Cisplatin

Uses

Cisplatin is used for first line therapy for lung cancer, head & neck cancer and for the treatment of advanced and metastatic ovarian carcinoma, bladder carcinoma and testis carcinoma.

Cisplatin is also used to associated treatment for these conditions: Advanced Pancreatic Cancer, Breast Cancer, Cervical Cancers, Esophageal Cancers, Head and Neck Carcinoma, Hepatobiliary Cancers, Hepatoblastomas, Malignant Neoplasm of Stomach, Medulloblastomas, Metastatic Melanoma, Multiple Myeloma (MM), Neuroblastomas, Non-Small Cell Lung Carcinoma (NSCLC), Ovarian Cancer Metastatic, Pleural Mesotheliomas, Primary Central Nervous System Lymphoma (PCNSL), Recurrent Endometrial Cancer, Refractory Hodgkin Lymphoma, Sarcoma, Osteogenic, Small Cell Lung Cancer (SCLC), Thymic Cancer, Advanced Bladder cancer, Metastatic Anal cancer, Metastatic Endometrial cancer, Metastatic Penile cancer, Metastatic Testicular cancer, Refractory Non-Hodgkin's lymphoma, Refractory gestational trophoblastic disease

How Cisplatin works

Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations.

Dosage

Cisplatin dosage

Metastatic ovarian cancer: As monotherapy: 100 mg/m2 per cycle, given as a single dose infused in 0.9% sodium chloride or glucose once every 4 wk. For combination therapy with cyclophosphamide: 75-100 mg/m2 on day 1 of every 4-wk cycle.

Metastatic testicular tumours: 20 mg/m2 BSA daily for 5 days per cycle.

Advanced bladder cancer: 50-70 mg/m2 per cycle once every 3-4 wk, depending on the extent of prior exposure to radiation and/or chemotherapy treatment. An initial dose of 50 mg/m2 every 4 wk may be used in heavily pre-treated patients.

Usual dosage and schedule: 40 to 120 mg/m2 I.V. on day 1 as infusion every 3 weeks. 15 to 20 mg/m2 I.V. on days 1 to 5 as infusion every 3 to 4 weeks. The usual dose in adults and children when used as single agent therapy is 50-100 mg/m2.

Cisplatin lyophilized powder for injection 10 mg and 50 mg should be reconstituted with 10 ml and 50 ml of water for inj. respectively.

Cisplatin solution after reconstitution should be added to 2 liters of 5% glucose or 0.9% saline and intravenously administered in 6-8 hours; after administration an adequate hydration and diuresis should be maintained during 24 hours.

Side Effects

Severe nausea and vomiting. Serious toxic effects on the kidneys, bone marrows and ears. Hypomagnesaemia, hypocalcaemia, hyperuricaemia. Peripheral neuropathies, papilloedema, optic neuritis, seizures. Ototoxicity (children) manifested as tinnitus, loss of hearing, deafness or vestibular toxicity.

Precaution

Patients with renal or hepatic disorder, myelosuppression. Monitor renal, neurological and auditory function. Perform blood counts regularly. Maintain adequate hydration before and 24 hr after admin to minimise nephrotoxicity.

Interaction

Synergistic with 5-fluorouracil and etoposide. Efficacy increased and toxicity reduced when combined with radioprotecting agent WR 2721. At doses ≤100 mg, cisplatin is an ideal drug to combine with other cytotoxic drugs; unlike other antineoplastic drugs, it causes little myelosuppression.

Food Interaction

• Avoid echinacea. Echinacea should be used with caution, if at all, in patients receiving therapeutic immunosuppressants. Monitor for reduced efficacy of the immunosuppressant during concomitant use.

Cisplatin Drug Interaction

Moderate: doxorubicin, doxorubicin, dexamethasone, dexamethasoneMinor: gemcitabine, gemcitabineUnknown: palonosetron, palonosetron, lorazepam, lorazepam, bevacizumab, bevacizumab, prochlorperazine, prochlorperazine, trastuzumab, trastuzumab, cholecalciferol, cholecalciferol, ondansetron, ondansetron

Cisplatin Disease Interaction

Major: infections, hearing loss, myelosuppression, peripheral neuropathy, renal dysfunctionModerate: hemolytic anemia, ocular toxicity

Volume of Distribution

Volume of distribution at steady state = 11-12 L/m^2

Elimination Route

Following cisplatin doses of 20 to 120 mg/m^2, the concentrations of platinum are highest in liver, prostate, and kidney; somewhat lower in bladder, muscle, testicle, pancreas, and spleen; and lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum. Platinum is present in tissues for as long as 180 days after the last administration.

Half Life

Cisplatin decays monoexponentially with a half life of 20 to 30 minutes following administrations of 50 or 100 mg/m^2. Cisplatin has a plasma half-life of 30 minutes. The complexes between albumin and the platinum from cisplatin do not dissociate to a significant extent and are slowly eliminated with a minimum half-life of five days or more.

Clearance

• 15-16 L/h/m^2 [total body clearance, 7-hour infusion of 100 mg/m^2]
• 62 mL/min/m^2 [renal clearance, 2-hour infusion of 100 mg/m^2]
• 50 mL/min/m^2 [renal clearance, 6- to 7-hour infusion of 100 mg/m^2] The renal clearance of free (ultrafilterable) platinum also exceeds the glomerular filtration rate indicating that cisplatin or other platinum-containing molecules are actively secreted by the kidneys. The renal clearance of free platinum is nonlinear and variable and is dependent on dose, urine flow rate, and individual variability in the extent of active secretion and possible tubular reabsorption.

Elimination Route

The parent compound, cisplatin, is excreted in the urine. Although small amounts of platinum are present in the bile and large intestine after administration of cisplatin, the fecal excretion of platinum appears to be insignificant.

Pregnancy & Breastfeeding use

Pregnancy Category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Cisplatin is contraindicated in patients with pre-existing renal impairment. Cisplatin should not be employed in myelosuppressed patients, or patients with hearing impairment. It is also contraindicated in patients with a history of allergic reactions to cisplatin or other platinum-containing compounds.

Acute Overdose

Acute overdosage may result in kidney failure, liver failure, deafness, ocular toxicity, significant myelosuppression, intractable nausea and vomiting and/or neuritis. Death may also occur following overdosage. Treatment should include general supportive measures.

Storage Condition

Stability: The cisplatin remaining in vial following initial entry is stable for 28 days protected from light or for 7 days under fluorescent room light.

Storage: Product should be stored at controlled room temperature 25° C and protected from light.

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