Cisplatin-Teva (Concentrate) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Pharmachemie, B.V. (Netherlands)

ATC Code

L01XA01 (Cisplatin)

Active Substance

Cisplatin (Rec.INN registered by WHO)

Dosage Forms

	Cisplatin-Teva	Concentrate for solution for infusion 0.5 mg/1 ml: 50 ml or 100 ml vial
		Concentrate for solution for infusion 1 mg/1 ml: 50 ml or 100 ml vial
		Lyophilisate for solution for injection 10 mg: 1 or 49 vials
		Lyophilisate for solution for injection 50 mg: 1 or 25 vials
		Solution for injection 10 mg/10 ml: 1 vial
		Solution for injection 10 mg/20 ml: 1, 49 or 60 vials
		Solution for injection 25 mg/25 ml: 1 vial
		Solution for injection 25 mg/50 ml: 1 or 36 vials
		Solution for injection 50 mg/50 ml: 1 vial
		Solution for injection 100 mg/200 ml: 1 or 16 vials

Dosage Form, Packaging, and Composition

Solution for injection clear, light yellow in color.

Excipients : sodium chloride, hydrochloric acid or sodium hydroxide (for pH adjustment), water for injections.

100 ml – dark glass vials (1) – cardboard boxes.
100 ml – dark glass vials (25) – cardboard boxes.

Lyophilisate for solution for injection as a light yellow powder.

Excipients : sodium chloride, mannitol.

Dark glass vials (1) – cardboard boxes.
Dark glass vials (49) – cardboard boxes.

Lyophilisate for solution for injection as a light yellow powder.

Excipients : sodium chloride, mannitol.

Dark glass vials (1) – cardboard boxes.
Dark glass vials (25) – cardboard boxes.

Solution for injection clear, light yellow in color.

Excipients : sodium chloride, hydrochloric acid or sodium hydroxide (for pH adjustment), water for injections.

10 ml – dark glass vials (1) – cardboard boxes.

Solution for injection clear, light yellow in color.

Excipients : sodium chloride, hydrochloric acid or sodium hydroxide (for pH adjustment), water for injections.

20 ml – dark glass vials (1) – cardboard boxes.
20 ml – dark glass vials (49) – cardboard boxes.
20 ml – dark glass vials (60) – cardboard boxes.

Solution for injection clear, light yellow in color.

Excipients : sodium chloride, hydrochloric acid or sodium hydroxide (for pH adjustment), water for injections.

200 ml – dark glass vials (1) – cardboard boxes.
200 ml – dark glass vials (16) – cardboard boxes.

Solution for injection clear, light yellow in color.

Excipients : sodium chloride, hydrochloric acid or sodium hydroxide (for pH adjustment), water for injections.

25 ml – dark glass vials (1) – cardboard boxes.

Solution for injection clear, light yellow in color.

Excipients : sodium chloride, hydrochloric acid or sodium hydroxide (for pH adjustment), water for injections.

50 ml – dark glass vials (1) – cardboard boxes.
50 ml – dark glass vials (36) – cardboard boxes.

Solution for injection clear, light yellow in color.

Excipients : sodium chloride, hydrochloric acid or sodium hydroxide (for pH adjustment), water for injections.

100 ml – dark glass vials (1) – cardboard boxes.
100 ml – dark glass vials (25) – cardboard boxes.
100 ml – dark glass vials (30) – cardboard boxes.

Solution for injection clear, light yellow in color.

Excipients : sodium chloride, hydrochloric acid or sodium hydroxide (for pH adjustment), water for injections.

50 ml – dark glass vials (1) – cardboard boxes.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, alkylating compound

Pharmacological Action

Cisplatin (cis-diamminedichloroplatinum) is an antineoplastic drug containing the heavy metal platinum.

Cisplatin has properties similar to those of bifunctional alkylating agents, forming interstrand and intrastrand cross-links in DNA, thereby disrupting its functions, which leads to cell death; the drug does not have cycle or phase specificity. It has immunosuppressive and radiosensitizing properties.

Pharmacokinetics

After rapid intravenous infusion (15 minutes – 1 hour), the appearance of cisplatin in the blood plasma and its peak concentration is determined immediately after administration. With intravenous infusion over 6-24 hours, the concentration of the drug in the plasma increases gradually during the infusion, reaching a maximum by the end of the administration.

