Platidiam (Lyophilisate, Concentrate) Instructions for Use

ATC Code

L01XA01 (Cisplatin)

Active Substance

Cisplatin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, alkylating compound

Pharmacological Action

Antineoplastic agent containing platinum. The mechanism of action is similar to that of alkylating drugs and consists of disrupting DNA strand function and forming cross-links between them.

Pharmacokinetics

After rapid intravenous infusion (15 min – 1 h), the C_max of cisplatin is achieved immediately after administration. During intravenous infusion over 6-24 hours, the plasma concentration of cisplatin increases gradually, reaching a maximum by the end of the infusion. Binding to plasma proteins (as metabolites) is 90%.

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

Cisplatin poorly penetrates the blood-brain barrier. T_1/2 in the initial phase is 25-49 min; in the terminal phase with normal renal excretory function – 58-73 h, with anuria – up to 240 h. It is excreted by the kidneys, 27-43% within 5 days; platinum can be detected in tissues for up to 6 months after administration.

Indications

In monotherapy or as part of combination chemotherapy for the treatment of the following solid tumors: germ cell tumors in women and men, ovarian and testicular cancer, lung cancer, squamous cell carcinoma of the head and neck, bladder cancer, cervical cancer (including in combination with radiation therapy).

In addition, Cisplatin has antitumor activity in the following types of tumors: osteosarcoma, melanoma, neuroblastoma, esophageal cancer.

ICD codes

Dosage Regimen

Determine the dosage individually based on the specific malignancy, disease stage, patient performance status, and the chosen chemotherapy protocol.

Administer as a slow intravenous infusion. Do not administer as a rapid intravenous bolus. Pre-treatment hydration with 1-2 liters of fluid is mandatory to reduce nephrotoxicity.

For monotherapy in adults, a common dose is 50-70 mg/m² every 3-4 weeks. Alternatively, use 15-20 mg/m² daily for 5 days, repeating the cycle every 3-4 weeks.

For combination chemotherapy, adjust the dose according to the specific regimen. A typical dose is 75-100 mg/m² once every 3-4 weeks, often combined with other cytotoxic agents.

In pediatric patients, use doses and schedules established in pediatric oncology protocols, adjusted for body surface area.

Do not initiate a subsequent cycle until specific recovery criteria are met: serum creatinine must be below 1.5 mg/dL (or 130 µmol/L), blood urea nitrogen (BUN) below 25 mg/dL, and platelet count above 100,000/µL and absolute neutrophil count (ANC) above 1,500/µL.

Reduce the dose by 25-50% for patients with mild to moderate renal impairment. Contraindicated in patients with severe baseline renal impairment or pre-existing hearing deficit.

Monitor renal function (serum creatinine, BUN, creatinine clearance), audiometry, complete blood count (CBC), and serum electrolytes (sodium, potassium, magnesium, calcium) before each dose and regularly during treatment.

Aggressively manage nausea and vomiting with prophylactic intravenous antiemetics. Maintain adequate hydration and diuresis during and after infusion to minimize renal damage.

Inspect the injection site for signs of extravasation. Discontinue the infusion immediately and manage appropriately if extravasation occurs.

Adverse Reactions

From the nervous system rarely – peripheral neuropathy, seizures, leukoencephalopathy (including posterior reversible leukoencephalopathy syndrome); frequency unknown – stroke (hemorrhagic, ischemic), loss of taste, Lhermitte’s sign (an electric shock-like pain radiating down the arms or trunk upon neck flexion), myelopathy, autonomic neuropathy.

From the organ of vision: frequency unknown – blurred vision, change in color perception, especially in the yellow-blue part of the spectrum, acquired color blindness, optic neuritis, optic disc edema, cortical blindness, irregular retinal pigmentation in the macular area.

From the organ of hearing and labyrinthine disorders: infrequently – unilateral or bilateral tinnitus, hearing loss, especially in the high-frequency range (4000-8000 Hz); frequency unknown – deafness.

From the digestive system rarely – inflammation of the oral mucosa; frequency unknown – nausea, hiccups, vomiting, diarrhea, anorexia.

From the cardiovascular system often – arrhythmia, bradycardia, tachycardia; rarely – myocardial infarction; very rarely – cardiac arrest; frequency unknown – thrombotic microangiopathy (hemolytic-uremic syndrome), cerebral arteritis, Raynaud’s phenomenon, pulmonary embolism.

From the reproductive system infrequently – impaired spermatogenesis.

From the urinary system: frequency 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 creatinine clearance.

From the hematopoietic system very often – thrombocytopenia, leukopenia, anemia, myelosuppression (after the use of cisplatin in high doses, severe bone marrow suppression is possible, including agranulocytosis and/or aplastic anemia); rarely – acute leukemia; frequency unknown – Coombs-positive hemolytic anemia.

From the immune system: infrequently – anaphylactoid reactions (redness and swelling of the face, bronchospasm, wheezing in the lungs, tachycardia, decreased blood pressure); very rarely – urticaria, maculopapular skin rash.

Infectious diseases often – sepsis; frequency unknown – infection (including fatal).

