Cisplatin

Cisplatin for injection is a platinum-based drug indicated for the treatment of:

• Advanced testicular cancer ( 1.1 )
• Advanced ovarian cancer ( 1.2 )
• Advanced bladder cancer ( 1.3 )

1.1 Advanced Testicular Cancer Cisplatin for injection is indicated for the treatment of advanced testicular cancer.

1.2 Advanced Ovarian Cancer Cisplatin for injection is indicated for the treatment of advanced ovarian cancer.

1.3 Advanced Bladder Cancer Cisplatin for injection is indicated for the treatment of advanced bladder cancer.

Cisplatin for injection, USP: single-dose vials containing 50 mg of cisplatin as white to light yellow lyophilized powder for reconstitution. Lyophilized powder: Single-dose vials containing 50 mg ( 3 )

Cisplatin for injection is contraindicated in patients with severe hypersensitivity to cisplatin [see Warnings and Precautions ( 5.4 )] . Severe hypersensitivity to cisplatin ( 4 )

• Hypersensitivity reactions: Anaphylaxis and death may occur; monitor for and treat accordingly ( 5.5 )
• Ototoxicity: Cumulative toxicity may be severe particularly in pediatric patients; consider audiometric and vestibular function monitoring ( 5.6 , 8.4 )
• Ocular toxicity: Optic neuritis, papilledema, and cortical blindness may occur ( 5.7 )
• Secondary leukemia: Secondary acute leukemia may occur ( 5.8 )
• Embryo-fetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. ( 5.9 , 8.1 , 8.3 )

5.1 Nephrotoxicity Cisplatin for injection can cause dose-related nephrotoxicity, including acute renal failure that becomes more prolonged and severe with repeated courses of the drug. Renal toxicity typically begins during the second week after a dose of cisplatin for injection. Patients with baseline renal impairment, geriatric patients, patients who are taking other nephrotoxic drugs, or patients who are not well hydrated may be more susceptible to nephrotoxicity [see Use in Specific Populations ( 8.5 , 8.6 )] . Ensure adequate hydration before, during, and after cisplatin for injection administration [see Dosage and Administration ( 2.1 )] . Measure serum creatinine, blood urea nitrogen, creatinine clearance, and serum electrolytes including magnesium prior to initiating therapy, and as clinically indicated. Consider magnesium supplementation as clinically needed. Consider alternative treatments or reduce the dose of cisplatin for injection for patients with baseline renal impairment or who develop significant reductions in creatinine clearance during treatment with cisplatin for injection according to clinical treatment guidelines [see Dosage and Administration ( 2.5 )].

5.2 Peripheral Neuropathy Cisplatin for injection can cause dose-related peripheral neuropathy that becomes more severe with repeated courses of the drug. Neurologic symptoms have been reported to occur after a single dose. Neuropathy can also have a delayed onset from 3 to 8 weeks after the last dose of cisplatin for injection. Manifestations include paresthesias in a stocking-glove distribution, areflexia, and loss of proprioception and vibratory sensation. The neuropathy may progress further even after stopping treatment. Peripheral neuropathy may be irreversible in some patients. Perform a neurological examination before initiating cisplatin for injection, at appropriate intervals during therapy, and after completion of therapy. Consider discontinuation of cisplatin for injection for patients who develop symptomatic peripheral neuropathy. Geriatric patients may be more susceptible to peripheral neuropathy [see Use in Specific Populations ( 8.5 )] .

5.3 Nausea and Vomiting Cisplatin for injection is a highly emetogenic antineoplastic agent. Premedicate with anti-emetic agents [see Dosage and Administration ( 2.1 )] . Without antiemetic therapy, marked nausea and vomiting occur in almost all patients treated with cisplatin for injection 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 72 hours. Maximal intensity occurs 48 to 72 hours after administration. 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 for injection therapy. Consider the use of additional anti-emetics following infusion.

5.4 Myelosuppression Myelosuppression suppression occurs in 25% to 30% of patients treated with cisplatin for injection. Fever and infection have been reported in patients with neutropenia. Potential fatalities due to infection (secondary to myelosuppression) have been reported. Geriatric patients may be more susceptible to myelosuppression [see Use in Specific Populations ( 8.5 )] . Perform standard hematologic tests before initiating cisplatin for injection, before each subsequent course, and as clinically indicated. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with cisplatin for injection. For patients who develop severe myelosuppression during treatment with cisplatin for injection, consider dose modifications and manage according to clinical treatment guidelines.

