Carboplatin

INDICATIONS Initial Treatment of Advanced Ovarian Carcinoma Carboplatin injection is indicated for the initial treatment of advanced ovarian carcinoma in established combination with other approved chemotherapeutic agents. One established combination regimen consists of carboplatin and cyclophosphamide. Two randomized controlled studies conducted by the NCIC and SWOG with carboplatin versus cisplatin, both in combination with cyclophosphamide, have demonstrated equivalent overall survival between the two groups (see CLINICAL STUDIES ). There is limited statistical power to demonstrate equivalence in overall pathologic complete response rates and long-term survival (≥ 3 years) because of the small number of patients with these outcomes: the small number of patients with residual tumor < 2 cm after initial surgery also limits the statistical power to demonstrate equivalence in this subgroup. Secondary Treatment of Advanced Ovarian Carcinoma Carboplatin injection is indicated for the palliative treatment of patients with ovarian carcinoma recurrent after prior chemotherapy, including patients who have been previously treated with cisplatin. Within the group of patients previously treated with cisplatin, those who have developed progressive disease while receiving cisplatin therapy may have a decreased response rate.

CLINICAL PHARMACOLOGY Carboplatin, like cisplatin, produces predominantly interstrand DNA cross-links rather than DNA-protein cross-links. This effect is apparently cell-cycle nonspecific. The aquation of carboplatin, which is thought to produce the active species, occurs at a slower rate than in the case of cisplatin. Despite this difference, it appears that both carboplatin and cisplatin induce equal numbers of drug-DNA cross-links, causing equivalent lesions and biological effects. The differences in potencies for carboplatin and cisplatin appear to be directly related to the difference in aquation rates. In patients with creatinine clearances of about 60 mL/min or greater, plasma levels of intact carboplatin decay in a biphasic manner after a 30-minute intravenous infusion of 300 mg/m 2 to 500 mg/m 2 of carboplatin. The initial plasma half-life (alpha) was found to be 1.1 to 2 hours (n=6), and the postdistribution plasma half-life (beta) was found to be 2.6 to 5.9 hours (n=6). The total body clearance, apparent volume of distribution and mean residence time for carboplatin are 4.4 L/hour, 16 L and 3.5 hours, respectively. The C max values and areas under the plasma concentration versus time curves from 0 to infinity (AUC inf) increase linearly with dose, although the increase was slightly more than dose proportional. Carboplatin, therefore, exhibits linear pharmacokinetics over the dosing range studied (300 mg/m 2 to 500 mg/m 2 ). Carboplatin is not bound to plasma proteins. No significant quantities of protein-free, ultrafilterable platinum-containing species other than carboplatin are present in plasma. However, platinum from carboplatin becomes irreversibly bound to plasma proteins and is slowly eliminated with a minimum half-life of 5 days. The major route of elimination of carboplatin is renal excretion. Patients with creatinine clearances of approximately 60 mL/min or greater excrete 65% of the dose in the urine within 12 hours and 71% of the dose within 24 hours. All of the platinum in the 24-hour urine is present as carboplatin. Only 3% to 5% of the administered platinum is excreted in the urine between 24 and 96 hours. There are insufficient data to determine whether biliary excretion occurs. In patients with creatinine clearances below 60 mL/min, the total body and renal clearances of carboplatin decrease as the creatinine clearance decreases. Carboplatin dosages should therefore be reduced in these patients (see DOSAGE AND ADMINISTRATION ). The primary determinant of carboplatin injection clearance is glomerular filtration rate (GFR) and this parameter of renal function is often decreased in elderly patients. Dosing formulas incorporating estimates of GFR (see DOSAGE AND ADMINISTRATION ) to provide predictable carboplatin injection plasma AUCs should be used in elderly patients to minimize the risk of toxicity.

