Platinol

PLATINOL® (cisplatin for injection, USP)

NDC xxxxx-xxx-xx—Each amber vial contains 50 mg of cisplatin

REFERENCES

1. 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.

2. 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/otm_vi/otm_vi_2.html.

3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.

4. Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Society.

Manufactured by: Corden Pharma Latina S.p.A. Sermoneta-Latina 04013 Italy. Rev December 2011

PLATINOL (cisplatin for injection, USP) 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 PLATINOL and cyclophosphamide. PLATINOL, as a single agent, is indicated as secondary therapy in patients with metastatic ovarian tumors refractory to standard chemotherapy who have not previously received PLATINOL therapy.

Advanced Bladder Cancer

PLATINOL 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.

PLATINOL is administered by slow intravenous infusion. PLATINOL SHOULD NOT BE GIVEN BY RAPID INTRAVENOUS INJECTION.

Note: Needles or intravenous sets containing aluminum parts that may come in contact with PLATINOL should not be used for preparation or administration. Aluminum reacts with PLATINOL, causing precipitate formation and a loss of potency.

Metastatic Testicular Tumors

The usual PLATINOL dose for the treatment of testicular cancer in combination with other approved chemotherapeutic agents is 20 mg/m² IV daily for 5 days per cycle.

Metastatic Ovarian Tumors

The usual PLATINOL dose for the treatment of metastatic ovarian tumors in combination with cyclophosphamide is 75 to 100 mg/m² IV per cycle once every 4 weeks (DAY 1).

The dose of cyclophosphamide when used in combination with PLATINOL is 600 mg/m² IV once every 4 weeks (DAY 1).

For directions for the administration of cyclophosphamide, refer to the cyclophosphamide package insert.

In combination therapy, PLATINOL and cyclophosphamide are administered sequentially.

As a single agent, PLATINOL should be administered at a dose of 100 mg/m² IV per cycle once every 4 weeks.

Advanced Bladder Cancer

PLATINOL should be administered as a single agent at a dose of 50 to 70 mg/m² IV per cycle once every 3 to 4 weeks depending on the extent of prior exposure to radiation therapy and/or prior chemotherapy. For heavily pretreated patients an initial dose of 50 mg/m² per cycle repeated every 4 weeks is recommended.

All Patients

Pretreatment hydration with 1 to 2 liters of fluid infused for 8 to 12 hours prior to a PLATINOL dose is recommended. The drug is then diluted in 2 liters of 5% Dextrose in ½ or ⅓ 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. Adequate hydration and urinary output must be maintained during the following 24 hours.

A repeat course of PLATINOL should not be given until the serum creatinine is below 1.5 mg/100 mL, and/or the BUN is below 25 mg/100 mL. A repeat course should not be given until circulating blood elements are at an acceptable level (platelets ≥ 100,000/mm³, WBC ≥ 4000/mm³). Subsequent doses of PLATINOL 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 powder and preparing the solution of cisplatin. 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 PLATINOL for injection.

Skin reactions associated with accidental exposure to cisplatin may occur. The use of gloves is recommended. If PLATINOL powder or PLATINOL solution 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 50 mg vials should be reconstituted with 50 mL of Sterile Water for Injection, USP. Each mL of the resulting solution will contain 1 mg of PLATINOL.

Reconstitution as recommended results in a clear, colorless to slight yellow solution.

The reconstituted 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 PLATINOL overdosage. Please call prescriber if dose is greater than 100 mg/m² per cycle. Aluminum and flip-off seal of vial have been imprinted with the following statement:

CALL DR. IF DOSE > 100 MG/M2/CYCLE.

Stability

Unopened vials of dry powder are stable for the lot life indicated on the package when stored at room temperature (25° C, 77° F).

The reconstituted solution is stable for 20 hours at room temperature (25° C, 77° F). Solution removed from the amber vial should be protected from light if it is not to be used within six hours.

Important Note: Once reconstituted, the solution should be kept at room temperature (25° C, 77° F). If the reconstituted solution is refrigerated a precipitate will form.

PLATINOL is contraindicated in patients with preexisting renal impairment. PLATINOL should not be employed in myelosuppressed patients, or in patients with hearing impairment.

PLATINOL is contraindicated in patients with a history of allergic reactions to PLATINOL or other platinum-containing compounds.

WARNINGS

PLATINOL (cisplatin for injection, USP) 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, PLATINOL should not be given more frequently than once every 3 to 4 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 PLATINOL or greater dose frequencies than those recommended. These neuropathies may be irreversible and are seen as paresthesias in a stocking-glove distribution, areflexia, and loss of proprioception and vibratory sensation. Elderly patients may be more susceptible to peripheral neuropathy (see PRECAUTIONS: Geriatric Use).

