Cisplatin

Cisplatin is intended for the treatment of: • advanced or metastasised testicular cancer • advanced or metastasised ovarian cancer • advanced or metastasised bladder carcinoma • advanced or metastasised squamous cell carcinoma of the head and neck • advanced or metastasised non-small cell lung carcinoma • advanced or metastasised small cell lung carcinoma.

• Cisplatin is indicated in the treatment of cervical carcinoma in combination with other chemotherapeutics or with radiotherapy. • Cisplatin can be used as monotherapy and in combination therapy.

Posology Adults and children:

The cisplatin dosage depends on the primary disease, the expected reaction, and on whether cisplatin is used for monotherapy or as a component of combination chemotherapy. The dosage directions are applicable for both adults and children.

For monotherapy, the following two dosage regimens are recommended: << Single dose of 50 to 120 mg/m2 body surface every 3 to 4 weeks; < 15 to 20 mg/m2/day for five days, every 3 to 4 weeks. If cisplatin is used in combination therapy, the dose of cisplatin must be reduced.

A typical dose is 20 mg/m2 or more once every 3 to 4 weeks. For treatment of cervical cancer cisplatin is used in combination with radiotherapy. A typical dose is 40 mg/m2 weekly for 6 weeks. 4). 3). ) should be administered by intravenous infusion over a period of 6 to 8 hours.

Adequate hydration must be maintained from 2 to 12 hours prior to administration until minimum 6 hours after the administration of cisplatin. Hydratation is necessary to cause sufficient diuresis during and after treatment with cisplatin.

9% and glucose solution 5% (1:1). Method of administration Cisplatin 1 mg/ml sterile concentrate is to be diluted before administration. 6. The diluted solution should be administered only intravenously by infusion (see below). For administration, any device containing aluminum that may come in contact with cisplatin (sets for intravenous infusion, needles, catheters, syringes) must be avoided.

Hydration prior to treatment with cisplatin:

Intravenous infusion of 100 to 200ml/hour for a period of 6 to 12 hours, with a total amount of at least 1litre.

Hydration after termination of the administration of cisplatin:

Intravenous infusion of another 2 liters at a rate of 100 to 200 ml per hour for a period of 6 to 12 hours. Forced diuresis may be required should the urine secretion be less than 100 to 200 ml/hour after hydration. 5g mannitol as a 10% solution (375 ml mannitol solution 10%), or by administration of a diuretic if the kidney functions are normal.

The administration of mannitol or a diuretic is also required when the administrated cisplatin dose is higher than 60 mg/m2 of body surface. It is necessary that the patient drinks large quantities of liquids for 24 hours after the cisplatin infusion to ensure adequate urine secretion.

The most frequently reported adverse events (>10%) of cisplatin were haematological (leukopenia, thrombocytopenia and anaemia), gastrointestinal (anorexia, nausea, vomiting and diarrhoea), ear disorders (hearing impairment), renal disorders (renal failure, nephrotoxicity, hyperuricemia) and fever.

Serious toxic effects on the kidneys, bone marrow and ears have been reported in up to about one third of patients given a single dose of cisplatin; the effects are generally dose-related and cumulative. Ototoxicity may be more severe in children.

Frequencies are defined using the following convention:

Very common (≤1/10); common (≤1/100 to <1/10); uncommon (≤1/1,000 to <1/100); rare (≤1/10,000 to ≤1/1,000); very rare (≤1/10,000), not known (cannot be estimated from the available data). Table of Adverse Drug Events Reported During Clinical or Postmarketing Experience (MedDRA terms).

System Organ Class Frequency MedDRA term Not known Infectiona Infections and infestations Common Sepsis Very common Bone marrow failure, thrombocytopenia, leukopenia, anaemia Blood and lymphatic system disorders Not known Coombs positive haemolytic anaemia Neoplasm benign, malignant, and unspecified Rare Acute leukaemia Immune system disorders Uncommon Anaphylactoidb reaction Endocrine disorders Not known Blood amylase increased, inappropriate antidiuretic hormone secretion Not known Dehydration, hypokalaemia, hypophosphatemia, hyperuricemia, hypocalcaemia, tetany Uncommon Hypomagnesaemia Metabolism and nutrition disorders Very common Hyponatraemia Not known Cerebrovascular accident, haemorrhagic stroke, ischaemic stroke ageusia, cerebral arteritis, Lhermitte's sign, myelopathy, autonomic neuropathy Nervous system disorders Rare Convulsion, neuropathy peripheral, leukoencephalopathy, reversible posterior leukoencephalopathy syndrome Eye disorders Not known Vision blurred, colour blindness acquired, blindness cortical, optic neuritis, papilledema, retinal pigmentation Uncommon OtotoxicityEar and labyrinth disorders Not known Tinnitus, deafness Not known Cardiac disorder Common Arrhythmia, bradycardia, tachycardia Rare Myocardial infarction Cardiac disorders Very rare Cardiac arrest Common Venous thromboembolismVascular disorders Not known Thrombotic microangiopathy (haemolytic uremic syndrome), Raynaud's phenomenon Not known Vomiting, nausea, anorexia, hiccups, diarrhoea Gastrointestinal disorders Rare Stomatitis Hepatobiliary disorders Not known Hepatic enzymes increased, blood bilirubin increased Respiratory, thoracic and mediastinal disorders Not known Pulmonary embolism Skin and subcutaneous tissue disorders Not known Rash, alopecia Musculoskeletal, connective tissue and bone disorders Not known Muscle spasms Renal and urinary disorders Not known Renal failure acute, renal failurec , renal tubular disorder Reproductive system and breast disorders Uncommon Abnormal spermatogenesis General disorders and administration site condition Not known Pyrexia (very common), asthenia, malaise, injection site extravasationd a: Infectious complications have led to death in some patients.