Cisplatin is characterized by extensive distribution in the body’s biological fluids and tissues; the highest concentrations are achieved in the kidneys, liver, and prostate gland. Platinum released from cisplatin is rapidly bound to tissue and plasma proteins. Two hours after the end of a three-hour infusion, 90% of the platinum in the plasma is protein-bound. Cisplatin has the ability to accumulate in the body and be detected in some tissues for up to six months after the last dose of the drug is administered. The biotransformation of cisplatin occurs through rapid non-enzymatic conversion to form inactive metabolites. Only unbound cisplatin or its platinum-containing metabolites have cytotoxic activity.

The half-life of total platinum is highly variable individually and ranges from 2-72 hours in healthy individuals, and 1-240 hours in severe renal failure. Cisplatin is excreted primarily in the urine. Cisplatin can be removed from the systemic circulation by dialysis, but only during the first 3 hours after drug administration.

Indications

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

• Germ cell tumors in women and men;
• Ovarian and testicular cancer;
• Lung cancer;
• Head and neck tumors

In addition, Cisplatin has antineoplastic activity in the following types of tumors

• Cervical cancer;
• Bladder cancer;
• Osteosarcomas;
• Melanoma;
• Neuroblastoma;
• Esophageal cancer.

ICD codes

Dosage Regimen

Cisplatin can be used both as monotherapy and in combination with other cytostatics in various doses depending on the therapy regimen. When individually selecting the dose, one should be guided by data from specialized literature.

Cisplatin is administered intravenously or, when indicated (intraperitoneal tumors), into the abdominal cavity.

Cisplatin as monotherapy or in combination with other chemotherapeutic agents is administered at a dose of 50-100 mg/m² as an intravenous infusion every 3-4 weeks or 15-20 mg/m² intravenously by drip daily for 5 days every 3-4 weeks.

To stimulate diuresis (up to 100 ml/h) and to maximally reduce the nephrotoxic effect of the drug, hydration is performed. Before the administration of Cisplatin, up to 2 liters of fluid (0.9% sodium chloride solution or 5% dextrose solution) are administered intravenously by drip. After the end of the infusion, an additional 400 ml of 0.9% sodium chloride solution or 5% dextrose solution is administered. Abundant fluid intake and maintenance of diuresis must be observed for 24 hours. If intensive hydration to maintain adequate diuresis is insufficient, an osmotic diuretic (e.g., mannitol) can be administered.

Cisplatin is administered intravenously by drip at a rate not exceeding 1 mg/min. Prolonged infusions are carried out over 6-8-24 hours, provided there is sufficient diuresis before and during the administration of the drug.

Cisplatin is diluted in 0.9% sodium chloride solution to a concentration of 1 mg/ml. The Cisplatin lyophilisate should first be dissolved in 10-25 ml of water for injections.

Do not use dextrose (glucose) solutions to dilute Cisplatin.

Note: since aluminum reacts with cisplatin and inactivates it, and also causes the formation of a precipitate, it is very important not to use needles and other equipment containing aluminum when preparing and administering Cisplatin.

Adverse Reactions

Urinary system: nephrotoxicity (is cumulative and is the main toxic factor limiting the dose of Cisplatin). Kidney damage, which is accompanied by damage to the renal tubules, may be first detected in the second week after dose administration and is manifested by an increase in serum creatinine, urea, uric acid levels and/or a decrease in creatinine clearance. Renal failure is usually mild or moderate and is reversible at conventional doses of Cisplatin.

Digestive system: nausea and vomiting, which usually begin within the first hour of therapy and continue for 24 hours or more, occur in 65% of patients. These side effects are only partially relieved by standard antiemetic drugs. The severity of these symptoms can be reduced by dividing the total dose calculated for the therapy cycle into smaller doses administered once daily for five days.

Other frequently observed adverse events from the gastrointestinal tract include abdominal pain, diarrhea, and constipation. Slight and transient increases in serum AST and ALT levels may occasionally occur.

Hematopoietic system: frequent – myelosuppression, (in most cases it is mild or moderate and is reversible when conventional doses are used). The lowest levels of leukocytes and platelets are usually detected at about 2 weeks; their baseline level is restored in most patients within 4 weeks. Anemia may also be observed.

Hearing system: unilateral or bilateral tinnitus, with or without hearing loss, is noted in approximately 10% of patients; usually this side effect is reversible. It has been established that damage to the hearing organ is dose-dependent and cumulative, and this side effect is more often observed in very young or elderly patients. There are reports of the drug’s toxic effect on the vestibular apparatus.

CNS and peripheral nervous system: peripheral neuropathies occur infrequently. They are usually sensory in nature (e.g., paresthesias of the upper and lower extremities), but motor disturbances (decreased reflexes and weakness in the lower extremities) may also occur. Autonomic neuropathy, seizures, slurred speech, loss of taste, and memory loss may also be noted. The development of Lhermitte’s syndrome (spinal myelopathy and autonomic neuropathy) has been reported in the literature. Treatment should be discontinued at the first appearance of these symptoms.