5.5 Hypersensitivity Reactions Cisplatin for injection can cause severe hypersensitivity reactions, including anaphylaxis and death. Manifestations have included facial edema, wheezing, tachycardia, and hypotension. Hypersensitivity reactions have occurred within minutes of administration to patients with prior exposure to cisplatin for injection. Monitor patients receiving cisplatin for injection for possible hypersensitivity reactions. Ensure supportive equipment and medications are available to treat severe hypersensitivity reactions. Severe hypersensitivity reactions require immediate discontinuation of cisplatin for injection and aggressive therapy. Patients with a history of severe hypersensitivity reactions should not be rechallenged with cisplatin for injection [see Contraindications ( 4 )] . Cross-reactivity between platinum-based antineoplastic agents has been reported. Cases of severe hypersensitivity reactions have recurred after rechallenging patients with a different platinum agent.

5.6 Ototoxicity Cisplatin for injection can cause ototoxicity, which is cumulative and may be severe. Consider audiometric and vestibular function monitoring. Ototoxicity is manifested by tinnitus, hearing loss in the high frequency range (4,000 to 8,000 Hz) and/or decreased ability to hear normal conversational tones. Ototoxicity can occur during or after treatment and can be unilateral or bilateral. Deafness after the initial dose of cisplatin for injection has been reported. Vestibular toxicity has also been reported. Ototoxic effects can be more severe and detrimental in pediatric patients, particularly in patients less than 5 years of age. The prevalence of hearing loss in pediatric patients is estimated to be 40-60%. Additional risk factors for ototoxicity include simultaneous cranial irradiation, treatment with other ototoxic drugs and renal impairment. Consider audiometric and vestibular testing in all pediatric patients receiving cisplatin [see Use in Specific Populations ( 8.4 )]. Genetic factors (e.g. variants in the thiopurine S-methyltransferase [TPMT] gene) may also contribute to the cisplatin-induced ototoxicity; although this association has not been consistent across populations and study designs.

5.7 Ocular Toxicity Optic neuritis, papilledema, and cortical blindness have been reported in patients receiving standard recommended doses of cisplatin for injection. Blurred vision and altered color perception have been reported after the use of regimens with higher doses and dose frequencies of cisplatin for injection. The altered color perception manifests as a loss of color discrimination, particularly in the blue-yellow axis and irregular retinal pigmentation of the macular area on fundoscopic exam. Improvement and/or total recovery usually occurs after discontinuing cisplatin for injection but can be delayed.

5.8 Secondary Malignancies The development of acute leukemia secondary to the use of cisplatin for injection has been reported. In these reports, cisplatin for injection was generally given in combination with other leukemogenic agents.

5.9 Embryo-Fetal Toxicity Based on human data, cisplatin for injection can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 14 months after the last dose of cisplatin for injection. […]

The following adverse reactions are described in greater detail, in other sections:

