cisplatin (cis-platinum)
Platinol, Platinol-AQ

Available forms
Available by prescription only
Injection: 1 mg/ml (50-mg or 100-mg vials)

Indications and dosages
Indications and dosages may vary. Check current literature for recommended protocol.
 Adjunctive therapy in metastatic testicular cancer. Adults: 20 mg/m² I.V. daily for 5 days. Repeat q 3 weeks for three cycles or more. Usually used with bleomycin and vinblastine.
 Adjunctive therapy in metastatic ovarian cancer. Adults: 75 to 100 mg/m² I.V. Repeat q 4 weeks or 50 mg/m² I.V. q 3 weeks with concurrent doxorubicin hydrochloride therapy.
 Treatment of advanced bladder cancer. Adults: 50 to 70 mg/m² I.V. once q 3 to 4 weeks. Patients who have received other antineoplastics or radiation therapy should receive 50 mg/m² q 4 weeks.
 Head and neck cancer ◇. Adults: 80 to 120 mg/m² I.V. once q 3 weeks.
 Cervical cancer ◇. Adults: 50 mg/m² I.V. once q 3 weeks.
 Non-small-cell lung cancer ◇. Adults: 75 to 100 mg/m² I.V. once q 3 to 4 weeks.
 Brain tumor ◇. Children: 60 mg/m² I.V. for 2 days q 3 to 4 weeks.
 Osteogenic sarcoma or neuroblastoma ◇. Children: 90 mg/m² I.V. q 3 weeks.

Pharmacodynamics
Antineoplastic action: Cisplatin exerts its cytotoxic effects by binding with DNA and inhibiting DNA synthesis and, to a lesser extent, by inhibiting protein and RNA synthesis. Cisplatin also acts as a bifunctional alkylating agent, causing intrastrand and interstrand cross-links of DNA. Interstrand cross-linking appears to correlate well with the cytotoxicity of drug.

Pharmacokinetics
Absorption: Administered I.V.
Distribution: Distributed widely into tissues, with highest levels found in the kidneys, liver, and prostate. Drug can accumulate in body tissues, with drug being detected up to 6 months after the last dose. Cisplatin doesn’t readily cross the blood-brain barrier. Drug is extensively and irreversibly bound to plasma proteins and tissue proteins.
Metabolism: Metabolic fate is unclear.
Excretion: Excreted primarily unchanged in urine. In patients with normal renal function, the half-life of the initial elimination phase is 25 to 79 minutes and the terminal phase is 58 to 78 hours. The terminal half-life of total cisplatin is up to 10 days.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug or other platinum-containing compounds and in those with severe renal disease, hearing impairment, or myelosuppression.

Interactions
Drug-drug. Aminoglycosides: Potentiates cumulative nephrotoxicity. Don’t use aminoglycosides within 2 weeks of cisplatin, and monitor renal function test results carefully.
Aspirin: Increases risk of bleeding. Avoid use together.
Loop diuretics: Increases risk of ototoxicity. Closely monitor patient’s audiologic status.
Phenytoin: May decrease serum phenytoin level. Monitor phenytoin level.

Adverse reactions
CNS: peripheral neuritis, seizures, neuropathy.
EENT: tinnitus, hearing loss, ototoxicity, vestibular toxicity.
GI: nausea, vomiting (beginning 1 to 4 hours after dose and lasting 24 hours), loss of taste.
GU: PROLONGED AND SEVERE RENAL TOXICITY with repeated courses of therapy.
Hematologic: MYELOSUPPRESSION (nadirs in circulating platelet and WBC counts on days 18 to 23, with recovery by day 39).
Metabolic: hypomagnesemia, hypokalemia, hypocalcemia, hyponatremia, hypophosphatemia, hyperuricemia.
Other: anaphylactoid reaction.

Effects on lab test results
• May increase uric acid levels. May decrease magnesium, potassium, calcium, sodium, and phosphate levels.
• May decrease hemoglobin and WBC and platelet counts.

