Cisplatin

CLINICAL USE

Antineoplastic agent:Testicular and metastatic ovarian tumours Cervical tumours Lung carcinoma Bladder cancer

DOSE IN NORMAL RENAL FUNCTION

Single agent therapy: 50–120 mg/m 2 as a single dose every 3–4 weeks or 15–20 mg/m2 daily for 5 days every 3–4 weeksCombination therapy: 20 mg/m 2 and upward, every 3–4 weeks

PHARMACOKINETICS

Molecular weight :300

%Protein binding :>90

%Excreted unchanged in urine : 27–45

Volume of distribution (L/kg) :0.5

half-life – normal/ESRD (hrs) :0.3–1 (terminal T½ 2–5 days)/–

DOSE IN RENAL IMPAIRMENT

GFR (mL/MIN)

20 to 50 : See ‘Other Information’

10 to 20 : See ‘Other Information’

<10 : See ‘Other Information’

DOSE IN PATIENTS UNDERGOING RENAL REPLACEMENT THERAPIES

CAPD :Unknown dialysability. Dose as in GFR <10 mL/min

HD :Not dialysed. Dose as in GFR <10 mL/min

HDF/high flux :Dialysed. Dose as in GFR

<10 : mL/min

CAV/VVHD :Unknown dialysability. Dose as in GFR 10 to 20 mL/min

IMPORTANT DRUG INTERACTIONS

Potentially hazardous interactions with other drugsAminoglycosides: increased risk of nephrotoxicity and possibly ototoxicity with aminoglycosides, capreomycin, polymyxins or vancomycinAntipsychotics: avoid concomitant use with clozapine, increased risk of agranulocytosisCytotoxics: increased pulmonary toxicity with bleomycin and methotrexate

ADMINISTRATION

Reconstition

Water for injection to form a 1 mg/mL solution

Route

IV infusion

Rate of Administration

Over 6–8 hours

Comments

Pre-treatment hydration, with 1–2 litres of fluid infused for 8–12 hours prior to cisplatin dose, is recommended in order to initiate diuresis. The drug is then well diluted in 2 litres sodium chloride 0.9% or glucose-saline solutions to ensure hydration and maintain urine output. Adequate hydration must be maintained during the following 24 hours, with potassium and magnesium supplementation given as necessaryCisplatin solutions react with aluminium – do not use equipment containing aluminium

OTHER INFORMATION

Dose modification depends not only on the degree of renal dysfunction, but also on the intended dose and the therapeutic end-point. In general, any patient with a GFR<70 mL/min should be highlighted as ‘at risk’ from cisplatin renal toxicity. Kintzel PE, Dorr RT. Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function. Cancer Treat Rev. 1995; 21: 33–64GFR (mL/min) Dose<60 100%50–60 75%40–50 50%<40 AvoidBennett <50 100%10–50 75%

<10 : and

HD : 50%An alternative approach is to consider changing to carboplatin, which can be dosed specifically according to GFRNon-enzymatically transformed into multiple metabolites. Good uptake of cisplatin in the kidneys, liver and intestine. Distributes into third spaces such as ascites and pleural fluid. Elimination of intact drug and metabolites is via the urine. In the first 24 hrs 20–80% is excretedOtotoxicity, nephrotoxicity and myelosuppression reported. Check hearing, renal function and haematology before treatment and before each subsequent courseToxicity is also associated with cumulative doses of cisplatin Hypomagnesaemia, hypocalcaemia and hyperuricaemia observedThe addition of mannitol to the infusion may aid diuresis and protect the kidneys.

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