Cisplatin

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 Injection 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.

2 DOSAGE AND ADMINISTRATION • Administer pre-treatment hydration and pre- and post-treatment antiemetics. ( 2.1 ) • Cisplatin injection has been administered intravenously at: o Advanced testicular cancer: 20 mg/m2 daily for 5 days per cycle ( 2.2 ) o Advanced ovarian cancer: 75 mg/m2 to 100 mg/m2 per cycle once every 3 to 4 weeks ( 2.3 ) o Advanced bladder cancer: 50 mg/m2 to 70 mg/m2 intravenously per cycle once every 3 to 4 weeks ( 2.4 ) Refer to current treatment guidelines for specific dosing information. • Administer by slow intravenous infusion. Avoid contact of cisplatin injection with aluminum parts. ( 2.6 ) 2.1 Hydration and Anti-Emetic Treatment Patients treated with cisplatin injection must receive appropriate pre-treatment hydration. Maintain adequate hydration and urinary output for 24 hours after cisplatin injection administration [see Warnings and Precautions ( 5.1 )] . Administer pre-treatment and post-treatment antiemetics as appropriate [see Warnings and Precautions ( 5.7 )] . 2.2 Advanced Testicular Cancer Cisplatin injection has been administered at 20 mg/m 2 intravenously daily for 5 days per cycle. Other doses and combination regimens have been used. 2.3 Advanced Ovarian Cancer Cisplatin injection has been administered at 75 mg/m 2 to 100 mg/m 2 intravenously per cycle once every 3 to 4 weeks on Day 1. Other doses and combination regimens have been used. 2.4 Advanced Bladder Cancer Cisplatin injection has been administered at 50 mg/m 2 to 70 mg/m 2 intravenously per cycle once every 3 to 4 weeks. For heavily pretreated patients, an initial dose of 50 mg/m 2 per cycle repeated every 4 weeks is recommended. Other doses and combination in regimens have been used. 2.5 Dose Modifications Consider alternative treatments or dose reductions for patients with impaired creatinine clearance, myelosuppression, or neuropathy. Consider permanent discontinuation for Grade 3-4 neuropathy. [See Warnings and Precautions ( 5.1 )] 2.6 Preparation, Handling, and Administration Do not use needles or intravenous sets containing aluminum parts that can come in contact with cisplatin injection during preparation or administration. Aluminum reacts with cisplatin injection, causing precipitate formation and a loss of potency. Cisplatin injection is a cytotoxic drug. Follow applicable special handling and disposable procedures. 1 Instructions for Preparation The aqueous solution should be used intravenously only and should be administered by IV infusion over a 6- 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/m 2 per cycle. Aluminum flip-off seal of vial have been imprinted with the following statement: CALL DR. IF DOSE > 100 MG/M 2 /CYCLE. Administration Administer cisplatin injection by slow intravenous infusion.

3 DOSAGE FORMS AND STRENGTHS Cisplatin injection, USP, is a clear, colorless to pale yellow, sterile aqueous solution available in sterilie multiple-dose vials containing 50 mg/50 mL (1 mg/mL) 100 mg/100 mL (1 mg/mL) Cisplatin injection, USP, is multiple-dose vials containing 50 mg/50 mL (1 mg/mL) ( 3 ) 100 mg/100 mL (1 mg/mL) ( 3 )

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.

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/m 2 . 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- 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/m 2 , 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/m 2 ). 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 to 4 hours after treatment and last up to 24 hours. Various degrees of vomiting, nausea and/or anore …

