Kyxata Drug Information

Initial Treatment of Advanced Ovarian Carcinoma

KYXATA, as part of a combination regimen, is indicated for the initial treatment of adults with advanced ovarian carcinoma.

Recurrent Advanced Ovarian Carcinoma

KYXATA is indicated for treatment of adults with ovarian carcinoma recurrent after prior chemotherapy.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Initial Treatment of Advanced Ovarian Cancer The safety of KYXATA in combination with cyclophosphamide for initial treatment of advanced ovarian cancer was evaluated in two randomized controlled studies conducted by NCIC and SWOG. Patients in the carboplatin arm received carboplatin in combination with cyclophosphamide and patients in the active-comparator arm received cisplatin in combination with cyclophosphamide. Tables 3 and 4 summarize the adverse reactions and laboratory abnormalities in the NCIC study, respectively.

Table 3: Adverse Reactions (≥ 5%) in Patients with Advanced Ovarian Cancer - NCIC Study * Values are in percent of evaluable patients. Adverse Reaction Carboplatin in combination with cyclophosphamide (N=224) (%)* Cisplatin in combination with cyclophosphamide (N=223) (%)* Gastrointestinal (GI) Nausea and vomiting 93 98 Vomiting 84 97 Other GI adverse reactions 50 62 Mucositis 10 9 Skin and Subcutaneous Tissue Alopecia 50 62 General Asthenia 40 33 Pain 36 37 Cardiovascular 15 19 Infection 14 12 Hypersensitivity 12 9 Hemorrhage 10 4 Genitourinary 10 10 Respiratory 8 9 Neurologic Central neurotoxicity 28 40 Peripheral neuropathies 16 42 Ototoxicity 13 33 Other sensory disorders 6 10 Table 4: Laboratory Abnormalities in Patients with Advanced Ovarian Cancer - NCIC Study * Values are in percent of evaluable patients. Laboratory Abnormality Carboplatin in combination with cyclophosphamide (N=224)* Cisplatin in combination with cyclophosphamide (N=223)* (%) (%) Hematology Decreased neutrophils <2000 cells/mm 3 97 96 Decreased neutrophils <1000 cells/mm 3 81 79 Decreased hemoglobin <11 g/dL 91 91 Decreased hemoglobin <8 g/dL 18 12 Decreased platelets <100,000/mm 3 70 29 Decreased platelets <50,000/mm 3 41 6 Chemistry Decreased magnesium 63 88 Increased blood urea nitrogen 17 31 Increased AST 17 13 Decreased potassium 16 22 Decreased calcium 16 19 Decreased sodium 10 20 Increased serum creatinine 5 13 Increased bilirubin 5 3 Tables 5 and 6 summarize the adverse reactions and laboratory abnormalities in the SWOG study, respectively.

Table 5: Adverse Reactions (≥ 5%) in Patients with Ovarian Cancer – SWOG Study * Values are in percent of evaluable patients. Adverse Reaction Carboplatin in combination with cyclophosphamide (N=171) (%)* Cisplatin in combination with cyclophosphamide (N=171) (%)* Gastrointestinal (GI) Nausea and vomiting 94 96 Vomiting 82 91 Other GI side effects 40 48 General Pain 54 52 Alopecia 43 57 Asthenia 43 46 Cardiovascular 23 30 Respiratory 12 11 Genitourinary 11 13 Hypersensitivity 10 11 Mucositis 6 11 Neurologic Central neurotoxicity 23 29 Peripheral neuropathies 13 28 Ototoxicity 12 30 Other sensory side effects - 6 Table 6: Laboratory Abnormalities in Patients with Advanced Ovarian Cancer - SWOG Study * Values are in percent of evaluable patients. Laboratory Abnormality Carboplatin in combination with cyclophosphamide (N=171) (%)* Cisplatin in combination with cyclophosphamide (N=171) (%)* Hematology Decreased neutrophils <2000 cells/mm 3 95 97 Decreased neutrophils <1000 cells/mm 3 84 78 Decreased hemoglobin <11 g/dL 88 87 Decreased hemoglobin <8 g/dL 8 24 Decreased platelets <100,000/mm 3 59 35 Decreased platelets <50,000/mm 3 22 11 Chemistry Decreased magnesium 58 77 Increased alkaline phosphatase 29 20 Increased AST 23 16 Increased serum creatinine 7 38 Increased bilirubin 5 - Recurrent Ovarian Cancer The safety of carboplatin as a single agent for patients with ovarian carcinoma recurrent after prior chemotherapy was evaluated in two prospective, randomized controlled studies.

