Pharmacology.
Cisplatin is a planar coordinate dichlorodiamino compound of platinum in the +II valence state. It is aquated in vivo to a positively charged species that can alkylate nucleophilic sites in DNA such as purine and pyrimidine bases. Its action is cell-cycle phase nonspecific.
Administration and Adult Dosage.
IV bolus or continuous infusion (usually with aggressive hydration) single doses of up to 120 mg/m2 have been used.
IV in the Einhorn testicular cancer regimen 20 mg/m2/day for 5 days.
Special Populations.
Pediatric Dosage.
IV 10-20 mg/m2/day for 4-5 days, repeat q 3-4 weeks.
IV maximum single dose is 100 mg/m2 given q 2-3 weeks.
Geriatric Dosage.
Same as adult dosage but adjust for age-related reduction in renal function.
Other Conditions.
Reduce dosage in renal impairment; specific dosage reduction guidelines have not been established.
Dosage Forms.
Inj 50, 100 mg.
Patient Instructions.
Be prepared for severe nausea and vomiting after drug administration.
Pharmacokinetics.
Serum Levels.
In vitro cell culture data suggest cytotoxicity at levels of 50 mg/L for 1 hr or 5 mg/L for 8 hr.
Fate.
Peak serum levels of free platinum after a 100 mg/m2 bolus are about 3.4 mg/L when given with mannitol (12.5 g) and 2.7 mg/L without mannitol. Over 90% of platinum is protein bound to RBCs, albumin, and prealbumin. It is freely distributed to most organs including kidneys, liver, skin, and lungs and has minimal accumulation in CSF only after repeated doses. Cumulative 24-hr urinary excretion of platinum is 20% with mannitol, 40% without.
t1⁄₂.
(Free platinum) 59 min (with mannitol); 48 min (without mannitol). Terminal half-life is 58-73 hr, probably reflecting slow release of protein-bound drug.
Adverse Reactions.
Emetic potential is high. Nausea and vomiting are severe and often prolonged (days) and can be managed with aggressive prophylaxis using a serotonin 5HT3-antagonist, butyrophenone (eg, droperidol), metoclopramide, a high-dose glucocorticoid, or a combination. Primary toxicity is dose-related nephrotoxicity, especially proximal tubular impairment. Ototoxicity and elevated hepatic enzymes occur frequently; total dose-related hypomagnesemia and severe cumulative peripheral neuropathy occur. Slight leukopenia, thrombocytopenia, and frequent anemia also occur. Epoetin alfa is useful in preventing severe anemia caused by cisplatin. Rare toxicities include transient cortical dysfunction (blindness) and hypersensitivity (including anaphylaxis).
Contraindications.
Renal insufficiency (Crs >1.5-2 mg/dL or Clcr <60 mL/min); myelosuppression; hearing impairment; previous anaphylaxis. However, some patients with prior anaphylaxis have been successfully retreated with cisplatin and concomitant antihistamine, epinephrine, and glucocorticoid.
Precautions.
Use with caution in renal impairment and with other nephrotoxic drugs, especially aminoglycosides. Assure adequate hydration before administration. Both furosemide and mannitol are used to decrease platinum nephrotoxicity, although each apparently retards free platinum elimination.
Drug Interactions.
Cisplatin can enhance nephrotoxicity and ototoxicity of the aminoglycosides. Use with ifosfamide can increase nephrotoxicity and potassium and magnesium loss, especially in children. Furosemide ototoxicity might be increased by cisplatin. Cisplatin can increase methotrexate serum levels and its toxicity. Cisplatin can decrease absorption and serum levels of valproic acid. Phenytoin serum levels can be decreased after cisplatin-containing combination regimens.
Parameters to Monitor.
Assess renal function before each dose (eg, serial BUN or Crs) and serum magnesium levels periodically.
Notes.
Reconstitute with sterile water; it may then be mixed in saline-containing solutions. It is stable for 24 hr in mannitol. Do not expose solution to metals (eg, metal drippers or cannulae) because platinum can rapidly plate onto these surfaces.
Hydrate the patient with at least 1 L of a saline-containing solution with 20 mEq of KCl and 3 g of MgSO4/L.