b: Symptoms reported for anaphylactoid reaction such as facial edema (PT-face oedema), wheezing, bronchospasm, tachycardia, and hypotension will be included in the parentheses for anaphylactoid reaction in the AE frequency table. c: Elevations in BUN and creatinine, serum uric acid, and/or a decrease in creatinine clearance are subsumed under renal insufficiency/failure.

d: Local soft tissue toxicity including cellulitis, fibrosis, and necrosis (common) pain (common), oedema (common) and erythema (common) as the result of extravasation. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard.

1. Cisplatin may give allergic reactions in some patients. Use is contraindicated in those patients with a history of allergic reaction to cisplatin or other platinum containing compounds, or any component of the formulation. Cisplatin induces nephrotoxicity which is cumulative.

It is therefore contraindicated in patients with pre-existing renal impairment. Cisplatin has also been shown to be cumulatively neurotoxic (in particular ototoxic) and should not be given to patients with pre-existing hearing impairment.

Cisplatin is also contraindicated in myelosuppressed patients and those who are dehydrated. 6). Concurrent administration of yellow fever vaccine is contraindicated.

Cisplatin Injection BP is indicated as palliative therapy, to be employed in addition to other modalities, or in established combination therapy with other chemotherapeutic agents in the following: • Metastatic Testicular Tumors: In patients who have already received appropriate surgical and/or radiotherapeutic and/or chemotherapeutic procedures.

• Metastatic Ovarian Tumors: As secondary therapy in patients refractory to standard chemotherapy. • Advanced Bladder Cancer: As a single agent for patients with transitional cell bladder cancer. 3 Special Populations – Pediatrics). 2 Geriatrics Geriatric patients, patients with baseline renal impairment, patients who are taking other nephrotoxic drugs, or patients who are not well hydrated may be more susceptible to nephrotoxicity.

Geriatric patients may be more susceptible to myelosuppression. Geriatric patients may be more susceptible to peripheral neuropathy. 4 Special Populations – Geriatric.

2 Recommended Dose and Dosage Adjustment The recommended dose of Cisplatin Injection BP in adults and children as single-agent therapy is 50 to 75 mg/m2 as a single intravenous dose every 3 to 4 weeks, or 15 to 20 mg/m2 intravenous daily for 5 days, every 3 to 4 weeks.

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 cells/mm3, WBC 4,000 cells/mm3). Subsequent dose of Cisplatin Injection BP should not be given until an audiometric analysis indicates that auditory acuity is within normal limits.

When employed in combination with other antitumor drugs, the dose of Cisplatin Injection BP should be adjusted appropriately. 3 Reconstitution Preparation of intravenous solutions IV needles, syringes or sets having aluminum components should not be employed in preparation or administration of Cisplatin Injection BP solutions.

An interaction will occur between aluminum and platinum from cisplatin, causing formation of a black precipitate, which is visible in the reconstituted solution, and a loss of potency. 5 g of mannitol. Diluted Cisplatin Injection BP solution is suitable for intravenous infusion.

This solution is not preserved and it should be used within 24 hours. Any unused portion should be discarded after that time, in order to avoid risk of microbial contamination. As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit.

Solutions showing haziness, particulate matter, precipitate, discoloration or leakage should not be used. 4 Administration Pre-treatment hydration with 1 to 2 L of fluid infused for 8 to 12 hours prior to a cisplatin dose is recommended.

5 g of mannitol, and infused over a 6 to 8-hour period. Adequate hydration and urinary output must be maintained during the following 24 hours. Cisplatin is a cytotoxic agent. Caution should be utilized during handling and preparation.

3 Reconstitution and 7 WARNINGS AND PRECAUTIONS, General and 12 SPECIAL HANDLING INSTRUCTIONS). If cisplatin solution contacts the skin, immediately wash thoroughly with soap and water. If cisplatin solution contacts mucous membranes, flush thoroughly with water.

) • Infections, such as sepsis, including fatal cases (see 7 WARNINGS AND PRECAUTIONS and 8 ADVERSE REACTIONS) • Myelosuppression (including fatal cases) such as neutropenia, leukopenia, thrombocytopenia (see 7 WARNINGS AND PRECAUTIONS and 8 ADVERSE REACTIONS) • Neurotoxicity (see 7 WARNINGS AND PRECAUTIONS and 8 ADVERSE REACTIONS): - Leukoencephalopathy, including fatal case - Peripheral neuropathy - Posterior reversible encephalopathy syndrome, including fatal cases • Renal toxicity (see 2 CONTRAINDICATIONS, 7 WARNINGS, AND PRECAUTIONS and 8 ADVERSE REACTIONS) • Cardiovascular toxicity, such as venous thromboembolic events and pulmonary embolism, including fatal cases (see 7 WARNINGS AND PRECAUTIONS and 8 ADVERSE REACTIONS) • Administration of cisplatin prior to an infusion with paclitaxel may increase exposure to paclitaxel by 33% and can therefore intensify neutropenia and neurotoxicity.