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.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) Females and Males of Reproductive Potential: Verify pregnancy status prior to initiation of cisplatin injection. Can impair fertility. ( 8.3 ) 8.1 Pregnancy Risk Summary Based on human data from published literature, cisplatin injection can cause fetal harm when administered to pregnant women. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Data demonstrates transplacental transfer of cisplatin. Exposure of pregnant women to cisplatin-containing chemotherapy has been associated with oligohydramnios, intrauterine growth restriction, and preterm birth. Cases of neonatal acute respiratory distress syndrome, cytopenias, and hearing loss have been reported. Cisplatin injection administration to animals during and after organogenesis resulted in teratogenicity. A published study in mice showed placental transfer of cisplatin increased with placenta maturation. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. 8.2 Lactation Risk Summary Limited data from published literature report the presence of cisplatin in human milk in low amounts. Because of the potential for serious adverse reactions from cisplatin injection in a breastfed child and because of the potential for tumorigenicity shown for cisplatin injection, advise lactating women not to breastfeed during treatment with cisplatin injection. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiation of cisplatin injection. Contraception Females Cisplatin injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use effective contraception during treatment and for 14 months following the last dose of cisplatin injection. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 11 months after the last dose of cisplatin injection. Infertility Females The use of cisplatin has been associated with cumulative dose-dependent ovarian failure, premature menopause, and reduced fertility. Males The use of cisplatin has been associated with a cumulative dose-dependent impairment of spermatogenesis (oligospermia, azoospermia; possibly irreversible) and reduced fertility. 8.4 Pediatric Use Ototoxic effects may be more severe and detrimental in pediatric patients receiving cisplatin injection, particularly in patients less than 5 years of age. Consider audiometric and vestibular function monitoring in all patients receiving cisplatin injection. The prevalence of hearing loss in pediatric patients is particularly high and is estimated to be 40% to 60%. Earlier detection of hearing loss can limit the potential impact of hearing impairment on a pediatric patient’s cognitive and social development [see Warnings and Precautions ( 5.6 )]. 8.5 Geriatric Use For the treatment of metastatic testicular tumors or advanced bladder cancer, clinical studies of cisplatin injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In four clinical trials of combination chemotherapy for advanced ovarian carcinoma, 1,484 patients received cisplatin either in combination with cyclophosphamide or with 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, geriatric patients were found to have shorter survival compared with younger patients. In all four trials, geriatric patients experienced more severe neutro …

12.1 Mechanism of Action The main mechanism of the cytotoxic action involves the binding of cisplatin to genomic DNA in the cell nucleus to form interstrand and intrastrand cross-links. This interferes with normal transcription and/or DNA replication mechanisms and triggers cytotoxic processes that lead to cell death.

DESCRIPTION Cisplatin Injection infusion concentrate is a clear, colorless, sterile aqueous solution. Each 50 mL or 100 mL amber vial of Cisplatin Injection contains: 1 mg/mL cisplatin, 9 mg/mL sodium chloride, hydrochloric acid and/or sodium hydroxide to adjust pH, and water for injection to a final volume of 50 mL or 100 mL, respectively. The pH range of Cisplatin Injection is 3.8 to 5.9. Cisplatin Injection infusion concentrate must be further diluted prior to administration (see DOSAGE AND ADMINISTRATION, All Patients ). The active ingredient, cisplatin, is a yellow to orange crystalline powder with the molecular formula PtCl 2 H 6 N 2 , and a molecular weight of 300.1. Cisplatin is a heavy metal complex containing a central atom of platinum surrounded by two chloride atoms and two ammonia molecules in the cis position. It is soluble in water or saline at 1 mg/mL and in dimethylformamide at 24 mg/mL. It has a melting point of 207°C. chemical structure

10 OVERDOSAGE Acute overdosage with cisplatin injection may result in renal failure, hepatic failure, hearing loss, ocular toxicity, myelosuppression, nausea and vomiting, and neuritis. In addition, death can occur following overdosage. Management of overdosage should include general supportive measures to sustain the patient through any period of toxicity that may occur. Important measures include renal protection by intravenous hydration with or without the use of an osmotic diuretic. Hemodialysis is not effective because of the high degree of protein binding of cisplatin injection. Plasmapheresis has been used to treat cases of cisplatin injection overdosage, but the optimal treatment regimen has not been established. For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org .

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Cisplatin injection, USP NDC 68001-283-24—Each multiple-dose amber vial contains 50 mg/50 mL (1 mg/mL) of cisplatin USP as a clear, colorless to pale yellow, sterile aqueous solution. NDC 68001-283-33—Each multiple-dose amber vial contains 100 mg/100 mL (1 mg/mL) of cisplatin USP as a clear, colorless to pale yellow, sterile aqueous solution. The above products are multiple dose vials packaged individually per shelf pack with NDC 68001-283-27 for 50mL and NDC 68001-283-32 for 100mL. Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not refrigerate or freeze cisplatin solution since a precipitate or crystal will form. If precipitate or crystal observed inside the vial, keep it at recommended storage condition till clear solution obtained. 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. Handling and Disposal Cisplatin injection, USP, is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1