ADVERSE REACTIONS SECTION.

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 single dose of 50 mg/m2. It is first noted during the second week after dose and is manifested by elevations in BUN and creatinine, serum uric acid and/or 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 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 single dose of cisplatin 50 mg/m2, and is manifested by tinnitus and/or hearing loss in the high frequency range (4000 to 8000 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 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 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, Coombs positive hemolytic anemia has been reported. In the presence of cisplatin hemolytic anemia, 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 to hours after treatment and last up to 24 hours. Various degrees of vomiting, nausea and/or anorexia may persist for up to 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 TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537 or drug.safetytevapharm.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Plasma concentrations of the parent compound, cisplatin, decay monoexponentially with half-life of about 20 to 30 minutes following bolus administrations of 50 or 100 mg/m2 doses. Monoexponential decay and plasma half-lives of about 0.5 hour are also seen following 2-hour or 7-hour infusions of 100 mg/m2. After the latter, the total-body clearances and volumes of distribution at steady-state for cisplatin are about 15 to 16 L/h/m2 and 11 to 12 L/m2.Due to its unique chemical structure, the chlorine atoms of cisplatin are more subject to chemical displacement reactions by nucleophiles, such as water or sulfhydryl groups, than to enzyme-catalyzed metabolism. At physiological pH in the presence of 0.1M NaCl, the predominant molecular species are cisplatin and monohydroxymonochloro cis-diammine platinum (II) in nearly equal concentrations. The latter, combined with the possible direct displacement of the chlorine atoms by sulfhydryl groups of amino acids or proteins, accounts for the instability of cisplatin in biological matrices. The ratios of cisplatin to total free (ultrafilterable) platinum in the plasma vary considerably between patients and range from 0.5 to 1.1 after dose of 100 mg/m2.Cisplatin does not undergo the instantaneous and reversible binding to plasma proteins that is characteristic of normal drug-protein binding. However, the platinum from cisplatin, but not cisplatin itself, becomes bound to several plasma proteins, including albumin, transferrin, and gamma globulin. Three hours after bolus injection and two hours after the end of three-hour infusion, 90% of the plasma platinum is protein bound. The complexes between albumin and the platinum from cisplatin do not dissociate to significant extent and are slowly eliminated with minimum half-life of five days or more.Following cisplatin doses of 20 to 120 mg/m2, 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. With the exception of intracerebral tumors, platinum concentrations in tumors are generally somewhat lower than the concentrations in the organ where the tumor is located. Different metastatic sites in the same patient may have different platinum concentrations. Hepatic metastases have the highest platinum concentrations, but these are similar to the platinum concentrations in normal liver. Maximum red blood cell concentrations of platinum are reached within 90 to 150 minutes after 100 mg/m2 dose of cisplatin and decline in biphasic manner with terminal half-life of 36 to 47 days.Over dose range of 40 to 140 mg cisplatin/m2 given as bolus injection or as infusions varying in length from hour to 24 hours, from 10% to about 40% of the administered platinum is excreted in the urine in 24 hours. Over five days following administration of 40 to 100 mg/m2 doses given as rapid, 2- to 3-hour, or 6- to 8-hour infusions, mean of 35% to 51% of the dosed platinum is excreted in the urine. Similar mean urinary recoveries of platinum of about 14% to 30% of the dose are found following five daily administrations of 20, 30, or 40 mg/m2/day. Only small percentage of the administered platinum is excreted beyond 24 hours post-infusion and most of the platinum excreted in the urine in 24 hours is excreted within the first few hours. Platinum-containing species excreted in the urine are the same as those found following the incubation of cisplatin with urine from healthy subjects, except that the proportions are different.The parent compound, cisplatin, is excreted in the urine and accounts for 13% to 17% of the dose excreted within one hour after administration of 50 mg/m2. The mean renal clearance of cisplatin exceeds creatinine clearance and is 62 and 50 mL/min/m2 following administration of 100 mg/m2 as 2-hour or 6- to 7-hour infusions, respectively.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.There is potential for accumulation of ultrafilterable platinum plasma concentrations whenever cisplatin is administered on daily basis but not when dosed on an intermittent basis.No significant relationships exist between the renal clearance of either free platinum or cisplatin and creatinine clearance.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.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Cisplatin Injection is administered by slow intravenous infusion. CISPLATIN INJECTION SHOULD NOT BE GIVEN BY RAPID INTRAVENOUS INJECTION.Note: Needles or intravenous sets containing aluminum parts that may come in contact with Cisplatin Injection should not be used for preparation or administration. Aluminum reacts with Cisplatin Injection, causing precipitate formation and loss of potency.. Metastatic Testicular Tumors. The usual Cisplatin Injection dose for the treatment of testicular cancer in combination with other approved chemotherapeutic agents is 20 mg/m2 IV daily for days per cycle.. Metastatic Ovarian Tumors. The usual Cisplatin Injection dose for the treatment of metastatic ovarian tumors in combination with cyclophosphamide is 75 to 100 mg/m2 IV per cycle once every four weeks (DAY 1).The dose of cyclophosphamide when used in combination with Cisplatin Injection is 600 mg/m2 IV once every weeks (DAY 1).For directions for the administration of cyclophosphamide, refer to the cyclophosphamide package insert.In combination therapy, Cisplatin Injection and cyclophosphamide are administered sequentially.As single agent, Cisplatin Injection should be administered at dose of 100 mg/m2 IV per cycle once every four weeks.. Advanced Bladder Cancer. Cisplatin Injection should be administered as single agent at dose of 50 to 70 mg/m2 IV per cycle once every to 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 weeks is recommended.. All Patients. Pretreatment hydration with to liters of fluid infused for to 12 hours prior to Cisplatin Injection dose is recommended. The drug is then diluted in liters of 5% Dextrose in 1/2 or 1/3 normal saline containing 37.5 of mannitol, and infused over 6- to 8-hour period. If diluted solution is not to be used within hours, protect solution from light. Do not dilute Cisplatin Injection in just 5% Dextrose Injection. Adequate hydration and urinary output must be maintained during the following 24 hours.A repeat course of Cisplatin Injection 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. repeat course should not be given until circulating blood elements are at an acceptable level (platelets >= 100,000/mm3, WBC >= 4000/mm3). Subsequent doses of Cisplatin Injection should not be given until an audiometric analysis indicates that auditory acuity is within normal limits.

