carboplatin 10 MG/ML Injectable Solution [Kyxata]

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 Injection 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.

DOSAGE AND ADMINISTRATION NOTE: Aluminum reacts with carboplatin causing precipitate formation and loss of potency, therefore, needles or intravenous sets containing aluminum 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 intravenous on day 1 every 4 weeks (alternatively see Formula Dosing ). In general, however, single intermittent courses of carboplatin injection 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 injection - 300 mg/m 2 intravenous on day 1 every 4 weeks for 6 cycles (alternatively see Formula Dosing ). Cyclophosphamide - 600 mg/m 2 intravenous 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 injection 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. * 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. Platelets Neutrophils Adjusted Dose* (From Prior Course) >100,000 >2,000 125% 50 to 100,000 500 to 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 to 59 mL/min 250 mg/m 2 16 to 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 dosage, based upon a patient’s glomerular filtration rate (GFR in mL/min) and carboplatin injection target area under the concentration versus time curve (AUC in mg/mL.min), has been proposed by Calvert. In these studies, GFR was measured by 51 Cr-EDTA clearance. CALVERT FORMULA FOR CARBOPLATIN DOSING Total Dose (mg) = (target AUC) x (GFR + 25) Note: With the Calvert formula, the total dose of carboplatin is calculated in mg, not mg/m 2 . The target AUC of 4 mg/mL·min to 6 mg/mL·min using single-agent carboplatin appears to provide the most appropriate dose range in previously treated patients. This study also showed a trend between the AUC of single-agent carboplatin administered to previously treated patients and the likelihood of developing toxicity. % Actual Toxicity in Previously Treated Patients AU C (mg/mL·min) Gr 3 or Gr 4 Thrombocytopenia Gr 3 or Gr 4 Leukopenia 4 to 5 16% 13% 6 to 7 33% 34% Geriatric Dosing Because renal function is often decreased in elderly patients, formula dosing of carboplatin injection based on estimates of GFR should be used in elderly patients to provide predictable plasma carboplatin injection AUCs and thereby minimize the risk of toxicity. PREPARATION OF INTRAVENOUS SOLUTIONS Carboplatin injection is a premixed aqueous solution of 10 mg/mL carboplatin. Carboplatin aqueous solution can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D 5 W) or 0.9% Sodium Chloride Injection, USP. When prepared as directed, carboplatin aqueous solutions are stable for 8 hours at room temperature (25°C). Since no antibacterial preservative is contained in the formulation, it is recommended that carboplatin aqueous solutions be discarded 8 hours after dilution.

