Data from FDA - Curated by Toby Galbraith - Last updated 09 October 2017

Indication(s)

INDICATIONS Cisplatin Injection is indicated as therapy to be employed as follows: Metastatic Testicular Tumors In established combination therapy with other approved chemotherapeutic agents in patients with metastatic testicular tumors who have already received appropriate surgical and/or radiotherapeutic procedures. Metastatic Ovarian Tumors In established combination therapy with other approved chemotherapeutic agents in patients with metastatic ovarian tumors who have already received appropriate surgical and/or radiotherapeutic procedures. An established combination consists of cisplatin and cyclophosphamide. Cisplatin Injection, as a single agent, is indicated as secondary therapy in patients with metastatic ovarian tumors refractory to standard chemotherapy who have not previously received Cisplatin Injection therapy. Advanced Bladder Cancer Cisplatin Injection is indicated as a single agent for patients with transitional cell bladder cancer which is no longer amenable to local treatments, such as surgery and/or radiotherapy.

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Advisory information

contraindications
CONTRAINDICATIONS Cisplatin is contraindicated in patients with pre-existing renal impairment. Cisplatin should not be employed in myelosuppressed patients, or in patients with hearing impairment. Cisplatin is contraindicated in patients with a history of allergic reactions to cisplatin or other platinum containing compounds.
Special warnings and precautions
PRECAUTIONS Peripheral blood counts should be monitored weekly. Liver function should be monitored periodically. Neurologic examination should also be performed regularly (see ADVERSE REACTIONS ). Drug Interactions Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin therapy. In a randomized trial in advanced ovarian cancer, response duration was adversely affected when pyridoxine was used in combination with altretamine (hexamethylmelamine) and cisplatin. Carcinogenesis, Mutagenesis, Impairment of Fertility (See WARNINGS ). Pregnancy Pregnancy Category D (See WARNINGS ). Nursing Mothers Cisplatin has been reported to be found in human milk; patients receiving cisplatin should not breast-feed. Pediatric Use Safety and effectiveness in pediatric patients have not been established. All children should have audiometric monitoring performed prior to initiation of therapy, prior to each subsequent dose, and for several years post therapy. Advanced testing methods may allow for earlier detection of hearing loss in an attempt to facilitate the rapid initiation of interventions that can limit the potential adverse impact of hearing impairment on a child's cognitive and social development. Geriatric Use Insufficient data are available from clinical trials of cisplatin in the treatment of metastatic testicular tumors or advanced bladder cancer to determine whether elderly patients respond differently than younger patients. In four clinical trials of combination chemotherapy for advanced ovarian carcinoma, 1,484 patients received cisplatin either in combination with cyclophosphamide or paclitaxel. Of these, 426 (29%) were older than 65 years. In these trials, age was not found to be a prognostic factor for survival. However, in a later secondary analysis for one of these trials, elderly patients were found to have shorter survival compared with younger patients. In all four trials, elderly patients experienced more severe neutropenia than younger patients. Higher incidences of severe thrombocytopenia and leukopenia were also seen in elderly compared with younger patients, although not in all cisplatin-containing treatment arms. In the two trials where nonhematologic toxicity was evaluated according to age, elderly patients had a numerically higher incidence of peripheral neuropathy than younger patients. Other reported clinical experience suggests that elderly patients may be more susceptible to myelosuppression, infectious complications, and nephrotoxicity than younger patients. Cisplatin is known to be substantially excreted by the kidney and is contraindicated in patients with pre-existing renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.
Adverse reactions
ADVERSE REACTIONS Nephrotoxicity Dose-related and cumulative renal insufficiency, including acute renal failure, is the major dose-limiting toxicity of cisplatin. Renal toxicity has been noted in 28% to 36% of patients treated with a single dose of 50 mg/m2. It is first noted during the second week after a dose and is manifested by elevations in BUN and creatinine, serum uric acid and/or a decrease in creatinine clearance. Renal toxicity becomes more prolonged and severe with repeated courses of the drug. Renal function must return to normal before another dose of cisplatin can be given. Elderly patients may be more susceptible to nephrotoxicity (see PRECAUTIONS, Geriatric Use ). Impairment of renal function has been associated with renal tubular damage. The administration of cisplatin using a 6 hour to 8 hour infusion with intravenous hydration, and mannitol has been used to reduce nephrotoxicity. However, renal toxicity still can occur after utilization of these procedures. Ototoxicity Ototoxicity has been observed in up to 31% of patients treated with a single dose of cisplatin 50 mg/m2, and is manifested by tinnitus and/or hearing loss in the high frequency range (4,000 to 8,000 Hz). The prevalence of hearing loss in children is particularly high and is estimated to be 40 to 60%. Decreased ability to hear normal conversational tones may occur. Deafness after the initial dose of cisplatin has been reported. Ototoxic effects may be more severe in children receiving cisplatin. Hearing loss can be unilateral or bilateral and tends to become more frequent and severe with repeated cisplatin doses. It is unclear whether cisplatin-induced ototoxicity is reversible. Vestibular toxicity has also been reported. Ototoxic effects may be related to the peak plasma concentration of cisplatin. Ototoxicity can occur during treatment or be delayed. Audiometric monitoring should be performed prior to initiation of therapy, prior to each subsequent dose, and for several years post therapy. The risk of ototoxicity may be increased by prior or simultaneous cranial irradiation, and may be more severe in patients less than 5 years of age, patients being treated with other ototoxic drugs (e.g., aminoglycosides and vancomycin), and in patients with renal impairment. Genetic factors (e.g., variants in the thiopurine S-methyltransferase [TPMT] gene) may contribute to cisplatin-induced ototoxicity; although this association has not been consistent across populations and study designs. Hematologic Myelosuppression occurs in 25% to 30% of patients treated with cisplatin. The nadirs in circulating platelets and leukocytes occur between days 18 to 23 (range 7.5 to 45) with most patients recovering by day 39 (range 13 to 62). Leukopenia and thrombocytopenia are more pronounced at higher doses (>50 mg/m2). Anemia (decrease of 2 g hemoglobin/100 mL) occurs at approximately the same frequency and with the same timing as leukopenia and thrombocytopenia. Fever and infection have also been reported in patients with neutropenia. Potential fatalities due to infection (secondary to myelosuppression) have been reported. Elderly patients may be more susceptible to myelosuppression (see PRECAUTIONS, Geriatric Use ). In addition to anemia secondary to myelosuppression, a Coombs' positive hemolytic anemia has been reported. In the presence of cisplatin hemolytic anemia, a further course of treatment may be accompanied by increased hemolysis and this risk should be weighed by the treating physician. The development of acute leukemia coincident with the use of cisplatin has been reported. In these reports, cisplatin was generally given in combination with other leukemogenic agents. Gastrointestinal Marked nausea and vomiting occur in almost all patients treated with cisplatin, and may be so severe that the drug must be discontinued. Nausea and vomiting may begin within 1 hour to 4 hours after treatment and last up to 24 hours. Various degrees of vomiting, nausea and/or anorexia may persist for up to 1 week after treatment. Delayed nausea and vomiting (begins or persists 24 hours or more after chemotherapy) has occurred in patients attaining complete emetic control on the day of cisplatin therapy. Diarrhea has also been reported. To report SUSPECTED ADVERSE REACTIONS, contact Alvogen, Inc. at 1-866-770-3024 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Usage information