PRECAUTIONS SECTION.

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 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. Teratogenic Effects. 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 childs 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, 1484 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 prognostic factor for survival. However, in 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 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 preexisting 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.

REFERENCES SECTION.

REFERENCES. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling occupational exposure to hazardous drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otmvi/otmvi2.html. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am Health-Syst Pharm. 2006;63:1172-1193. Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Society. Rev. 6/2015Manufactured In The Netherlands By:Pharmachemie B.V.Haarlem, The NetherlandsManufactured For:TEVA PHARMACEUTICALS USA, INC.North Wales, PA 19454. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling occupational exposure to hazardous drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otmvi/otmvi2.html. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am Health-Syst Pharm. 2006;63:1172-1193. Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Society.

WARNINGS SECTION.

WARNINGS. Cisplatin produces cumulative nephrotoxicity which is potentiated by aminoglycoside antibiotics. The serum creatinine, blood urea nitrogen (BUN), creatinine clearance, and magnesium, sodium, potassium, and calcium levels should be measured prior to initiating therapy, and prior to each subsequent course. At the recommended dosage, cisplatin should not be given more frequently than once every to weeks (see ADVERSE REACTIONS). Elderly patients may be more susceptible to nephrotoxicity (see PRECAUTIONS, Geriatric Use).There are reports of severe neuropathies in patients in whom regimens are employed using higher doses of cisplatin or greater dose frequencies than those recommended. These neuropathies may be irreversible and are seen as paresthesias in stocking-glove distribution, areflexia, and loss of proprioception and vibratory sensation. Elderly patients may be more susceptible to peripheral neuropathy (seePRECAUTIONS, Geriatric Use).Loss of motor function has also been reported.Anaphylactic-like reactions to cisplatin have been reported. These reactions have occurred within minutes of administration to patients with prior exposure to cisplatin, and have been alleviated by administration of epinephrine, corticosteroids, and antihistamines.Cisplatin can commonly cause ototoxicity which is cumulative and may be severe. Audiometric testing should be performed prior to initiating therapy and prior to each subsequent dose of drug (see ADVERSE REACTIONS). All pediatric patients receiving cisplatin should have audiometric testing at baseline, prior to each subsequent dose, of drug and for several years post therapy.Cisplatin can cause fetal harm when administered to pregnant woman. Cisplatin is mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue culture. In mice cisplatin is teratogenic and embryotoxic. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Patients should be advised to avoid becoming pregnant.The carcinogenic effect of cisplatin was studied in BD IX rats. Cisplatin was administered intraperitoneally (i.p.) to 50 BD IX rats for weeks, X mg/kg body weight per week. Four hundred and fifty-five days after the first application, 33 animals died, 13 of them related to malignancies: 12 leukemias and renal fibrosarcoma.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.Injection site reactions may occur during the administration of cisplatin (see ADVERSE REACTIONS). Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration. specific treatment for extravasation reactions is unknown at this time.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Nephrotoxicity Inform patients that Cisplatin Injection can cause nephrotoxicity and that renal function and electrolyte monitoring during treatment is necessary. If indicated, inform patients about the use of electrolyte supplements [see Warnings and Precautions (5.1)].Peripheral Neuropathy Advise patients to report any new paresthesias to their healthcare provider [see Warnings and Precautions (5.2)].Nausea and Vomiting Advise patients concerning the use of antiemetics to prevent nausea and vomiting and to report persistent or severe symptoms to their healthcare provider [see Warnings and Precautions (5.3)].Myelosuppression Advise patients that Cisplatin Injection can reduce the absolute neutrophil count and the platelet count resulting in an increased risk of infection and bleeding and to contact their healthcare provider for new onset fever, symptoms of infection, or bleeding [see Warnings and Precautions (5.4)].Ototoxicity Advise patients to report any symptoms of hearing loss or vestibular dysfunction to their healthcare provider and that periodic monitoring of hearing may be performed [see Warnings and Precautions (5.6)].Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to fetus and to inform their healthcare provider if they are pregnant or become pregnant [see Warnings and Precautions 5.9 and 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 [see Use in Specific Populations (8.3)]. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 11 months following the last dose of Cisplatin Injection [see Use in Specific Populations (8.3)].Lactation Advise females not to breastfeed during treatment with Cisplatin Injection [see Use in Specific Populations (8.2)].Infertility Inform patients that treatment with Cisplatin Injection may lead to permanent impairment of spermatogenesis, ovarian failure or premature menopause, and reduced fertility in both genders [see Use in Specific Populations (8.3)].Alopecia Inform patients that Cisplatin Injection can cause alopecia.Manufactured for: Teva Pharmaceuticals USA, Inc., North Wales, PA 19454Rev. 8/2022. Advise females of reproductive potential of the potential risk to fetus and to inform their healthcare provider if they are pregnant or become pregnant [see Warnings and Precautions 5.9 and 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 [see Use in Specific Populations (8.3)]. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 11 months following the last dose of Cisplatin Injection [see Use in Specific Populations (8.3)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Distribution Cisplatin dose not undergo the instantaneously and reversible binding to plasma protein that is characteristic of normal drug-protein binding. Platinum from cisplatin, but not cisplatin itself, becomes bound to several plasma proteins, including albumin, transferrin, and gamma globulin. Three hours after bolus injection and hours after the end of 3-hour infusion, 90% of the plasma platinum is protein bound. The complexes between albumin and the platinum from cisplatin do not dissociate to significant extent and are slowly eliminated with minimum half-life of days or more.Following cisplatin doses of 20 mg/m2 to 120 mg/m2, platinum is present in tissues for as long as 180 days after the last administration. With the exception of intracerebral tumors, platinum concentrations in tumors are generally somewhat lower than the concentrations in the organ where the tumor is located. Hepatic metastases have the highest platinum concentrations, but these are similar to the platinum concentrations in normal liver. Maximum red blood cell concentrations of platinum are reached within 90 to 150 minutes after 100 mg/m2 dose of cisplatin and decline in biphasic manner with terminal half-life of 36 to 47 days.Metabolism The chlorine atoms of cisplatin are more subject to chemical displacement reactions by nucleophiles, such as water or sulfhydryl groups, than to enzyme-catalyzed metabolism. At physiological pH, the predominant molecular species are cisplatin and monohydroxymonochloro cis-diamine platinum (II) in nearly equal concentrations. The latter, combined with the possible direct displacement of the chlorine atoms by sulfhydryl groups of amino acids or proteins, accounts for the instability of cisplatin in biological matrices. The ratios of cisplatin to total free (ultrafilterable) platinum in the plasma vary considerably between patients and range from 0.5 to 1.1 after dose of 100 mg/m2.Elimination Over dose range of 40 mg to 140 mg cisplatin per m2 given as bolus injection or as infusions varying in length from hour to 24 hours, from 10% to about 40% of the administered platinum is excreted in the urine in 24 hours. Over days following administration of 40 mg/m2 to 100 mg/m2 doses given as rapid, 2- to 3-hour or 6- to 8-hour infusions, mean of 35% to 51% of the dosed platinum is excreted in the urine. Similar mean urinary recoveries of platinum of about 14% to 30% of the dose are found following daily administrations of 20 mg/m2 per day, 30 mg/m2 per day, or 40 mg/m2 per day. Only small percentage of the administered platinum is excreted beyond 24 hours post-infusion and most of the platinum excreted in the urine in 24 hours is excreted within the first few hours.The parent compound, cisplatin, is excreted in the urine and accounts for 13% to 17% of the dose excreted within hour after administration of 50 mg/m2. The mean renal clearance of cisplatin exceeds creatinine clearance and was 62 mL/min per m2 and 50 mL/min per m2 following administration of 100 mg/m2 as 2-hour or 6- to 7-hour infusions, respectively.Plasma concentrations of the parent compound, cisplatin, decrease monoexponentially with half-life of about 20 to 30 minutes following bolus administrations of 50 mg/m2 or 100 mg/m2 doses. Monoexponential decreases and plasma half-lives of about 0.5 hour are also seen following 2-hour or 7-hour infusions of 100 mg/m2. After the latter, the total body clearances and volumes of distribution at steady-state for cisplatin are about 15 Liters per hour per m2 to 16 Liters per hour per m2 and 11 Liters per m2 to 12 Liters per m2.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.No significant relationships exist between the renal clearance of either free platinum or cisplatin and creatinine clearance.