Loss of motor function has also been reported.

Anaphylactic-like reactions to PLATINOL have been reported. These reactions have occurred within minutes of administration to patients with prior exposure to PLATINOL, and have been alleviated by administration of epinephrine, corticosteroids, and antihistamines.

PLATINOL 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).

Certain genetic variants in the thiopurine S-methyltransferase (TPMT) gene are associated with increased risk of ototoxicity in children administered conventional doses of cisplatin (see CLINICAL PHARMACOLOGY). Children who do not have one of these TPMT gene variants remain at risk for ototoxicity. All pediatric patients receiving cisplatin should have audiometric testing at baseline, prior to each subsequent dose, of drug and for several years post therapy.

PLATINOL can cause fetal harm when administered to a pregnant woman. PLATINOL is mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue culture. In mice PLATINOL 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 PLATINOL was studied in BD IX rats. PLATINOL was administered intraperitoneally (i.p.) to 50 BD IX rats for 3 weeks, 3 X 1 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 1 renal fibrosarcoma.

The development of acute leukemia coincident with the use of PLATINOL has been reported. In these reports, PLATINOL was generally given in combination with other leukemogenic agents.

Injection site reactions may occur during the administration of PLATINOL (see ADVERSE REACTIONS). Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration. A specific treatment for extravasation reactions is unknown at this time.

PRECAUTIONS

Peripheral blood counts should be monitored weekly. Liver function should be monitored periodically. Neurologic examination should also be performed regularly (see ADVERSE REACTIONS).

Carcinogenesis, Mutagenesis, Impairment of Fertility

See WARNINGS.

Pregnancy

Category D. See WARNINGS.

Nursing Mothers

Cisplatin has been reported to be found in human milk; patients receiving PLATINOL should not breast-feed.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Variants in the thiopurine S-methyltransferase (TPMT) gene are associated with an increased risk of ototoxicity in children treated with cisplatin (see CLINICAL PHARMACOLOGY).

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, 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 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 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.

SIDE EFFECTS

Nephrotoxicity

Dose-related and cumulative renal insufficiency, including acute renal failure, is the major dose-limiting toxicity of PLATINOL. Renal toxicity has been noted in 28% to 36% of patients treated with a single dose of 50 mg/m². It is first noted during the second week after a dose and is manifested by elevations in BUN and creatinine, serum uric acid and/or a decrease in creatinine clearance. Renal toxicity becomes more prolonged and severe with repeated courses of the drug. Renal function must return to normal before another dose of PLATINOL 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 PLATINOL 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 PLATINOL 50 mg/m², and is manifested by tinnitus and/or hearing loss in the high frequency range (4000 to 8000 Hz). The prevelance of hearing loss in children is particularly high and is estimated to be 40-60%. Decreased ability to hear normal conversational tones may occur. Deafness after the initial dose of PLATINOL has been reported. Ototoxic effects may be more severe in children receiving PLATINOL.

Hearing loss can be unilateral or bilateral and tends to become more frequent and severe with repeated cisplatin doses. It is unclear whether PLATINOL-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. Variants in the thiopurine S-methyltransferase gene (TPMT) have been reported to be associated with an increased risk of ototoxicity in children treated with cisplatin (see CLINICAL PHARMACOLOGY).

Other genetic factors may also contribute to the cisplatin-induced ototoxicity.

Hematologic

Myelosuppression occurs in 25% to 30% of patients treated with PLATINOL. The nadirs in circulating platelets and leukocytes occur between days 18 to 23 (range 7.5 to 45) with most patients recovering by day 39 (range 13 to 62). Leukopenia and thrombocytopenia are more pronounced at higher doses ( > 50 mg/m²). Anemia (decrease of 2 g hemoglobin/100 mL) occurs at approximately the same frequency and with the same timing as leukopenia and thrombocytopenia. Fever and infection have also been reported in patients with neutropenia. Potential fatalities due to infection (secondary to myelosuppression) have been reported. Elderly patients may be more susceptible to myelosuppression (see PRECAUTIONS: Geriatric Use).

In addition to anemia secondary to myelosuppression, a Coombs' positive hemolytic anemia has been reported. In the presence of cisplatin hemolytic anemia, a further course of treatment may be accompanied by increased hemolysis and this risk should be weighed by the treating physician.

The development of acute leukemia coincident with the use of PLATINOL has been reported. In these reports, PLATINOL was generally given in combination with other leukemogenic agents.

Gastrointestinal

Marked nausea and vomiting occur in almost all patients treated with PLATINOL, 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 PLATINOL therapy.

Diarrhea has also been reported.

Other Toxicities

Vascular toxicities coincident with the use of PLATINOL 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 PLATINOL. It has been suggested that hypomagnesemia developing coincident with the use of PLATINOL 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 PLATINOL 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 PLATINOL.