Dosing and administration
DOSAGE AND ADMINISTRATION Cisplatin is administered by slow intravenous infusion. CISPLATIN SHOULD NOT BE GIVEN BY RAPID INTRAVENOUS INJECTION. Note: Needles or intravenous sets containing aluminum parts that may come in contact with cisplatin should not be used for preparation or administration. Aluminum reacts with cisplatin, causing precipitate formation and a loss of potency. Metastatic Testicular Tumors The usual cisplatin dose for the treatment of testicular cancer in combination with other approved chemotherapeutic agents is 20 mg/m2 IV daily for 5 days per cycle. Metastatic Ovarian Tumors The usual cisplatin dose for the treatment of metastatic ovarian tumors in combination with cyclophosphamide is 75 to 100 mg/m2 IV per cycle once every 4 weeks (DAY 1). The dose of cyclophosphamide when used in combination with cisplatin is 600 mg/m2 IV once every 4 weeks (DAY 1). For directions for the administration of cyclophosphamide, refer to the cyclophosphamide package insert. In combination therapy, cisplatin and cyclophosphamide are administered sequentially. As a single agent, cisplatin should be administered at a dose of 100 mg/m2 IV per cycle once every 4 weeks. Advanced Bladder Cancer Cisplatin should be administered as a single agent at a dose of 50 to 70 mg/m2 IV per cycle once every 3 to 4 weeks depending on the extent of prior exposure to radiation therapy and/or prior chemotherapy. For heavily pretreated patients an initial dose of 50 mg/m2 per cycle repeated every 4 weeks is recommended. All Patients Pretreatment hydration with 1 to 2 liters of fluid infused for 8 to 12 hours prior to a cisplatin dose is recommended. The drug is then diluted in 2 liters of 5% Dextrose in 1/2 or 1/3 normal saline containing 37.5 g of mannitol, and infused over a 6 hour to 8 hour period. If diluted solution is not to be used within 6 hours, protect solution from light. Do not dilute cisplatin in just 5% Dextrose Injection. Adequate hydration and urinary output must be maintained during the following 24 hours. A repeat course of cisplatin should not be given until the serum creatinine is below 1.5 mg/100 mL, and/or the BUN is below 25 mg/100 mL. A repeat course should not be given until circulating blood elements are at an acceptable level (platelets ≥ 100,000/mm3, WBC ≥ 4,000/mm3). Subsequent doses of cisplatin should not be given until an audiometric analysis indicates that auditory acuity is within normal limits. Preparation of Intravenous Solutions Preparation Precautions Caution should be exercised in handling the aqueous solution. Procedures for proper handling and disposal of anticancer drugs should be utilized. Several guidelines on this subject have been published.1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials and IV sets containing cisplatin. Skin reactions associated with accidental exposure to cisplatin may occur. The use of gloves is recommended. If cisplatin contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosa with water. More information is available in the references listed below. Instructions for Preparation The aqueous solution should be used intravenously only and should be administered by IV infusion over a 6 hour to 8 hour period (see DOSAGE AND ADMINISTRATION ). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. NOTE TO PHARMACIST: Exercise caution to prevent inadvertent cisplatin overdosage. Please call prescriber if dose is greater than 100 mg/m2 per cycle. Aluminum and flip-off seal of vial have been imprinted with the following statement: CALL DR. IF DOSE > 100 MG/M 2 /CYCLE. Stability Cisplatin is a sterile, multiple dose vial without preservatives. Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Do not refrigerate. Protect unopened container from light. The cisplatin remaining in the amber vial following initial entry is stable for 28 days protected from light or for 7 days under fluorescent room light.
Pregnancy and lactation
Nursing Mothers Cisplatin has been reported to be found in human milk; patients receiving cisplatin should not breast-feed.