Overdose and treatment
Signs and symptoms of overdose include leukopenia, thrombocytopenia, nausea, and vomiting.
 Treatment is generally supportive and includes transfusion of blood components, antibiotics for possible infections, and antiemetics. Cisplatin can be removed by dialysis, but only within 3 hours after administration.

Special considerations
• Prehydration and mannitol diuresis may significantly reduce renal toxicity and ototoxicity.
• Review hematologic status and creatinine clearance before therapy.
• Reconstitute 10-mg vial with 10 ml and 50-mg vial with 50 ml of sterile water for injection to yield a concentration of 1 mg/ml. The drug may be diluted further in a saline solution for I.V. infusion.
• Don’t use aluminum needles for reconstitution or administration of cisplatin; a black precipitate may form. Use stainless steel needles.
• Drug is stable for 24 hours in normal saline solution at room temperature. Don’t refrigerate because precipitation may occur. Discard solution containing precipitate.
• Infusions are most stable in normal saline solution, half-normal saline solution, or 0.225% saline solution.
• Mannitol may be given as a 12.5-g I.V. bolus before starting cisplatin infusion. Follow by infusion of mannitol at up to 10 g/hour, as needed, to maintain urine output during cisplatin infusion and for 6 to 24 hours after infusion.
• I.V. sodium thiosulfate may be administered with cisplatin infusion to decrease risk of nephrotoxicity.
• Avoid contact with skin. If contact occurs, wash drug off immediately with soap and water.
• Hydrate patient, with P.O. fluids if possible, or with normal saline solution before giving drug. Maintain urine output of 100 ml/hour for 4 consecutive hours before and 24 hours after infusion.
• Nausea and vomiting may be severe and protracted (up to 24 hours). Antiemetics can be started 24 hours before therapy. Monitor fluid intake and output. Continue I.V. hydration until patient can tolerate adequate oral intake.
• High-dose metoclopramide (2 mg/kg I.V.) has been used to prevent and treat nausea and vomiting. Dexamethasone 10 to 20 mg has been administered I.V. with metoclopramide to alleviate nausea and vomiting. Many patients respond favorably to treatment with ondansetron (Zofran). Pretreatment with this 5-HT3 antagonist should begin 30 minutes before cisplatin therapy is started.
• Treat extravasation with local injections of a 1/6 M sodium thiosulfate solution (prepared by mixing 4 ml of sodium thiosulfate 10% and 6 ml of sterile water for injection).
• Anaphylactoid reaction usually responds to immediate treatment with epinephrine, corticosteroids, or antihistamines.
• Monitor CBC, platelet count, and renal function studies before first and subsequent doses. Don’t repeat dose unless platelet count is more than 100,000/mm³, WBC count is more than 4,000/mm³, serum creatinine level is less than 1.5 mg/dl, or BUN level is less than 25 mg/dl.
• Renal toxicity becomes more severe with repeated doses. Renal function must return to normal before next dose can be given.
• Monitor electrolyte levels extensively; aggressive supplementation is often required after a course of therapy.
Pregnant patients
• Caution woman of childbearing age not to become pregnant during therapy. Recommend that she obtain medical advice before becoming pregnant.
Breast-feeding patients
• It isn’t known if cisplatin appears in breast milk. However, because of risk to infant of serious adverse reactions, mutagenicity, and carcinogenicity, breast-feeding isn’t recommended during therapy.
Pediatric patients
• Pediatric dosages of cisplatin haven’t been fully established.
• Unlabeled uses of cisplatin include osteogenic sarcoma and neuroblastoma.
• Ototoxicity appears to be more severe in children.

Patient education
• Stress importance of adequate fluid intake and increase in urine output, to facilitate uric acid excretion.
• Tell patient to report tinnitus immediately, to prevent permanent hearing loss. Patient should have audiometric tests before first and subsequent courses of drug therapy.
• Advise patient to avoid exposure to people with infections.
• Inform patient to promptly report unusual bleeding or bruising.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use