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/m², 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 PLATINOL neuropathy usually develop during treatment, symptoms of neuropathy may begin 3 to 8 weeks after the last dose of PLATINOL. PLATINOL 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 PLATINOL 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 PLATINOL. Improvement and/or total recovery usually occurs after discontinuing PLATINOL. 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 PLATINOL 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 PLATINOL. 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 PLATINOL 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 PLATINOL 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 PLATINOL. Severity of the local tissue toxicity appears to be related to the concentration of the PLATINOL solution. Infusion of solutions with a PLATINOL concentration greater than 0.5 mg/mL may result in tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema.

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 PLATINOL.

Category D. See WARNINGS.

Nephrotoxicity

Dose-related and cumulative renal insufficiency, including acute renal failure, is the major dose-limiting toxicity of PLATINOL. Renal toxicity has been noted in 28% to 36% of patients treated with a single dose of 50 mg/m². It is first noted during the second week after a dose and is manifested by elevations in BUN and creatinine, serum uric acid and/or a decrease in creatinine clearance. Renal toxicity becomes more prolonged and severe with repeated courses of the drug. Renal function must return to normal before another dose of PLATINOL 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 PLATINOL 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 PLATINOL 50 mg/m², and is manifested by tinnitus and/or hearing loss in the high frequency range (4000 to 8000 Hz). The prevelance of hearing loss in children is particularly high and is estimated to be 40-60%. Decreased ability to hear normal conversational tones may occur. Deafness after the initial dose of PLATINOL has been reported. Ototoxic effects may be more severe in children receiving PLATINOL.

Hearing loss can be unilateral or bilateral and tends to become more frequent and severe with repeated cisplatin doses. It is unclear whether PLATINOL-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. Variants in the thiopurine S-methyltransferase gene (TPMT) have been reported to be associated with an increased risk of ototoxicity in children treated with cisplatin (see CLINICAL PHARMACOLOGY).

Other genetic factors may also contribute to the cisplatin-induced ototoxicity.

Hematologic

Myelosuppression occurs in 25% to 30% of patients treated with PLATINOL. The nadirs in circulating platelets and leukocytes occur between days 18 to 23 (range 7.5 to 45) with most patients recovering by day 39 (range 13 to 62). Leukopenia and thrombocytopenia are more pronounced at higher doses ( > 50 mg/m²). Anemia (decrease of 2 g hemoglobin/100 mL) occurs at approximately the same frequency and with the same timing as leukopenia and thrombocytopenia. Fever and infection have also been reported in patients with neutropenia. Potential fatalities due to infection (secondary to myelosuppression) have been reported. Elderly patients may be more susceptible to myelosuppression (see PRECAUTIONS: Geriatric Use).

In addition to anemia secondary to myelosuppression, a Coombs' positive hemolytic anemia has been reported. In the presence of cisplatin hemolytic anemia, a further course of treatment may be accompanied by increased hemolysis and this risk should be weighed by the treating physician.

The development of acute leukemia coincident with the use of PLATINOL has been reported. In these reports, PLATINOL was generally given in combination with other leukemogenic agents.

Gastrointestinal

Marked nausea and vomiting occur in almost all patients treated with PLATINOL, 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 PLATINOL therapy.

Diarrhea has also been reported.

Other Toxicities

Vascular toxicities coincident with the use of PLATINOL 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 PLATINOL. It has been suggested that hypomagnesemia developing coincident with the use of PLATINOL 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 PLATINOL 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 PLATINOL.

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/m², 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 PLATINOL neuropathy usually develop during treatment, symptoms of neuropathy may begin 3 to 8 weeks after the last dose of PLATINOL. PLATINOL 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 PLATINOL 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 PLATINOL. Improvement and/or total recovery usually occurs after discontinuing PLATINOL. 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 PLATINOL 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 PLATINOL. 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 PLATINOL 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 PLATINOL 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 PLATINOL. Severity of the local tissue toxicity appears to be related to the concentration of the PLATINOL solution. Infusion of solutions with a PLATINOL concentration greater than 0.5 mg/mL may result in tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema.

Caution should be exercised to prevent inadvertent overdosage with PLATINOL.

Acute overdosage with this drug may result in kidney failure, liver failure, deafness, ocular toxicity (including detachment of the retina), significant myelosuppression, intractable nausea and vomiting and/or neuritis. In addition, death can occur following overdosage.

No proven antidotes have been established for PLATINOL overdosage. Hemodialysis, even when initiated four hours after the overdosage, appears to have little effect on removing platinum from the body because of PLATINOL's rapid and high degree of protein binding. Management of overdosage should include general supportive measures to sustain the patient through any period of toxicity that may occur.