USE IN SPECIFIC POPULATIONS SECTION.

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). 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 SummaryBased 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 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. 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% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.. 8.2 Lactation. Risk SummaryLimited 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 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 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 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 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 pediatric patients 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 prognostic factor for survival. However, in 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 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 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 Injection for patients with baseline renal impairment or who develop significant reductions in creatinine clearance during treatment with Cisplatin Injection according to clinical treatment guidelines [see Dosage and Administration (2.5)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 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 fetus and use of effective contraception. (5.9, 8.1, 8.3). 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 fetus and use of effective contraception. (5.9, 8.1, 8.3). 5.1 Nephrotoxicity. Cisplatin 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 dose of Cisplatin 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 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 Injection for patients with baseline renal impairment or who develop significant reductions in creatinine clearance during treatment with Cisplatin Injection according to clinical treatment guidelines [see Dosage and Administration (2.5)].. 5.2 Peripheral Neuropathy. Cisplatin 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 single dose. Neuropathy can also have delayed onset from to weeks after the last dose of Cisplatin Injection. Manifestations include paresthesias in 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 neurological examination before initiating Cisplatin Injection, at appropriate intervals during therapy, and after completion of therapy. Consider discontinuation of Cisplatin 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 Injection is 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 Injection and may be so severe that the drug must be discontinued. Nausea and vomiting may begin within to 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 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 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 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 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 Injection. For patients who develop severe myelosuppression during treatment with Cisplatin Injection, consider dose modifications and manage according to clinical treatment guidelines.. 5.5 Hypersensitivity Reactions. Cisplatin 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 Injection.Monitor patients receiving Cisplatin 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 Injection and aggressive therapy. Patients with history of severe hypersensitivity reactions should not be rechallenged with Cisplatin 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 different platinum agent.. 5.6 Ototoxicity. Cisplatin 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 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 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 Injection. Blurred vision and altered color perception have been reported after the use of regimens with higher doses and dose frequencies of Cisplatin Injection. The altered color perception manifests as 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 Injection but can be delayed.. 5.8 Secondary Malignancies. The development of acute leukemia secondary to the use of Cisplatin Injection has been reported. In these reports, Cisplatin Injection was generally given in combination with other leukemogenic agents.. 5.9 Embryo-Fetal Toxicity. Based on human data, Cisplatin Injection can cause fetal harm when administered to pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment and for 14 months after the last dose of Cisplatin Injection. 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 [see Use in Specific Populations (8.1, 8.3)].. 5.10 Injection Site Reactions. Injection site reactions can occur during the administration of Cisplatin Injection. Local soft tissue toxicity has been reported following extravasation of Cisplatin Injection. Severity of the local tissue toxicity appears to be related to the concentration of the Cisplatin Injection solution. Infusion of solutions with Cisplatin Injection concentration greater than 0.5 mg/mL may result in tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema.Because of the possibility of extravasation, closely monitor the infusion site during drug administration.