Composition, form of production and packaging
Concentrate for the preparation of a solution for infusions in the form of a clear solution from colorless to pale yellow.
1 ml
cisplatin 500 Ојg
Auxiliary substances: sodium chloride, hydrochloric acid, water d / u.
20 ml - bottles of dark glass (1) - cardboard boxes.
Concentrate for the preparation of a solution for infusions in the form of a clear solution from colorless to pale yellow.
1 ml
cisplatin 500 Ојg
Auxiliary substances: sodium chloride, hydrochloric acid, water d / u.
100 ml - bottles of dark glass (1) - carton boxes.
INSTRUCTION FOR THE SPECIALIST.
The product description was approved by the manufacturer for the 2009 print edition.
PHARMACHOLOGIC EFFECT
Cisplatin (cis-diamine-dichloroplatinum), is an antitumor drug containing a heavy metal platinum. Cisplatin possesses properties similar to the properties of bifunctional alkylating agents forming interstitial and interstitial crosslinks in DNA, thereby violating its functions, which leads to cell death; the preparation does not have cyclic and phase specificity. Has immunosuppressive and radiosensitizing properties.
PHARMACOKINETICS
After rapid IV infusion (15 minutes - 1 hour), the appearance of cisplatin in the blood plasma and C max is determined immediately after administration. With IV infusions 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; with the highest concentrations 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. Cytotoxic action has only cisplatin unbound with proteins, or its platinum-containing metabolites.
After an inkjet injection or intravenous infusion of 2 to 7 hours in a dose range of 50 to 100 mg / m 2, T 1/2 of cisplatin from the blood plasma is approximately 30 minutes. After a dose of 100 mg / m, the ratio between cisplatin and total free (ultrafiltrating) platinum in plasma is 0.5 to 1.1. 3 hours after the bolus and 2 hours after the end of the 3-hour infusion, 90% of the total free platinum in plasma appears in the 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 6 months after the last dose of the drug. T 1/2 of the 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 the tubular secretion and the reabsorption in the patient of a 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 blood flow by dialysis, but only within the first 3 hours after the administration of the drug.
INDICATIONS
Cisplatin, usually as part of combined chemotherapy, is widely used in the treatment of the following solid tumors:
- germinogenic 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;
- bladder cancer.
In addition, cisplatin has antitumor activity in the following types of tumors:
- cervical cancer;
osteosarcoma;
- melanoma;
- a neuroblastoma;
- esophageal carcinoma.
DOSING MODE
The hemoplasm can be used both as a monotherapy and in combination with other cytostatics in different doses depending on the therapy scheme. For individual dose selection, reference should be made to the literature. The hemoplasm is administered intravenously or with indications (intraperitoneal tumors) into the abdominal cavity.
The hemopoiesis in monotherapy and in combination with other chemotherapies is usually administered at a dose of 50-100 mg / m 2 in the form of an IV infusion every 3-4 weeks or 15-20 mg / m 2 IV drip daily for 5 days every 3 -4 weeks.
Recommendations for the preparation and administration of solutions for intravenous infusions
To stimulate diuresis (up to 100 ml / h) and to minimize the nephrotoxic effect of the drug, hydration is performed. Before the introduction of cisplatin iv / drift up to 2 liters of liquid is drip-fed. Fluid intake and diuresis should be maintained for 24 hours. If intensive hydration is insufficient to maintain adequate diuresis, an osmotic diuretic (eg, mannitol) can be administered.
Cisplatin is administered intravenously at the rate of not 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.
Cisplatin is diluted in one of the following infusion solutions: 0.9% solution of sodium chloride; 0.9%, 0.45% or 0.3% solution of sodium chloride in a 5% solution of glucose. Diluted solutions of the drug are stable for 6-8 hours at a temperature of no higher than 25 В° C in a dark place.
Note: aluminum reacts with cisplatin and inactivates it, and also causes the formation of a precipitate, it is very important when preparing and injecting cisplatin not to use needles and other equipment containing aluminum.
SIDE EFFECT
On the part of the urinary system: nephrotoxicity is cumulative and is the main toxic factor limiting the dose of cisplatin. Renal lesions, which are accompanied by damage to the renal tubules, can first be detected at week 2 after the dose is administered and can be manifested by an increase in the level of creatinine, urea, uric acid in the blood serum and / or a decrease in creatinine clearance. Renal toxicity, as a rule, is insignificant or moderately pronounced and is reversible at usual doses of Cisplatinum.
From the electrolyte balance: hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia and hypophosphatemia. Hypomagnesemia and / or hypocalcemia can be manifested clinically by increased muscle sensitivity or seizures, tremor, carpopedic spasm (cramps in hands and feet) and / or tetany. Hyponatremia is usually caused by the syndrome of inappropriate production of antidiuretic hormone.
On the part of the digestive system: nausea and vomiting, which usually begin within the first hour of therapy and last for 24 hours or more, are found 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 1 time / day for 5 days.
Of the other frequently observed adverse events on the part of the digestive system, abdominal pain, diarrhea and constipation are noted.
On the part of the hemopoietic system: on the background of cisplatin therapy, myelosuppression often develops, but in most cases it is expressed only slightly or moderately, and when applied to conventional doses is reversible. The lowest levels of leukocytes and platelets are usually observed from the 18th to the 23rd day after administration; in most patients, these rates are restored by day 39. Anemia can also occur.
