Carboplatin

KYXATA is a platinum-based drug indicated in adults: As part of a combination regimen, for the initial treatment of advanced ovarian carcinoma. ( 1.1 ) As a single-agent for the treatment of ovarian carcinoma recurrent after prior chemotherapy. ( 1.2 )

1.1 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.

1.2 Recurrent Advanced Ovarian Carcinoma KYXATA is indicated for treatment of adults with ovarian carcinoma recurrent after prior chemotherapy.

Injection: 20 mg/2 mL (10 mg/mL), 80 mg/8 mL (10 mg/mL), and 500 mg/50 mL (10 mg/mL) available as clear to pale yellow solution in multiple-dose vials. Injection : 20 mg/2 mL (10 mg/mL), 80 mg/8 mL (10 mg/mL), and 500 mg/50 mL (10 mg/mL) in multiple-dose vial. ( 3 )

None. None. ( 4 )

Myelosuppression : Myelosuppression (leukopenia, neutropenia, and thrombocytopenia) can cause severe or fatal infections or hemorrhage. Monitor complete blood counts prior to each treatment cycle, and as clinically indicated. If myelosuppression occurs, modify KYXATA dosage. ( 5.2 ) Nausea and Vomiting : Administer pre-treatment and post-treatment antiemetics as clinically indicated. ( 5.3 ) Peripheral Neuropathy : Peripheral neuropathy, including paresthesia, can occur in patients treated with KYXATA. Monitor for signs and symptoms of peripheral neuropathy and modify the dosage of KYXATA based on severity. ( 5.4 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.5 , 8.1 , 8.3 )

5.1 Hypersensitivity Reactions Hypersensitivity, including anaphylaxis, can occur in patients treated with KYXATA. Hypersensitivity reactions occurred in 2% of patients treated with carboplatin and included rash, urticaria, erythema, pruritus, bronchospasm, and hypotension. These adverse reactions may occur within minutes of administration and during any cycle. There is an increased risk of allergic reactions, including anaphylaxis, in patients previously exposed to platinum-based therapy or after 6 cycles of carboplatin [see Adverse Reactions (6.1) ]. Monitor patients receiving KYXATA for hypersensitivity reactions. Ensure supportive equipment and medications are available to treat severe hypersensitivity reactions. Severe hypersensitivity reactions may require immediate discontinuation of KYXATA.

5.2 Myelosuppression Myelosuppression (leukopenia, neutropenia, and thrombocytopenia) is dose-dependent may be severe, and can cause fatal infections or hemorrhage in patients treated with KYXATA. Grade 3–4 neutropenia occurred in 16% of the patients treated with carboplatin as a single agent. Grade 3-4 thrombocytopenia occurred in 25% of patients with ovarian cancer. Febrile neutropenia may occur. Blood product transfusions were required in 26% (44% of pretreated) of patients with ovarian cancer treated with carboplatin as a single agent. Infectious and hemorrhagic complications each occurred in 5% of the patients treated with carboplatin as a single agent. Fatal adverse reactions occurred in less than 1% of patients treated with carboplatin as a single agent. Patients with impaired kidney function are at increased risk of severe myelosuppression and may require dosage modifications [see Dosage and Administration (2.4) and Use in Specific Populations (8.6) ]. Monitor complete blood counts prior to each cycle and as clinically indicated. If myelosuppression occurs, modify KYXATA dosage when required [see Dosage and Administration (2.3) ].

5.3 Nausea and Vomiting KYXATA can induce emesis, which can be more severe in patients previously receiving emetogenic therapy, and is dose-dependent. Administer pre-treatment and post-treatment antiemetics as clinically indicated [see Dosage and Administration (2.1) ]. Monitor and manage patients with antiemetics, or fluid replacement, as clinically indicated. Consider withholding or delaying KYXATA if nausea or vomiting is severe or intolerable and is not responsive to antiemetics.