Immune system: allergic reactions are sometimes noted, manifested as redness and swelling of the face, wheezing in the lungs, tachycardia, and decreased blood pressure. These reactions can occur within a few minutes after the start of cisplatin administration. In rare cases, urticaria and maculopapular skin rash may be observed.

Visual system: in rare cases, optic neuritis, optic disc edema, and cortical blindness are noted. Changes in color perception, especially in the yellow-blue part of the spectrum, may also be observed. The only change in the fundus may be irregular pigmentation of the retina in the macular area.

These side effects are usually reversible and disappear after discontinuation of the drug.

Electrolyte balance disorders: hypomagnesemia, hypocalcemia, and hypokalemia. Hypomagnesemia and/or hypocalcemia may manifest clinically as increased muscle sensitivity or cramps, tremor, carpopedal spasm (cramps in the hands and feet), and/or tetany. Hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion is possible.

Local reactions: if the drug gets under the skin, phlebitis, cellulitis, and skin necrosis may develop.

Other: disorders of the cardiovascular system (coronary artery disease, congestive heart failure, arrhythmias, orthostatic hypotension, thrombotic microangiopathy, etc.), hyperuricemia, slight alopecia, myalgia, fever, and gingival platinum line. Cases of impaired spermatogenesis and azoospermia have been noted.

Contraindications

• Individual intolerance to cisplatin or other compounds containing platinum;
• Impaired renal function (serum creatinine level more than 115 µmol/liter);
• Bone marrow suppression;
• Heart failure;
• Pregnancy and lactation;
• Generalized infections.

Use in Pregnancy and Lactation

It is contraindicated to take the drug during pregnancy and lactation.

Use in Renal Impairment

It is prohibited to take in case of impaired renal function (serum creatinine level more than 115 µmol/liter).

Special Precautions

Administration of Cisplatin should be carried out under the supervision of a physician experienced in the use of antineoplastic drugs.

Men and women of reproductive age during treatment with Cisplatin should use reliable methods of contraception.

Patients undergoing treatment with Cisplatin should be periodically examined by a neurologist. If obvious symptoms of toxic effects on the central nervous system appear, Cisplatin therapy should be discontinued.

Audiometry should be performed before starting therapy, and in cases where symptoms of damage to the hearing organ appear or clinical hearing impairment is detected, repeat audiometry is indicated. In case of clinically significant hearing impairment, dose adjustment or discontinuation of therapy may be required.

During treatment with Cisplatin, periodic blood tests, determination of leukocyte, platelet, hemoglobin, blood cell counts, renal and liver function tests, as well as serum electrolyte levels are necessary.

When using Cisplatin, all standard instructions adopted for the use of cytotoxic drugs must be followed.

If the drug gets into the eyes, they should be immediately rinsed with plenty of water or a 0.9% sodium chloride solution. If the drug gets on the skin, the contact area should be immediately rinsed with plenty of water. If the drug is inhaled or enters the mouth, a doctor should be consulted immediately.

Overdose

The main expected complications of an overdose are impaired renal function, liver function, vision (including retinal detachment) and hearing (deafness), pronounced myelosuppression, intractable vomiting and/or severe neuritis. A fatal outcome is possible in case of an overdose.

There is no known antidote for cisplatin. Treatment is symptomatic. A partial effect may be achieved with hemodialysis performed within the first three hours after an overdose.

Drug Interactions

Simultaneous or sequential use of cisplatin with aminoglycoside antibiotics (gentamicin, kanamycin, streptomycin) or with other potentially nephrotoxic drugs (e.g., amphotericin B) may potentiate its nephrotoxic and ototoxic effects.

“Loop” diuretics (furosemide, clopamide, ethacrynic acid) may enhance the ototoxicity of cisplatin.

Cisplatin is known to impair the renal excretion of bleomycin and methotrexate (possibly due to cisplatin-induced nephrotoxicity) and enhance the toxicity of these drugs.

In patients receiving Cisplatin and anticonvulsant drugs, the serum concentration of the latter may decrease to subtherapeutic levels.

Cisplatin may cause an increase in blood uric acid concentration. Therefore, in patients who are simultaneously taking medications 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.

Storage Conditions

The drug should be stored at a temperature not exceeding 25°C (77°F) in a place protected from light and out of the reach of children.

Shelf Life

Solution 0.5 mg/1 ml – 2 years.

Solution 1 mg/1 ml – 3 years.

Lyophilisate – 3 years.

The drug should not be used after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.