WARNINGS Bone marrow suppression (leukopenia, neutropenia, and thrombocytopenia) is dose-dependent and is also the dose-limiting toxicity. Peripheral blood counts should be frequently monitored during carboplatin treatment and, when appropriate, until recovery is achieved. Median nadir occurs at day 21 in patients receiving single agent carboplatin. In general, single intermittent courses of carboplatin should not be repeated until leukocyte, neutrophil, and platelet counts have recovered. Since anemia is cumulative, transfusions may be needed during treatment with carboplatin, particularly in patients receiving prolonged therapy. Bone marrow suppression is increased in patients who have received prior therapy, especially regimens including cisplatin. Marrow suppression is also increased in patients with impaired kidney function. Initial carboplatin dosages in these patients should be appropriately reduced (see DOSAGE AND ADMINISTRATION ) and blood counts should be carefully monitored between courses. The use of carboplatin in combination with other bone marrow suppressing therapies must be carefully managed with respect to dosage and timing in order to minimize additive effects. Hemolytic anemia with the presence of serologic drug-induced antibodies has been reported in patients treated with carboplatin. This event can be fatal. Hemolytic-uremic syndrome is a potentially life-threatening side effect. Carboplatin should be discontinued at the first sign of microangiopathic hemolytic anemia, such as rapidly falling hemoglobin with concomitant thrombocytopenia or elevation of serum bilirubin, serum creatinine, blood urea nitrogen, or lactate dehydrogenase (LDH). Renal failure may not be reversible with discontinuation of therapy and dialysis may be required (see ADVERSE REACTIONS ). Carboplatin has limited nephrotoxic potential, but concomitant treatment with aminoglycosides has resulted in increased renal and/or audiologic toxicity, and caution must be exercised when a patient receives both drugs. Clinically significant hearing loss has been reported to occur in pediatric patients when carboplatin was administered at higher than recommended doses in combination with other ototoxic agents. Delayed onset hearing loss has been reported in pediatric patients. Long-term audiometric follow‑up in this population is recommended. Carboplatin can induce emesis, which can be more severe in patients previously receiving emetogenic therapy. The incidence and intensity of emesis have been reduced by using premedication with antiemetics. Although no conclusive efficacy data exist with the following schedules of carboplatin, lengthening the duration of single intravenous administration to 24 hours or dividing the total dose over five consecutive daily pulse doses has resulted in reduced emesis. Although peripheral neurotoxicity is infrequent, its incidence is increased in patients older than 65 years and in patients previously treated with cisplatin. Pre-existing cisplatin-induced neurotoxicity does not worsen in about 70% of the patients receiving carboplatin as secondary treatment. Loss of vision, which can be complete for light and colors, has been reported after the use of carboplatin with doses higher than those recommended in the package insert. Vision appears to recover totally or to a significant extent within weeks of stopping these high doses. As in the case of other platinum-coordination compounds, allergic reactions to carboplatin have been reported. These may occur within minutes of administration and should be managed with appropriate supportive therapy. There is increased risk of allergic reactions including anaphylaxis in patients previously exposed to platinum therapy (see CONTRAINDICATIONS and ADVERSE REACTIONS: Allergic Reactions ). Hypersensitivity reactions which progressed to Kounis syndrome have also been reported (see ADVERSE REACTIONS: Allergic Reactions ). Patients at high risk of Tumor Lysis Syndrome (TLS), such as those with high tumor burden, high sensitivity to cytotoxic agents, or tumors that have high proliferative rate, should be monitored closely and appropriate precaution taken. High dosages of carboplatin (more than four times the recommended dose) have resulted in severe abnormalities of liver function tests. Cases of hepatic veno-occlusive disease (sinusoidal obstructive syndrome) have been reported. Some of them were fatal. Carboplatin may cause fetal harm when administered to a pregnant woman. Carboplatin has been shown to be embryotoxic and teratogenic in rats. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