Tables 7 and 8 summarize the adverse reactions and laboratory abnormalities from these studies, respectively Table 7: Adverse Reactions (≥5%) in Patients Treated with Carboplatin (Single-agent) for Advanced Ovarian Cancer in Two Controlled Studies Adverse Reaction Carboplatin as a Second Line Single-Agent Therapy N=553 (%) Gastrointestinal (GI) Nausea and vomiting 92 Vomiting 81 Other GI side effects 21 Neurologic Pain 23 Asthenia 11 Peripheral neuropathies 6 Central neurotoxicity 5 General Cardiovascular 6 Respiratory 6 Infections 5 Bleeding 5 Clinically relevant adverse reactions in < 5% of patients who received carboplatin included allergic reactions, alopecia, mucositis, ototoxicity, and sensory disorders. Table 8: Laboratory Abnormalities in Patients Treated with Carboplatin as a Single-agent for Secondary Treatment of Advanced Ovarian Cancer in Two Prospective, Randomized Controlled Studies Laboratory Abnormality Carboplatin as a Second Line Single-Agent Therapy N=553 (%) Hematology Decreased hemoglobin <11 g/dL 90 Decreased hemoglobin <8 g/dL 21 Decreased neutrophils <2000 cells/mm 3 67 Decreased neutrophils <1000 cells/mm 3 21 Decreased platelets <100,000/mm 3 62 Decreased platelets <50,000/mm 3 35 Chemistry Decreased sodium 47 Decreased magnesium 43 Increased alkaline phosphatase 37 Decreased calcium 31 Decreased potassium 28 Increased blood urea 22 Increased AST 19 Increased serum creatinine 10 Increased bilirubin 5 Other Clinical Trials Experience The following adverse reactions occurred in patients treated with carboplatin for ovarian cancer as a single agent or in combination with chemotherapy in clinical trials: The following adverse reactions occurred in patients (n=1893) with solid tumors or hematological malignancies treated with single agent carboplatin in clinical trials: Gastrointestinal Disorders: diarrhea (6%), constipation (6%), dysgeusia (1%) Ocular Disorders: visual disturbances (1%). The following adverse reactions occurred in patients treated with carboplatin for ovarian cancer in combination with chemotherapy in clinical trials: Cardiovascular: arterial thromboembolic event, venous thromboembolic event General: fatigue, febrile neutropenia Musculoskeletal and Connective Tissue Disorders: fistula, wound-healing complication Renal and Urinary Disorders: proteinuria Respiratory : dyspnea

Postmarketing Experience

The following adverse reactions have been identified during post approval use of carboplatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Allergic reactions: anaphylaxis, bronchospasm, erythema, hypotension, pruritus, rash, urticaria Blood and Lymphatic System: hemolytic uremic syndrome, secondary acute myeloid leukemia Cardiovascular: cardiac failure, cerebrovascular accident, embolism, hemorrhage, hypertension Gastrointestinal: stomatitis General disorders: anorexia, dehydration, injection site reactions (including redness, pain, swelling, extravasation, and necrosis), malaise Infection: sepsis/septic shock Renal and Urinary Disorders: acute kidney injury

Use with Aminoglycosides

Avoid concomitant use of aminoglycosides with KYXATA. Concomitant use of KYXATA with aminoglycosides increased renal toxicity and ototoxicity.

Pregnancy Risk Summary Based on findings from animals and its mechanism of action , KYXATA can cause fetal harm when administered to a pregnant woman. Available data from case reports with carboplatin use in pregnant women are insufficient to inform a drug-associated risk. Administration of carboplatin to pregnant rats caused adverse developmental outcomes, including embryo-lethality and structural abnormalities (see Data). Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Carboplatin administered to pregnant rats was embryo-lethal and teratogenic.

Pediatric Use The safety and effectiveness of KYXATA in pediatric patients have not been established. Pediatric patients may be at risk of hearing loss if KYXATA is administered at higher than recommended dosages or in combination with other ototoxic agents.

There is no known antidote for KYXATA overdosage. The anticipated complications of overdosage would be secondary to bone marrow suppression and/or hepatic toxicity. Patients receiving overdosages of carboplatin experienced severe liver function test abnormalities.

Loss of vision, which can be complete for light and colors, has been reported after the use of carboplatin at doses higher than the recommended approved dosage for KYXATA. Vision recovers totally or to a significant extent after discontinuation of carboplatin. Clinically significant hearing loss has been reported to occur in pediatric patients when carboplatin was administered at higher than approved recommended doses for KYXATA and in combination with other ototoxic agents. KYXATA is removed by dialysis.

Closely monitor patients suspected of receiving an overdose, including for the adverse reactions described above, and administer appropriate supportive treatment.