5.4 Peripheral Neuropathy Peripheral neuropathy, including paresthesia, can occur in patients treated with KYXATA. Peripheral neuropathy occurred in 4% of patients receiving carboplatin as a single agent (6% of pretreated patients with ovarian cancer). Peripheral neuropathy occurred in 10% of patients older than 65 who were previously treated with carboplatin. Prolonged treatment, treatment with other platinum-containing therapies, or use in combination with other drugs that cause peripheral neuropathy may increase the incidence or severity of peripheral neuropathy. Monitor for signs and symptoms of peripheral neuropathy. Withhold, reduce, or discontinue KYXATA depending on the severity and persistence of peripheral neuropathy as clinically indicated.

5.5 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, KYXATA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . Administration of carboplatin to pregnant rats caused adverse developmental outcomes, including embryo-fetal lethality and structural abnormalities. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with KYXATA and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with KYXATA and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ].

The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity [see Warnings and Precautions (5.1) ] Myelosuppression [see Warnings and Precautions (5.2) ] Nausea and Vomiting [see Warnings and Precautions (5.3) ] Peripheral Neuropathy [see Warnings and Precautions (5.4) ] Most common adverse reactions, including laboratory abnormalities, in patients with advanced ovarian cancer who received KYXATA in combination with cyclophosphamide (≥30%) are leukopenia, neutropenia, nausea and vomiting, anemia, thrombocytopenia, hypomagnesemia, other gastrointestinal adverse reactions, alopecia, asthenia, and pain. ( 6.1 ) Most common adverse reactions, including laboratory abnormalities, in patients with recurrent ovarian cancer who received KYXATA as a single agent (≥30%) are nausea and vomiting, anemia, neutropenia, thrombocytopenia, hyponatremia, hypomagnesemia, hyperphosphatasemia, and hypocalcemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Avyxa Pharma, LLC at 1-888-520-0954 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 [see Clinical Studies (14.1) ]. 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 [see Clinical Studies (14.2) ]. 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

6.2 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. […]

Aminoglycosides : Avoid concomitant use with aminoglycosides. ( 7.1 )

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

Renal Impairment : Reduce the dose for patients with creatinine clearance of 16 to 59 mL/min who will be administered a dose based on body surface area. ( 8.6 , 2.4 ) Lactation : Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on findings from animals and its mechanism of action [see Clinical Pharmacology (12.1) ] , 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.

8.2 Lactation Risk Summary There are limited data on the presence of carboplatin or its metabolites in human milk, its effects on a breastfed child, or its effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with KYXATA and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential KYXATA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating KYXATA. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with KYXATA and for 6 months after the last dose. Males Based on genotoxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment with KYXATA and for 3 months after the last dose [see Nonclinical Toxicology (13.1) ] .

8.4 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.

8.5 Geriatric Use Of the 395 patients treated with carboplatin in combination with cyclophosphamide, 141 (36%) were over 65 years of age, and 22 (6%) were 75 years and older [see Clinical Studies (14.1) ]. No overall differences in effectiveness were observed between these patients and younger patients. Elderly patients treated with carboplatin were more likely to develop severe thrombocytopenia or peripheral neuropathy than younger patients [see Warnings and Precautions (5.2 , 5.4) ] Of the 1,942 patients with solid tumors or hematological malignancies from pooled clinical trials that received single-agent carboplatin, 414 (21%) were 65 years of age and older, and a similar incidence of other adverse reactions was seen in these older patients compared to patients less than 65 years of age. Consider renal function when selecting the KYXATA dose for older adults since they often have decreased renal function. To minimize the risk of toxicity in older adults, calculate the dose based on AUC [see Dosage and Administration (2.3) ].

8.6 Renal Impairment For patients administered a dose based on AUC , no dose modification is recommended for renal impairment. For patients administered a dose based on body surface area , reduce the dose if creatinine clearance (CLcr) is 16 to 59 mL/min [see Dosage and Administration (2.4) ] . A recommended dose of KYXATA has not been established for patients with CLcr <16 mL/min. Patients with impaired renal function are at increased risk of myelosuppression [see Warnings and Precautions (5.2) ] .

Carboplatin is a platinum-based drug that binds to DNA and forms DNA cross-links. These crosslinks inhibit DNA replication and transcription and trigger cytotoxic processes that lead to cell death.