CISPLATIN: 47,481 Adverse Event Reports & Safety Profile

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

INDICATIONS AND USAGE: 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.

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.

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/m 2 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/m 2 IV per cycle once every 4 weeks (DAY 1). The dose of cyclophosphamide when used in combination with cisplatin is 600 mg/m 2 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/m 2 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/m 2 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/m 2 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- 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/mm 3 , WBC ≥ 4,000/mm 3 ). 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- 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 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.

Metastatic Testicular Tumors

The usual cisplatin dose for the treatment of testicular cancer in combination with other approved chemotherapeutic agents is 20 mg/m 2 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/m 2 IV per cycle once every 4 weeks (DAY 1). The dose of cyclophosphamide when used in combination with cisplatin is 600 mg/m 2 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/m 2 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/m 2 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/m 2 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- 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/mm 3 , WBC ≥ 4,000/mm 3 ). 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- 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 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.

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 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 Fosun Pharma USA Inc. at 1-866-611-3762 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Other Toxicities

Vascular toxicities coincident with the use of cisplatin in combination with other antineoplastic agents have been reported. The events are clinically heterogeneous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (hemolytic-uremic syndrome [HUS]), or cerebral arteritis. Various mechanisms have been proposed for these vascular complications. There are also reports of Raynaud’s phenomenon occurring in patients treated with the combination of bleomycin, vinblastine with or without cisplatin. It has been suggested that hypomagnesemia developing coincident with the use of cisplatin may be an added, although not essential, factor associated with this event. However, it is currently unknown if the cause of Raynaud’s phenomenon in these cases is the disease, underlying vascular compromise, bleomycin, vinblastine, hypomagnesemia, or a combination of any of these factors.

Serum Electrolyte Disturbances

Hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia have been reported to occur in patients treated with cisplatin and are probably related to renal tubular damage. Tetany has been reported in those patients with hypocalcemia and hypomagnesemia. Generally, normal serum electrolyte levels are restored by administering supplemental electrolytes and discontinuing cisplatin. Inappropriate antidiuretic hormone syndrome has also been reported.

Hyperuricemia

Hyperuricemia has been reported to occur at approximately the same frequency as the increases in BUN and serum creatinine. It is more pronounced after doses greater than 50 mg/m 2 , and peak levels of uric acid generally occur between 3 to 5 days after the dose. Allopurinol therapy for hyperuricemia effectively reduces uric acid levels. Neurotoxicity (see WARNINGS ). Neurotoxicity, usually characterized by peripheral neuropathies, has been reported. The neuropathies usually occur after prolonged therapy (4 to 7 months); however, neurologic symptoms have been reported to occur after a single dose. Although symptoms and signs of cisplatin neuropathy usually develop during treatment, symptoms of neuropathy may begin 3 to 8 weeks after the last dose of cisplatin. Cisplatin therapy should be discontinued when the symptoms are first observed. The neuropathy, however, may progress further even after stopping treatment. Preliminary evidence suggests peripheral neuropathy may be irreversible in some patients. Elderly patients may be more susceptible to peripheral neuropathy (see PRECAUTIONS , Geriatric Use ). Lhermitte’s sign, dorsal column myelopathy, and autonomic neuropathy have also been reported. Loss of taste, seizures, leukoencephalopathy, and reversible posterior leukoencephalopathy syndrome (RPLS) have also been reported. Muscle cramps, defined as localized, painful, involuntary skeletal muscle contractions of sudden onset and short duration, have been reported and were usually associated in patients receiving a relatively high cumulative dose of cisplatin and with a relatively advanced symptomatic stage of peripheral neuropathy.

Ocular Toxicity

Optic neuritis, papilledema, and cerebral blindness have been reported in patients receiving standard recommended doses of cisplatin. Improvement and/or total recovery usually occurs after discontinuing cisplatin. Steroids with or without mannitol have been used; however, efficacy has not been established. Blurred vision and altered color perception have been reported after the use of regimens with higher doses of cisplatin or greater dose frequencies than recommended in the package insert. The altered color perception manifests as a loss of color discrimination, particularly in the blue-yellow axis. The only finding on funduscopic exam is irregular retinal pigmentation of the macular area. Anaphylactic-Like Reactions Anaphylactic-like reactions have been reported in patients previously exposed to cisplatin. The reactions consist of facial edema, wheezing, tachycardia, and hypotension within a few minutes of drug administration. Reactions may be controlled by intravenous epinephrine with corticosteroids and/or antihistamines as indicated. Patients receiving cisplatin should be observed carefully for possible anaphylactic-like reactions and supportive equipment and medication should be available to treat such a complication.

Hepatotoxicity

Transient elevations of liver enzymes, especially SGOT, as well as bilirubin, have been reported to be associated with cisplatin administration at the recommended doses.

Other Events

Cardiac abnormalities, hiccups, elevated serum amylase, rash, alopecia, malaise, asthenia, and dehydration have been reported. Local soft tissue toxicity has been reported following extravasation of cisplatin. Severity of the local tissue toxicity appears to be related to the concentration of the cisplatin solution. Infusion of solutions with a cisplatin concentration greater than 0.5 mg/mL may result in tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema.

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 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.5 , 8.6 )]</span> . Ensure adequate hydration before, during, and after cisplatin for injection administration <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 )]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span>.

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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.5 )]</span> .

5.3 Nausea and Vomiting Cisplatin for injection is a highly emetogenic antineoplastic agent. Premedicate with anti-emetic agents <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 )]</span> . 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.5 )]</span> . 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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.4 )]</span>. 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. 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span>.

5.10 Injection Site Reactions Injection site reactions can occur during the administration of cisplatin for injection. Local soft tissue toxicity has been reported following extravasation of cisplatin for injection. Severity of the local tissue toxicity appears to be related to the concentration of the cisplatin for injection solution. Infusion of solutions with a cisplatin for 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.

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.

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.

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.