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

CLINICAL PHARMACOLOGY Carboplatin, like cisplatin, produces predominantly inter strand DNA cross-links rather than DNA-protein cross-links. This effect is apparently cell-cycle nonspecific. The aquation of carboplatin, whichis 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. CLINICAL STUDIES Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer In two prospectively randomized, controlled studies conducted by the National Cancer Institute of Canada, Clinical Trials Group (NCIC) and the Southwest Oncology Group (SWOG), 789 chemotherapy naive patients with advanced ovarian cancer were treated with carboplatin or cisplatin, both in combination with cyclophosphamide every 28 days for 6 courses before surgical reevaluation. The following results were obtained from both studies: Comparative Efficacy Overview of Pivotal Trials NCIC SWOG Number of patients randomized 447 342 Median age (years) 60 62 Dose of cisplatin 75 mg/m 2 100 mg/m 2 Dose of carboplatin 300 mg/m 2 300 mg/m 2 Dose of cyclophosphamide 600 mg/m 2 600 mg/m 2 Residual tumor < 2 cm (number of patients) 39% (174/447) 14% (49/342) Clinical Response in Measurable Disease Patients NCIC SWOG Carboplatin (number of patients) 60% (48/80) 58% (48/83) Cisplatin (number of patients) 58% (49/85) 43% (33/76) 95% CI of difference (Carboplatin-Cisplatin) (-13.9%, 18.6%) (-2.3%, 31.1%) Pathologic Complete Response* NCIC SWOG Carboplatin (number of patients) 11% (24/224) 10% (17/171) Cisplatin (number of patients) 15% (33/223) 10% (17/171) 95% CI of difference (Carboplatin-Cisplatin) (-10.7%, 2.5%) (-6.9%, 6.9%) *114 Carboplatin and 109 Cisplatin patients did not undergo second look surgery in NCIC study. 90 Carboplatin and 106 Cisplatin patients did not undergo second look surgery in SWOG study. Progression-Free Survival (PFS) NCIC SWOG Median Carboplatin 59 weeks 49 weeks Cisplatin 61 weeks 47 weeks 2-year PFS* Carboplatin 31% 21% Cisplatin 31% 21% 95% CI of difference (Carboplatin-Cisplatin) (-9.3, 8.7) (-9, 9.4) 3-year PFS* Carboplatin 19% 8% Cisplatin 23% 14% 95% CI of difference (Carboplatin-Cisplatin) (-11.5, 4.5) (-14.1, 0.3) Hazard Ratio** 1.10 1.02 95% CI (Carboplatin-Cisplatin) (0.89, 1.35) (0.81, 1.29) * Kaplan-Meier Estimates Unrelated deaths occurring in the absence of progression were counted as events (progression) in this analysis. ** Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis. Survival NCIC SWOG Median Carboplatin 110 weeks 86 weeks Cisplatin 99 weeks 79 weeks 2-year Survival* Carboplatin 51.9 % 40.2 % Cisplatin 48.4 % 39 % 95% CI of difference (Carboplatin-Cisplatin) (-6.2, 13.2) (-9.8, 12.2) 3-year Survival* Carboplatin 34.6 % 18.3 % Cisplatin 33.1 % 24.9 % 95% CI of difference (Carboplatin-Cisplatin) (-7.7, 10.7) (-15.9, 2.7) Hazard Ratio** 95% CI (Carboplatin-Cisplatin) 0.98 (0.78, 1.23) 1.01 (0.78, 1.30) * Kaplan-Meier Estimates ** Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis. Comparative Toxicity The pattern of toxicity exerted by the carboplatin-containing regimen was significantly different from that of the cisplatin-containing combinations. Differences between the two studies may be explained by different cisplatin dosages and by different supportive care. The carboplatin-containing regimen induced significantly more thrombocytopenia and, in one study, significantly more leukopenia and more need for transfusional support. The cisplatin-containing regimen produced significantly more anemia in one study. However, no significant differences occurred in incidences of infections and hemorrhagic episodes. Non-hematologic toxicities (emesis, neurotoxicity, ototoxicity, renal toxicity, hypomagnesemia, and alopecia) were significantly more frequent in the cisplatin-containing arms. ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER NCIC STUDY Carboplatin Arm Percent* Cisplatin Arm Percent* P-Values** Bone Marrow Thrombocytopenia <100,000/mm 3 <50,000/mm 3 70 41 29 6 < 0.001 < 0.001 Neutropenia <2,000 cells/mm 3 <1000 cells/mm 3 97 81 96 79 ns ns Leucopenia <4,000 cells/mm 3 <2,000 cells/mm 3 98 68 97 52 ns 0.001 Anemia <11 g/dL < 8 g/dL 91 18 91 12 ns ns Infections 14 12 ns Bleeding 10 4 ns Transfusions 42 31 0.018 Gastrointestinal Nausea and vomiting 93 98 0.010 Vomiting 84 97 < 0.001 Other GI side effects 50 62 0.013 Neurologic Peripheral neuropathies 16 42 < 0.001 Ototoxicity 13 33 < 0.001 Other sensory side effects 6 10 ns Central neurotoxicity 28 40 0.009 Renal Serum creatinine elevations 5 13 0.006 Blood urea elevations 17 31 < 0.001 Hepatic Bilirubin elevations 5 3 ns SGOT elevations 17 13 ns Alkaline phosphatase elevations - - - Electrolytes loss Sodium 10 20 0.005 Potassium 16 22 ns calcium 16 19 ns Magnesium 63 88 < 0.001 Other side effects Pain 36 37 ns Asthenia 40 33 ns Cardiovascular 15 19 ns Respiratory 8 9 ns Allergic 12 9 ns Genitourinary 10 10 ns Alopecia † 50 62 0.017 Mucositis 10 9 ns * Values are in percent of evaluable patients ** ns = not significant, p > 0.05 † May have been affected by cyclophosphamide dosage delivered ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER SWOG STUDY Carboplatin Arm Percent* Cisplatin Arm Percent* P-Values** Bone Marrow Thrombocytopenia <100,000/mm 3 <50,000/mm 3 59 22 35 11 < 0.001 0.006 Neutropenia <2,000 cells/mm 3 <1,000 cells/mm 3 95