2 Recommended Dose and Dosage Adjustment The recommended dose of Cisplatin Injection BP in adults and children as single-agent therapy is 50 to 75 mg/m2 as a single intravenous dose every 3 to 4 weeks, or 15 to 20 mg/m2 intravenous daily for 5 days, every 3 to 4 weeks.

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 cells/mm3, WBC 4,000 cells/mm3). Subsequent dose of Cisplatin Injection BP should not be given until an audiometric analysis indicates that auditory acuity is within normal limits.

When employed in combination with other antitumor drugs, the dose of Cisplatin Injection BP should be adjusted appropriately. 3 Reconstitution Preparation of intravenous solutions IV needles, syringes or sets having aluminum components should not be employed in preparation or administration of Cisplatin Injection BP solutions.

An interaction will occur between aluminum and platinum from cisplatin, causing formation of a black precipitate, which is visible in the reconstituted solution, and a loss of potency. 5 g of mannitol. Diluted Cisplatin Injection BP solution is suitable for intravenous infusion.

This solution is not preserved and it should be used within 24 hours. Any unused portion should be discarded after that time, in order to avoid risk of microbial contamination. As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit.

Solutions showing haziness, particulate matter, precipitate, discoloration or leakage should not be used. 4 Administration Pre-treatment hydration with 1 to 2 L of fluid infused for 8 to 12 hours prior to a cisplatin dose is recommended.

5 g of mannitol, and infused over a 6 to 8-hour period. Adequate hydration and urinary output must be maintained during the following 24 hours. Cisplatin is a cytotoxic agent. Caution should be utilized during handling and preparation.

3 Reconstitution and 7 WARNINGS AND PRECAUTIONS, General and 12 SPECIAL HANDLING INSTRUCTIONS). If cisplatin solution contacts the skin, immediately wash thoroughly with soap and water. If cisplatin solution contacts mucous membranes, flush thoroughly with water.

5 OVERDOSAGE CAUTION SHOULD BE USED TO PREVENT INADVERTENT OVERDOSAGE WITH CISPLATIN INJECTION BP. 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 antidote has been established for cisplatin overdosage. Hemodialysis, even when initiated for hours after overdosage, appears to have little effect on removing platinum from the body because of rapid and high degree of protein binding of cisplatin.

Management of overdosage should include general supportive measures to sustain the patient through the period of toxicity that may occur. Patients should be monitored for 3-4 weeks in case of delayed toxicity. For management of a suspected drug overdose, contact your regional poison control centre.

PrCisplatin Injection BP – Product Monograph Page 7 of 31 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING Table – Dosage Forms, Strengths, Composition and Packaging Cisplatin Injection BP, 1 mg / mL, is supplied as a sterile aqueous solution for intravenous use, available in amber glass ONCO-TAIN® vials of 50 mL and 100 mL.

Each single-use vial is individually packaged in a carton. Cisplatin Injection BP is preservative-free. 7 WARNINGS AND PRECAUTIONS See 3 WARNINGS AND PRECAUTIONS BOX General CISPLATIN INJECTION BP IS A CYTOTOXIC DRUG AND SHOULD BE USED ONLY BY PHYSICIANS EXPERIENCED WITH CANCER CHEMOTHERAPEUTIC DRUGS.

BLOOD COUNTS AS WELL AS RENAL AND HEPATIC FUNCTION TESTS SHOULD BE TAKEN REGULARLY. DISCONTINUE THE DRUG IF ABNORMAL DEPRESSION OF BONE MARROW OR ABNORMAL RENAL OR HEPATIC FUNCTION IS SEEN. Cisplatin Injection BP should be administered under the supervision of a qualified physician experienced with the use of antineoplastic therapy.

The benefit to patient versus risk of toxicity must be carefully weighed. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available. An interaction will occur between aluminum and platinum from cisplatin, causing a black precipitate which is […]

• Cisplatin Injection BP is contraindicated in patients with pre-existing renal impairment and hearing impairment, unless in the judgment of the physician and patient, the possible benefits of treatment outweigh the risks. • Cisplatin Injection BP should not be employed in myelosuppressed patients • Cisplatin Injection BP is contraindicated in individuals who have demonstrated a previous hypersensitivity to it or other platinum-containing compounds or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container (see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING).

When used as indicated, the physician must carefully weigh the therapeutic benefit versus risk of toxicity which may occur.

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.

DOSAGE & 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.

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.

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.

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% ofpatients 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. , aminoglycosides and vancomycin), and in patients with renal impairment.

, 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.

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. 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. 5 mg/mL may result in tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema.

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.