacts with cisplatin and inactivates it, and causes sedimentation, do not use needles and other equipment containing aluminum when preparing and administering the Cisplatin-RONTS® preparation.

Begin the introduction of the solution immediately after its preparation.

Solution Cisplatin-RONTS® 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 Cisplatin-RONTS®.

Side effects:

On the part of the organs of hematopoiesis: thrombocytopenia, leukopenia, anemia.

Myelosuppression is very common, however, in most cases it is mild or moderately expressed and is reversible in normal doses. The lowest content of leukocytes and platelets, as a rule, are observed about 18-23 days after the administration of the drug; their initial value in most patients is restored within 4 weeks. Also hemolytic anemia (positive Coombs test) can be observed.

From the digestive system: nausea, vomiting, decreased appetite, hiccough, abdominal pain, diarrhea, platinum gum line, transient increase in the activity of "liver" transaminases, alkaline phosphatase and serum bilirubin concentration. In rare cases, inflammation of the mucous membranes of the mouth.

Nausea and vomiting, which usually begin within the first hour of therapy and last for 24 hours or more, occur in almost all patients. 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.

From the urinary system: increased serum levels of creatinine, urea / urea nitrogen, uric acid, decreased creatinine clearance. Impaired renal function, which is accompanied by damage to the renal tubules, may first be detected in the second week after dosing. Nephrotoxicity is cumulative. Renal insufficiency, as a rule, is insignificant or moderately pronounced and is reversible at usual doses of cisplatinum.

From the side of water-electrolyte exchange: hypomagnesemia, hypocalcemia, hypokalemia, hyponatremia, hypophosphataemia. Hypomagnesemia and / or hypocalcemia can be manifested clinically by increased muscular excitability, convulsions, tremor, carppedal spasm (cramps in hands and feet) and / or tetany. Hyponatremia is usually caused by the syndrome of inappropriate production of antidiuretic hormone. Very rarely, an increase in the iron content in serum is observed.

From the nervous system: dizziness, peripheral neuropathies, myasthenic syndrome, convulsions.

Peripheral neuropathies occur infrequently. They are usually sensory in nature (for example, paresthesia of the upper and lower extremities), but also motor disorders (decreased reflexes and weakness in the lower limbs) may occur. Cramps, slurred speech, loss of taste and loss of memory may also occur. The development of Lermitt's symptom, myelopathy of the vertebral column, neuropathy of the autonomic nervous system, reversible posterior leukoencephalopathy was reported.

From the side of the organ of hearing and balance: ototoxicity (develops in 10-30% of patients, mainly with high doses - one-sided or bilateral tinnitus, hearing loss up to one- or two-sided hearing loss within the frequency range of 4-8 thousand Hz). The defeat of the hearing organ is dose-dependent and cumulative, this side effect is more often observed in patients of very young or senile age. There are reports of a toxic effect of the drug on the vestibular apparatus. Children have a higher probability of ototoxicity than adults.

From the side of the organ of vision: visual impairment and color perception, in rare cases, neuritis of the optic nerve, edema of the optic nerve, cortical blindness, pigmentation of the retina are noted. These side effects are usually reversible and disappear after drug withdrawal.

From the cardiovascular system: arrhythmia, bradycardia, tachycardia, rarely myocardial infarction, very rarely sudden cardiac arrest; Thrombotic microangiopathy (hemolytic-uremic syndrome), Raynaud's syndrome, cerebrovascular disorders, hemorrhagic or ischemic stroke.

On the part of the respiratory system: shortness of breath, respiratory failure, embolism of the pulmonary artery.

From the skin and skin appendages: skin rash, alopecia

From the immune system: sometimes there are anaphylactoid reactions, manifested in the form of redness and swelling of the face, wheezing, bronchospasm, tachycardia and lowering blood pressure. These reactions can occur within a few minutes after the start of the drug administration. In rare cases, there may be urticaria, maculopapular skin rash, allergic pruritus.

Local reactions: phlebitis at the injection site; when the product gets under the skin, it is possible to develop erythema, tenderness, swelling, fibrosis, inflammation of the subcutaneous tissue and necrosis of surrounding tissues.

Other: asthenia, general malaise, fever, hypercholesterolemia, increased serum amylase concentration, attachment of secondary infections, sepsis. Rarely is the development of acute leukemia. Cases of amenorrhea, violations of spermatogenesis, azoospermia and gynecomastia have been noted.

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 aminoglycosides (gentamicin, kanamycin, streptomycin) or with other potentially nephrotoxic (eg,amphotericin B) and ototoxic drugs (eg, "loop" diuretics) can potentiate its nephrotoxic and ototoxic effect. "Loop" diuretics (furosemide, clopamide, ethacrynic acid), ifosfamide can enhance the ototoxicity of cisplatin.