On the part of the hearing organ: one-sided or bilateral tinnitus, with or without loss of hearing, is noted in about 10% of patients receiving cisplatin, usually this side effect is reversible. It is established that the damage to the hearing organ is dose-dependent and cumulative, and 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.
From the side of the central nervous system and the peripheral nervous system: 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. Also, vegetative pyropathy, convulsions, slurred speech, loss of taste and memory loss can be noted. The development of Lermitt's symptom, myelopathy of the spine and autonomic neuropathy have been reported. Treatment with the drug should be discontinued at the first appearance of such symptoms.
Hypersensitivity: sometimes there are allergic reactions, manifested in the form of redness and swelling of the face, wheezing in the lungs, tachycardia and arterial hypotension. These reactions can occur within a few minutes after the onset of cisplatin administration. In rare cases, there may be hives and spotted-papular skin rashes.
From the side of the organ of vision: in rare cases, neuritis of the optic nerve, edema of the nipple of the optic nerve, cortical blindness are noted. There may also be a change in the perception of colors, especially in the yellow-blue part of the spectrum, the only change in the fundus may be irregular pigmentation of the retina in the area of ​​the yellow spot. These side effects are usually reversible and disappear after drug withdrawal.
Hepatotoxic effect: occasionally minor and transient increases in the level of ACT, ALT and bilirubin in serum can occur.
Other: disorders of the cardiovascular system (IHD, myocardial infarction, stroke, congestive heart failure, arrhythmias, orthostatic hypotension, thrombotic microangiopathy, cerebral arteritis), hyperuricemia, increased serum amylase level, insignificant alopecia, myalgia, fever, hiccough and the gum line of platinum. If the product gets under the skin, it is possible to develop phlebitis, inflammation of the subcutaneous fat and skin necrosis.
Cases of spermatogenesis and azoospermia are noted.
CONTRAINDICATIONS
- impaired renal function (serum creatinine level more than 115 Ојmol / l);
- oppression of bone marrow hematopoiesis;
- Pregnancy;
- lactation period;
- Hypersensitivity to cisplatin or other compounds containing platinum.
With caution - hearing loss, polyneuritis, acute infectious diseases, chicken pox (including recent or recent contact with the patient), shingles, gout, history of nephrolithiasis, radiation or chemotherapy in history.
PREGNANCY AND LACTATION
Contraindicated in pregnancy and lactation.
Women of childbearing age are advised to use contraceptives during cisplatin treatment.
Men receiving cisplatin therapy should use barrier methods of contraception.
APPLICATION FOR FUNCTIONS OF THE LIVER
On the part of the urinary system: nephrotoxicity is cumulative and is the main toxic factor limiting the dose of cisplatin. Renal lesions, which are accompanied by damage to the renal tubules, can first be detected at week 2 after the dose is administered and can be manifested by an increase in the level of creatinine, urea, uric acid in the blood serum and / or a decrease in creatinine clearance. Renal toxicity, as a rule, is insignificant or moderately pronounced and is reversible at usual doses of Cisplatinum.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Hepatotoxic effect: occasionally minor and transient increases in the level of ACT, ALT and bilirubin in serum can occur.
SPECIAL INSTRUCTIONS
The drug should be administered under the supervision of a doctor who has experience in the use of antitumor drugs.
Patients on the background of cisplatin treatment should periodically be examined by a neuropathologist. With obvious symptoms of toxic effects on the central nervous system, cisplatin 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, periodic blood testing, determination of the white blood cell count, platelets, hemoglobin, blood elements, renal and hepatic functional tests, as well as the level of electrolytes in blood serum are needed.
The remedy should not be administered until the serum creatinine content is reduced to 1.5 mg / 100 ml or less and / or blood urea nitrogen does not decrease to 25 mg / 100 ml or less, the platelet count in the blood will not be 100,000 / mm 3 , leukocytes - not less than 4000 / mm 3 .
When developing allergic reactions in the form of edema of the face, bronchospasm, tachycardia and hypotension, adrenaline, corticosteroids and antihygmic preparations should be used.
When using Cisplatin, all the usual instructions 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.
OVERDOSE
Symptoms: renal, hepatic, visual impairment (including retinal detachment) and hearing (deafness), severe myelosuppression, uncontrollable nausea and vomiting, and / or neuritis. In case of an overdose, a lethal outcome is possible.
Treatment: the antidote in case of an overdose of Chemotherapy is unknown. The effect, at least partial, is achieved only by hemodialysis if it is used within the first 3 hours after an overdose, as platinum quickly binds to plasma proteins. Symptomatic therapy is used to treat overdose symptoms.
DRUG INTERACTION
Simultaneous or sequential use of cisplatin with aminoglycoside antibiotics (gentamicin, kanamycin, streptomycin) or other potentially nephrotoxic drugs (eg, amphotericin B) can potentiate its nephrotoxic and ototoxic effects.
"Loop" diuretics (furosemide, clopamid, ethacrynic acid) can enhance the ototoxicity of cisplatin.
It is known that cisplatin can disrupt the excretion via the kidneys of bleomycin and swordrexate (possibly due to cisplatin-induced nephrotoxic action) and enhance 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 serum concentration of the latter may decrease to subtherapeutic values.
Cisplatin may cause an increase in the concentration of uric acid in the blood. Therefore, in patients who simultaneously take medicines for the treatment of 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.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
List A. Store in a place protected from light and inaccessible to children at a temperature of 15-25 В° C. Shelf life - 2 years.