Interactions

Drug Interactions Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin therapy. In a randomized trial in advanced ovarian cancer, response duration was adversely affected when pyridoxine was used in combination with altretamine (hexamethylmelamine) and cisplatin.

More information

Category Value
Authorisation number ANDA207323
Agency product number Q20Q21Q62J
Orphan designation No
Product NDC 47781-610,47781-609
Date Last Revised 31-08-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 309311
Storage and handling Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Do not refrigerate. Protect from light. This container closure is not made with natural rubber latex.
Marketing authorisation holder Alvogen Inc.
Warnings WARNINGS Cisplatin should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available. Cumulative renal toxicity associated with cisplatin is severe. Other major dose-related toxicities are myelosuppression, nausea, and vomiting. Ototoxicity, which may be more pronounced in children, and is manifested by tinnitus, and/or loss of high frequency hearing and occasionally deafness, is significant. Anaphylactic-like reactions to cisplatin have been reported. Facial edema, bronchoconstriction, tachycardia, and hypotension may occur within minutes of cisplatin administration. Epinephrine, corticosteroids, and antihistamines have been effectively employed to alleviate symptoms (see WARNINGS and ADVERSE REACTIONS ). Exercise caution to prevent inadvertent cisplatin overdose. Doses greater than 100 mg/m2/cycle once every 3 to 4 weeks are rarely used. Care must be taken to avoid inadvertent cisplatin overdose due to confusion with carboplatin or prescribing practices that fail to differentiate daily doses from total dose per cycle.