• Nephrotoxicity [see Warnings and Precautions ( 5.1 )]
• Peripheral Neuropathy [see Warnings and Precautions ( 5.2 )]
• Nausea and vomiting [see Warnings and Precautions ( 5.3 )]
• Myelosuppression [see Warnings and Precautions ( 5.4 )]
• Hypersensitivity reactions [see Warnings and Precautions ( 5.5 )]
• Ototoxicity [see Warnings and Precautions ( 5.6 ]
• Ocular toxicity [see Warnings and Precautions ( 5.7 )]
• Secondary malignancies [see Warnings and Precautions ( 5.8 )]
• Injection site reactions [see Warnings and Precautions ( 5.10 )] Common adverse reactions are nephrotoxicity, peripheral neuropathy, nausea and vomiting myelosuppression, and ototoxicity. The following adverse reactions have been identified from clinical trials or post-marketing surveillance. Blood and lymphatic system disorders: Coombs‑positive hemolytic anemia. hemolytic uremic syndrome, thrombotic thrombocytopenic purpura Cardiovascular disorders: Venous thromboembolism, arterial thromboembolism, myocardial infarction, cerebrovascular accident, thrombotic microangiopathy, cerebral arteritis, pericardial effusion, cardiac failure, ventricular dysfunction, Raynaud’s phenomenon Eye disorders: Optic neuritis, papilledema, cortical blindness, blurred vision, color blindness, retinal pigmentation Gastrointestinal disorders: Nausea, vomiting, anorexia, diarrhea, stomatitis, gastrointestinal perforation, pancreatitis, hiccups General disorders: Asthenia, malaise Hepatobiliary disorders: Elevations of aminotransferases, lactate dehydrogenase, and bilirubin; hepatic failure Hypersensitivity: Anaphylaxis, facial edema, wheezing, tachycardia, and hypotension Local Site Reactions: Tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema Metabolism and nutrition disorders: Hypomagnesemia, often requiring magnesium supplementation; hyperuricemia, other electrolyte abnormalities (hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia), Syndrome of Inappropriate Antidiuretic Hormone Excretion (SIADH), dehydration, tumor lysis syndrome, increased serum amylase Musculoskeletal disorders: Muscle cramps (localized, painful, involuntary skeletal muscle contractions of sudden onset and short duration) Nervous system disorders: Peripheral neuropathy, Encephalopathy, loss of motor function, loss of taste, leukoencephalopathy, reversible posterior leukoencephalopathy syndrome, progressive multifocal leukoencephalopathy, seizures, Lhermitte’s sign, dorsal column myelopathy, autonomic neuropathy, seizures, involuntary skeletal muscle contractions, tetany (with hypocalcemia and hypomagnesemia) Ototoxicity: Tinnitus, hearing loss, deafness, vestibular toxicity Renal and urinary disorders: Nephrotoxicity including renal failure, renal electrolyte wasting, azotemia, decreased creatinine clearance Respiratory disorders: pneumonitis/interstitial lung disease, pulmonary embolism Skin and subcutaneous tissue disorders: Alopecia, rash Common adverse reactions are nephrotoxicity, peripheral neuropathy, nausea and vomiting, myelosuppression, and ototoxicity. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact WG Critical Care at 1-866-562-4708 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

The following drug interactions are described in other sections:

• Nephrotoxic drugs [see Warnings and Precautions ( 5.1 )]
• Ototoxic drugs [see Warnings and Precautions ( 5.6 )]

• Lactation: Advise not to breastfeed. ( 8.2 )
• Females and Males of Reproductive Potential: Verify pregnancy status prior to initiation of cisplatin for injection. Can impair fertility. ( 8.3 )

8.1 Pregnancy Risk Summary Based on human data from published literature, cisplatin for 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 for 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 for injection in a breastfed child and because of the potential for tumorigenicity shown for cisplatin for injection, advise lactating women not to breastfeed during treatment with cisplatin for 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 for injection. Contraception Females Cisplatin for 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 for 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 for 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 for injection, particularly in patients less than 5 years of age. Consider audiometric and vestibular function monitoring in all patients receiving cisplatin for 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 for 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 neutropenia than did younger patients. Higher incidences of severe thrombocytopenia and leukopenia were also seen in geriatric patients compared with younger patients, although not in all cisplatin-containing treatment arms. In the two trials where nonhematologic toxicity was evaluated according to age, geriatric patients had a numerically higher incidence of peripheral neuropathy than did younger patients. Other reported clinical experience suggests that geriatric patients may be more susceptible to nephrotoxicity, myelosuppression, and infectious complications than are younger patients [see Warnings and Precautions ( 5.1 , 5.2 , 5.4 )]. Cisplatin is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.

8.6 Use in Patients with Renal Impairment Patients with baseline renal impairment may be more susceptible to nephrotoxicity [see Warnings and Precautions ( 5.1 )] . Ensure adequate hydration before, during, and after cisplatin for injection administration [see Dosage and Administration ( 2.1 )]. Measure serum creatinine, blood urea nitrogen, creatinine clearance, and serum electrolytes prior to initiating therapy, and as clinically indicated. Consider alternative treatments or reduce the dose of cisplatin for injection for patients with baseline renal impairment or who develop significant reductions in creatinine clearance during treatment with cisplatin for injection according to clinical treatment guidelines [see Dosage and Administration ( 2.5 )].

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.