Cisplatin PhaRes

Approved Indications:

• Testicular Cancer: Metastatic testicular germ cell tumors, in combination with other chemotherapeutic agents.
• Ovarian Cancer: Advanced-stage ovarian epithelial carcinoma (as first-line or palliative therapy).
• Bladder Cancer: Advanced transitional cell carcinoma of the bladder.
• Head and Neck Cancer: Locally advanced squamous cell carcinoma, used concurrently with radiotherapy.
• Non-Small Cell Lung Cancer (NSCLC): In combination regimens for stage III or IV disease.
• Small Cell Lung Cancer (SCLC): In combination regimens.
• Cervical Cancer: Advanced stages (IB2 to IVA) with concurrent radiotherapy.

Clinically Accepted Off-Label Uses:

• Esophageal Cancer (with fluorouracil/radiation),
• Gastric Cancer,
• Pancreatic Cancer,
• Biliary Tract Cancer,
• Mesothelioma,
• Thymoma,
• Anal Carcinoma,
• Triple-Negative Breast Cancer, in various combinations.

Adults (general):

• Monotherapy or in combination: 50–100 mg/m² IV every 3–4 weeks.
• Typical combination regimen:
• Testicular cancer: 20 mg/m²/day IV on days 1–5 (with bleomycin and etoposide).
• Ovarian cancer: 75–100 mg/m² IV per cycle every 3–4 weeks.
• Bladder cancer: 50–70 mg/m² IV every 3–4 weeks.

Pediatrics:

• Common regimens involve 75–100 mg/m² IV every 3–4 weeks depending on malignancy type and protocol.

Special Populations:

• Renal impairment: Requires dose reduction. Avoid if CrCl < 30 mL/min unless benefits outweigh risks.
• Hepatic impairment: No specific adjustments, but caution advised in severe dysfunction.
• Elderly: Start at the lower end of dosing range; monitor renal and marrow function closely.

Administration Instructions:

• Route: IV infusion only.
• Administer in 1–2 liters of 0.9% saline with mannitol or furosemide to ensure adequate hydration.
• Infuse over 6–8 hours to reduce nephrotoxicity.
• Avoid aluminum-containing needles or IV sets.

Cisplatin is a platinum-based antineoplastic agent that forms highly reactive platinum complexes. Inside the cell, it undergoes aquation to form positively charged species that bind to DNA at the N7 position of guanine and adenine bases, causing DNA cross-linking, particularly intrastrand and interstrand adducts. These adducts disrupt DNA replication and transcription, ultimately triggering apoptotic cell death. Its cytotoxic effects are especially prominent in rapidly dividing tumor cells.

• Absorption: Not applicable (IV use only).
• Distribution: Rapidly distributes into tissues; protein binding ~90%. Highest levels in kidneys, liver, and intestines.
• Metabolism: Non-enzymatic activation via hydrolysis; no significant hepatic CYP450 involvement.
• Half-life: Biphasic elimination; initial half-life ~30–60 minutes, terminal half-life ~5 days due to tissue binding.
• Excretion: Primarily via kidneys—~90% excreted in urine within 5 days. Clearance reduced in renal impairment.
• Crosses the blood–brain barrier poorly.

• Pregnancy: Category D (positive evidence of fetal risk). Cisplatin is teratogenic and embryotoxic. Use only if life-threatening condition warrants.
• Lactation: Excreted in breast milk. Breastfeeding is contraindicated during treatment and for at least 2 weeks after the last dose.

• Primary Class: Antineoplastic Agent
• Subclass: Platinum-containing Alkylating-Like Agent

• Known hypersensitivity to cisplatin or other platinum compounds
• Preexisting renal impairment (severe) or hearing impairment
• Myelosuppression or severe bone marrow depression
• Pregnancy and breastfeeding
• Concomitant use of nephrotoxic or ototoxic drugs (relative contraindication)

• Nephrotoxicity: Dose-limiting toxicity; requires aggressive IV hydration and monitoring.
• Ototoxicity: Irreversible bilateral hearing loss (especially in children); audiometric testing recommended.
• Myelosuppression: Monitor CBC; may require dose delays.
• Neurotoxicity: Peripheral neuropathy, paresthesia, and loss of proprioception.
• Electrolyte disturbances: Hypomagnesemia, hypokalemia, and hypocalcemia.
• Anaphylaxis: May occur during or after infusion; immediate discontinuation and emergency treatment needed.
• Secondary malignancies: Long-term risk of leukemia.
• Use only under experienced oncologic supervision with supportive measures in place.

Common:

• Renal: Increased creatinine, decreased GFR
• GI: Nausea, vomiting (severe and early-onset), anorexia
• Hematologic: Anemia, leukopenia, thrombocytopenia
• Neurologic: Peripheral neuropathy, tinnitus, hearing loss
• Electrolytes: Hypomagnesemia, hypokalemia, hypocalcemia
• General: Fatigue, malaise, weight loss

Serious / Rare:

• Ototoxicity (irreversible)
• Nephrotoxicity requiring dialysis
• Anaphylactic shock
• Hemolytic-uremic syndrome
• Optic neuritis, seizures
• Myocardial infarction (rare)

Timing & Severity:

• Vomiting begins within hours of administration; other toxicities may occur with repeated cycles.

• Nephrotoxic drugs (e.g., aminoglycosides, amphotericin B): Potentiates renal toxicity
• Ototoxic drugs (e.g., loop diuretics): Increased risk of hearing loss
• Live vaccines: Immunosuppression increases infection risk
• Phenytoin: Reduced serum levels with long-term use
• Taxanes (e.g., paclitaxel): Administer taxanes before cisplatin to reduce myelosuppression
• No CYP450 metabolism involvement; drug interactions primarily pharmacodynamic or renal elimination-based

• NCCN Guidelines (2024): Continues to be first-line therapy for testicular, ovarian, bladder, and lung cancers.
• ASCO 2023: Emphasis on minimizing cumulative dose in pediatric populations to reduce long-term ototoxicity and nephropathy.
• WHO Model List (2023): Retained as essential cancer medication.
• New recommendations: Audiometry and renal function monitoring before and during treatment in all patients.

• Temperature: Store at 15°C to 25°C (room temperature). Do not refrigerate or freeze.
• Light: Protect from light; keep vials in original outer carton.
• Reconstitution/Handling:
• Use glass containers (not aluminum) for administration.
• Reconstituted solution should be used immediately or within 6–8 hours at room temperature.
• Precautions: Cytotoxic agent—use gloves, mask, and laminar flow cabinet when handling.