DOSAGE AND ADMINISTRATION NOTE: Aluminium reacts with carboplatin causing precipitate formation and loss of potency, therefore, needles or intravenous sets containing aluminium parts that may come in contact with the drug must not be used for the preparation or administration of carboplatin injection. Single Agent Therapy Carboplatin injection, as a single agent, has been shown to be effective in patients with recurrent ovarian carcinoma at a dosage of 360 mg/m 2 IV on day 1 every 4 weeks (alternatively see Formula Dosing ). In general, however, single intermittent courses of carboplatin should not be repeated until the neutrophil count is at least 2,000 and the platelet count is at least 100,000. Combination Therapy with Cyclophosphamide In the chemotherapy of advanced ovarian cancer, an effective combination for previously untreated patients consists of: Carboplatin - 300 mg/m 2 IV on day 1 every 4 weeks for 6 cycles (alternatively see Formula Dosing ). Cyclophosphamide - 600 mg/m 2 IV on day 1 every 4 weeks for 6 cycles. For directions regarding the use and administration of cyclophosphamide please refer to its package insert (See CLINICAL STUDIES .) Intermittent courses of carboplatin in combination with cyclophosphamide should not be repeated until the neutrophil count is at least 2,000 and the platelet count is at least 100,000. Dose Adjustment Recommendations Pretreatment platelet count and performance status are important prognostic factors for severity of myelosuppression in previously treated patients. The suggested dose adjustments for single agent or combination therapy shown in the table below are modified from controlled trials in previously treated and untreated patients with ovarian carcinoma. Blood counts were done weekly, and the recommendations are based on the lowest post-treatment platelet or neutrophil value. Platelets Neutrophils Adjusted Dose Percentages apply to carboplatin injection as a single agent or to both carboplatin and cyclophosphamide in combination. In the controlled studies, dosages were also adjusted at a lower level (50% to 60%) for severe myelosuppression. Escalations above 125% were not recommended for these studies. ( From Prior Course ) > 100,000 > 2,000 125% 50 - 100,000 500 - 2,000 No Adjustment < 50,000 < 500 75% Carboplatin injection is usually administered by an infusion lasting 15 minutes or longer. No pre- or post-treatment hydration or forced diuresis is required. Patients with Impaired Kidney Function Patients with creatinine clearance values below 60 mL/min are at increased risk of severe bone marrow suppression. In renally-impaired patients who received single agent carboplatin therapy, the incidence of severe leukopenia, neutropenia, or thrombocytopenia has been about 25% when the dosage modifications in the table below have been used. Baseline Creatinine Clearance Recommended Dose on Day 1 41 - 59 mL/min 250 mg/m 2 16 - 40 mL/min 200 mg/m 2 The data available for patients with severely impaired kidney function (creatinine clearance below 15 mL/min) are too limited to permit a recommendation for treatment. These dosing recommendations apply to the initial course of treatment. Subsequent dosages should be adjusted according to the patient's tolerance based on the degree of bone marrow suppression. Formula Dosing Another approach for determining the initial dose of carboplatin injection is the use of mathematical formulae, which are based on a patient's pre-existing renal function or renal function and desired platelet nadir. Renal excretion is the major route of elimination for carboplatin (See CLINICAL PHARMACOLOGY .) The use of dosing formulae, as compared to empirical dose calculation based on body surface area, allows compensation for patient variations in pretreatment renal function that might otherwise result in either underdosing (in patients with above average renal function) or overdosing (in patients with impaired renal function). A simple formula for calculating

ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS Contact Apotex Corp.at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . For a comparison of toxicities when carboplatin or cisplatin was given in combination with cyclophosphamide, see CLINICAL STUDIES : Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer: Comparative Toxicity. ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER * Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer: Data are based on the experience of 393 patients with ovarian cancer (regardless of baseline status) who received initial combination therapy with carboplatin and cyclophosphamide in two randomized controlled studies conducted by SWOG and NCIC (see CLINICAL STUDIES ). Combination with cyclophosphamide as well as duration of treatment may be responsible for the differences that can be noted in the adverse experience table. * * Single Agent Use for the Secondary Treatment of Ovarian Cancer: Data are based on the experience of 553 patients with previously treated ovarian carcinoma (regardless of baseline status) who received single agent carboplatin. First Line Combination Therapy * Percent Second Line Single Agent Therapy * * Percent Bone Marrow Thrombocytopenia <100,000/mm3 66 62 <50,000/mm3 33 35 Neutropenia <2,000 cells/mm3 96 67 <1,000 cells/mm3 82 21 Leukopenia <4,000 cells/mm3 97 85 <2,000 cells/mm3 71 26 Anemia <11 g/dL 90 90 <8g/dL 14 21 Infections 16 5 Bleeding 8 5 Transfusions 35 44 Gastrointestinal Nausea and vomiting 93 92 Vomiting 83 81 Other GI side effects 46 21 Neurologic Peripheral neuropathies 15 6 Ototoxicity 12 1 Other sensory side effects 5 1 Central neurotoxicity 26 5 Renal Serum creatinine elevations 6 10 Blood urea elevations 17 22 Hepatic Bilirubin elevations 5 5 SGOT elevations 20 19 Alkaline phosphatase elevations 29 37 Electrolytes loss Sodium 10 47 Potassium 16 28 Calcium 16 31 Magnesium 61 43 Other side effects Pain 44 23 Asthenia 41 11 Cardiovascular 19 6 Respiratory 10 6 Allergic 11 2 Genitourinary 10 2 Alopecia 49 2 Mucositis 8 1 In the narrative section that follows, the incidences of adverse events are based on data from 1,893 patients with various types of tumors who received carboplatin as single agent therapy. Hematologic Toxicity Bone marrow suppression is the dose-limiting toxicity of carboplatin. Thrombocytopenia with platelet counts below 50,000/mm 3 occurs in 25% of the patients (35% of pretreated ovarian cancer patients); neutropenia with granulocyte counts below 1,000/mm 3 occurs in 16% of the patients (21% of pretreated ovarian cancer patients); leukopenia with WBC counts below 2,000/mm 3 occurs in 15% of the patients (26% of pretreated ovarian cancer patients). The nadir usually occurs about day 21 in patients receiving single agent therapy. By day 28, 90% of patients have platelet counts above 100,000/mm 3 ; 74% have neutrophil counts above 2,000/mm 3 ; 67% have leukocyte counts above 4,000/mm 3 . Marrow suppression is usually more severe in patients with impaired kidney function. Patients with poor performance status have also experienced a higher incidence of severe leukopenia and thrombocytopenia. The hematologic effects, although usually reversible, have resulted in infectious or hemorrhagic complications in 5% of the patients treated with carboplatin, with drug related death occurring in less than 1% of the patients. Fever has also been reported in patients with neutropenia. Anemia with hemoglobin less than 11 g/dL has been observed in 71% of the patients who started therapy with a baseline above that value. The incidence of anemia increases with increasing exposure to carboplatin. Transfusions have been administered to 26% of the patients treated with carboplatin (44% of previously treated ovarian cancer patients). Bone marrow depression may be more severe when carboplatin is combined with other bone marrow suppressing drugs or with radiotherapy. Gastrointestinal Toxicity Vomiting occurs in 65% of

PRECAUTIONS General Needles or intravenous administration sets containing aluminium parts that may come in contact with carboplatin injection should not be used for the preparation or administration of the drug. Aluminium can react with carboplatin causing precipitate formation and loss of potency. Drug Interactions The renal effects of nephrotoxic compounds may be potentiated by carboplatin. Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of carboplatin has not been studied, but compounds with similar mechanisms of action and mutagenicity profiles have been reported to be carcinogenic. Carboplatin has been shown to be mutagenic both in vitro and in vivo . It has also been shown to be embryotoxic and teratogenic in rats receiving the drug during organogenesis. Secondary malignancies have been reported in association with multi-drug therapy. Pregnancy Pregnancy Category D See WARNINGS . Nursing Mothers It is not known whether carboplatin is excreted in human milk. Because there is a possibility of toxicity in nursing infants secondary to carboplatin treatment of the mother, it is recommended that breast-feeding be discontinued if the mother is treated with carboplatin injection. Pediatric Use Safety and effectiveness in pediatric patients have not been established (see WARNINGS: "audiologic toxicity"). Geriatric Use Of the 789 patients in initial treatment combination therapy studies (NCIC and SWOG), 395 patients were treated with carboplatin in combination with cyclophosphamide. Of these, 141 were over 65 years of age and 22 were 75 years or older. In these trials, age was not a prognostic factor for survival. In terms of safety, elderly patients treated with carboplatin were more likely to develop severe thrombocytopenia than younger patients. In a combined database of 1,942 patients (414 were ≥ 65 years of age) that received single agent carboplatin for different tumor types, a similar incidence of adverse events was seen in patients 65 years and older and in patients less than 65. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Because renal function is often decreased in the elderly, renal function should be considered in the selection of carboplatin injection dosage (see DOSAGE AND ADMINISTRATION ).

CONTRAINDICATIONS Carboplatin injection is contraindicated in patients with a history of severe allergic reactions to cisplatin or other platinum-containing compounds. Carboplatin injection should not be employed in patients with severe bone marrow depression or significant bleeding.

OVERDOSAGE There is no known antidote for carboplatin injection overdosage. The anticipated complications of overdosage would be secondary to bone marrow suppression and/or hepatic toxicity.