From laboratory parameters: very often – hyponatremia (may be due to the syndrome of inappropriate antidiuretic hormone secretion); infrequently – hypomagnesemia; rarely – hypercholesterolemia; very rarely – increased serum iron levels; frequency unknown – increased serum amylase activity, increased activity of liver enzymes and plasma bilirubin concentration, hypocalcemia, hypokalemia, hypophosphatemia, hyperuricemia.

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

Contraindications

Hypersensitivity to cisplatin or other platinum-containing compounds, impaired renal function (serum creatinine level more than 115 µmol/l); severe bone marrow suppression, hearing impairment; pregnancy, breastfeeding period.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding. If it is necessary to use during lactation, the issue of discontinuing breastfeeding should be decided.

Women of childbearing potential should use reliable methods of contraception during therapy with cisplatin.

In experimental studies, the teratogenic and embryotoxic effects of cisplatin have been established.

Use in Renal Impairment

Contraindicated in severe renal impairment (serum creatinine level more than 115 µmol/l).

Pediatric Use

Can be used in children according to indications in doses, regimens and dosage forms recommended according to age.

Special Precautions

The use of cisplatin should be carried out under the supervision of a qualified physician experienced in the use of anticancer chemotherapeutic drugs.

Men and women of childbearing potential should use reliable methods of contraception during treatment and for 6 months after the end of cisplatin therapy. Since irreversible infertility may develop during treatment, men should consider the possibility of cryopreservation of sperm in a bank before starting treatment.

During treatment with cisplatin, periodic examination by a neurologist is necessary. 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 hearing organ damage appear or clinical hearing impairment is detected, repeated audiometry is indicated. Ototoxicity may be more pronounced in children. In case of clinically significant hearing impairment, dose adjustment or discontinuation of therapy may be required.

Before, during, and after treatment with cisplatin, weekly monitoring of clinical blood count, renal and liver function tests, and serum electrolyte concentrations is necessary.

Cisplatin should not be re-administered until the serum creatinine concentration decreases to values <130 µmol/l, urea <250 mg/l; platelet count in the blood becomes >100×10%, leukocytes >4.0×10%. The lowest leukocyte and platelet counts in the blood are usually observed from day 18 to day 23 after cisplatin administration. In most patients, these indicators recover by day 39. After cisplatin administration, nausea, vomiting, and diarrhea often occur, which in most patients resolve within 24 hours. Mild nausea and lack of appetite may persist for 7 days after treatment. Prophylactic use of antiemetic drugs may reduce or prevent adverse reactions. In case of intense nausea and vomiting, antiemetic therapy and, if necessary, fluid replacement are required. If allergic reactions develop in the form of facial swelling, bronchospasm, tachycardia and decreased blood pressure, epinephrine, corticosteroids and antihistamines should be used.

A diuresis level of 100 ml/h and above helps reduce nephrotoxicity during treatment with cisplatin. Rehydration (colloidal solutions, 2 l IV) followed by hydration of 2500 ml/m for 24 hours is recommended. If impossible – forced diuresis (using, for example, mannitol).

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

Administration of live attenuated yellow fever vaccine is contraindicated during the use of cisplatin due to the possible risk of developing fatal systemic reactions to the vaccine. If necessary, an inactivated vaccine should be used.

Live viral vaccines are recommended to be used no earlier than 3 months after the end of cisplatin treatment.

Effect on the ability to drive vehicles and mechanisms

During the treatment period, patients should avoid driving vehicles and other activities requiring high concentration and speed of psychomotor reactions.

Drug Interactions

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

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

With simultaneous use, Cisplatin may impair the renal excretion of bleomycin and methotrexate (possibly due to cisplatin-induced nephrotoxicity) and enhance the toxicity of these drugs.

With simultaneous use, loop diuretics (furosemide, clopamide, ethacrynic acid), aminoglycosides, ifosfamide may enhance the ototoxicity of cisplatin.

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

In patients receiving Cisplatin and anticonvulsants, the serum concentration of the latter may decrease to subtherapeutic values. Cisplatin may reduce the absorption of phenytoin and thus reduce the effectiveness of antiepileptic therapy. It is contraindicated to start phenytoin treatment for the first time during the period of cisplatin use.

Cisplatin may cause an increase in the concentration of uric acid in the blood. 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 dose of these drugs to control hyperuricemia and gout attacks.

When cisplatin interacts with aluminum, a precipitate is formed.

If paclitaxel is administered after cisplatin, the clearance of paclitaxel may decrease by up to 33% and neurotoxicity may increase.

Simultaneous use of cisplatin and other drugs that suppress the function of the red bone marrow, or radiation therapy, enhances the myelosuppressive effect. The interaction of cisplatin and cyclosporine enhances the immunosuppressive effect and may lead to the development of lymphoproliferative diseases.

Cisplatin in combination with bleomycin and vinblastine may contribute to the development of Raynaud’s phenomenon.

During combination therapy with cisplatin, bleomycin and etoposide, a decrease in blood lithium concentration was recorded in several cases. Therefore, it is recommended to monitor the lithium concentration during treatment.

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

Simultaneous use of antihistamines, phenothiazines, thioxanthenes may mask the symptoms of ototoxicity (such as dizziness, ringing/tinnitus).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.