Combined use with antihistamines, phenothiazines, thioxanthenes may mask the symptoms of the ototoxic effect of cisplatin.

Cisplatin may interfere with the excretion of bleomycin and methotrexate through the kidneys (possibly due to cisplatin-induced nephrotoxic effects) and enhance the toxicity of these drugs.

In patients receiving cisplatin and anticonvulsants, the concentration of the latter in the serum can be reduced to subtherapeutic values. Cisplatinum can reduce the absorption of phenytoin and thus reduce the effectiveness of antiepileptic therapy. Primary administration of phenytoin against cisplatin is not recommended.

Cisplatin may cause an increase in the concentration of uric acid in the blood, and therefore with simultaneous use with uricosuric anti-gout patients, such as allopurinol, colchicine, probenecid or sulfinpyrazone, it may be necessary to adjust the doses of these drugs.

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

Simultaneous use of cisplatin with drugs that depress the function of the bone marrow, or with radiotherapy may increase myelosuppression.

When paclitaxel is administered after cisplatin, paclitaxel clearance is reduced by approximately 33%, with more pronounced myelosuppression, and therefore cisplatin it is recommended to administer after paclitaxel.

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

When cisplatin interacts with aluminum, a precipitate forms.

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.

With simultaneous administration with live viral vaccines, it is possible to intensify the replication process of the vaccine virus,increasing its adverse / adverse effects and / or reducing the production of antibodies in the patient's body in response to the introduction of the vaccine.

Special instructions:

- Introduction Cisplatin-RONTS® should be administered under the supervision of a physician experienced in the use of cytotoxic drugs. Continuous monitoring of possible toxic effects in the treatment of cisplatinum-RONTS® is mandatory.

- Before the start of therapy, it is necessary to monitor the kidneys, liver function, hematopoietic function (the number of red and white blood cells and platelets) and the concentration of electrolytes in the blood serum (calcium, sodium, potassium, magnesium) during the treatment (weekly) and after it,

- Women of childbearing age and men are recommended to use reliable contraceptive methods during treatment with cisplatin and at least 6 months after the end of treatment.

- During the treatment with cisplatin it is necessary to periodically perform a general blood test with determination of the content of leukocytes, platelets, hemoglobin, renal and hepatic functional tests, as well as the concentration of electrolytes in the blood serum.

- 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.

- To prevent nausea and vomiting, apply metoclopramide, ondansetron, tropospheric, granisetron and other antiemetics.

- Patients on the background of cisplatin treatment should periodically be examined by a neurologist. With obvious symptoms of toxic effects on the central nervous system, cisplatin should be discontinued.

- Before the start of therapy and during treatment, audiometry should be performed. In clinically significant hearing disorders, dose adjustments or cancellation of therapy may be required.

- When developing allergic reactions in the form of edema of the face, bronchospasm, tachycardia, lowering blood pressure should be applied epinephrine, glucocorticosteroids and antihistamines.

- When using Cisplatin-RONTS®, all the usual instructions adopted for the use of cytotoxic drugs should be observed.

- If the product gets into the eyes, they must be washed immediately with a large amount of water or a solution of sodium chloride.In case of contact with the skin, immediately contact the product with plenty of water. If the product is inhaled or if it gets into the mouth, immediately consult a doctor.

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

Given that dizziness, visual impairment and color perception may occur in patients using Cisplatin-RONTS®, one should refrain from controlling the vehicles and mechanisms and performing other works requiring concentration of attention and speed of psychomotor reactions at the time of drug administration.

Form release / dosage:

Concentrate for the preparation of a solution for infusions, 0.5 mg / ml and 1.0 mg / ml.

Packaging:

Concentrate for the preparation of solution for infusions of 0.5 mg / ml:

For 20 ml, 50 ml or 100 ml in bottles of dark glass, corked with rubber stoppers under running in aluminum caps.

For 1 bottle in a cardboard box with instructions for use.

Concentrate for solution for infusion 1.0 mg / ml:

For 10 ml, 20 ml or 50 ml in bottles of dark glass, corked with rubber stoppers under running in aluminum caps.

For 1 bottle in a cardboard box with instructions for use.

Storage conditions:

At a temperature of 15 to 25 ° C in a dry place protected from light.

Keep out of the reach of children.

Shelf life:

2 years.

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

The finished solution should be used immediately after preparation.

Terms of leave from pharmacies:On prescription

Registration number:LP-002388

Date of registration:28.02.2014

Date of cancellation:2019-02-28

The owner of the registration certificate:RNTS named after N.N. Blokhin RAMS RNTS named after N.N. Blokhin RAMS Russia

Manufacturer: & nbsp

RNTS named after N.N. Blokhin RAMS Russia

Information update date: & nbsp26.09.2015

Illustrated instructions

Instructions

Cisplatin-RONTS® (Cisplatin-RONC®)