KYXATA

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION Initial Treatment of Advanced Ovarian Carcinoma: KYXATA 300 mg/m 2 -OR- AUC of 4 mg/mL∙min to 6 mg/mL∙min intravenously in combination with cyclophosphamide on Day 1 every 4 weeks for each cycle. ( 2.2 ) Administer up to six cycles or until disease progression or unacceptable toxicity occurs. ( 2.2 ) Recurrent Advanced Ovarian Carcinoma as a Single Agent: KYXATA 360 mg/m 2 - OR - AUC of 4 mg/mL∙min to 6 mg/mL∙min intravenously on Day 1 every 4 weeks for each cycle until disease progression or unacceptable toxicity occurs. ( 2.2 ) Avoid contact of carboplatin with aluminum parts. ( 2.5 ) 2.1 Premedication and Supportive Medications Administer KYXATA in a setting where cardiopulmonary resuscitation medication and equipment are available [see Warnings and Precautions (5.1) ]. Premedicate patients with antiemetics prior to each infusion of KYXATA for the prevention of nausea and vomiting. Continue antiemetics following infusion as needed [see Warnings and Precautions (5.3) ]. 2.2 Recommended Dosage Initial Treatment of Advanced Ovarian Carcinoma with Cyclophosphamide KYXATA 300 mg/m 2 -OR- AUC of 4 mg/mL∙min to 6 mg/mL∙min* intravenously in combination with cyclophosphamide 600 mg/m 2 intravenously on Day 1 every 4 weeks for each cycle. *Carboplatin Dose (mg) = Target Area Under the Curve (AUC) (mg/mL/min) x (GFR + 25). Glomerular filtration rate (GFR) is commonly calculated as estimated creatinine clearance (CLcr) using the Cockroft-Gault formula. Administer up to six cycles or until disease progression or unacceptable toxicity occurs. Refer to cyclophosphamide prescribing information for additional information. For older adults, calculate the dose based on AUC to reduce risk of severe adverse reactions. Individualize the dose and dosing schedule of KYXATA based on the specific regimen administered, response to treatment, and patient risk factors [see Dosage and Administration (2.3 , 2.4) ]. Secondary Treatment of Advanced Ovarian Carcinoma as a Single Agent KYXATA 360 mg/m 2 -OR- AUC of 4 mg/mL ∙ min to 6 mg/mL ∙ min* intravenously on Day 1 every 4 weeks for each cycle until disease progression or unacceptable toxicity occurs. * Carboplatin Dose (mg) = Target AUC (mg/mL/min) x (GFR + 25). GFR is commonly calculated as estimated creatinine clearance (CLcr) using the Cockroft-Gault formula. For older adults, calculate the dose based on AUC to reduce risk of severe adverse reactions. Individualize the dose and dosing schedule of KYXATA based on response to treatment and patient risk factors [see Dosage and Administration (2.3, 2.4) ]. 2.3 Dosage Modifications for Adverse Reactions For a patients administered a dose based on body surface area as a single agent or combination, dosage modifications are shown in Table 1. Monitor complete blood counts prior to treatment, weekly during treatment, and as clinically indicated [see Warnings and Precautions (5.2) ]. Table 1: Recommended Dosage Modifications for Adverse Reactions for Patients Administered a Dose Based on Body-Surface Area Adverse Reaction Severity Dosage Modification Neutropenia [see Warnings and Precautions (5.2) ] Grade ≥ 4 ANC ≤ 0.5 x 10 9 / L ● Interrupt KYXATA until ≤ Grade 1. ● Reduce dose by 25% Thrombocytopenia [see Warnings and Precautions (5.2) ] Grade ≥ 3 Platelet count ≤ 50 x 10 9 / L ● Interrupt KYXATA until ≤ Grade 1. ● Reduce dose by 25% 2.4 Dosage Recommendations for Patients with 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 , the recommended doses for renal impairment are described in Table 2 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]. A recommended dose has not been established for patients with creatinine clearance <16 mL/min. Table 2: Recommended Dose for Patients with Renal Impairment Administered a Dose Based on Body Surface Area Creatinine Clearance (mL/min) R …

3 DOSAGE FORMS AND STRENGTHS 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 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS 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 Hypers …

7 DRUG INTERACTIONS 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.

8 USE IN SPECIFIC POPULATIONS 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) ] .

12.1 Mechanism of Action 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.

11 DESCRIPTION KYXATA is a platinum-based drug. The chemical name for carboplatin is platinum, diammine [1,1- cyclobutane-dicarboxylato(2-)-0,0']-,(SP-4-2) and carboplatin has the following structural formula: Carboplatin is a white crystalline powder with the molecular formula of C 6 H 12 N 2 O 4 Pt and a molecular weight of 371.26 g/mol. It is sparingly soluble in water and very slightly soluble in acetone and in alcohol. The pH of a 1% carboplatin solution in water is 5 to 7. KYXATA (carboplatin) injection is supplied as a sterile, clear to pale yellow solution as 20 mg/2 mL, 80 mg/8mL, 500 mg/50 mL in multiple-dose vials for administration by intravenous infusion. Each mL contains 10 mg carboplatin. Image

10 OVERDOSAGE 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 [see Drug Interactions (7) ]. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied KYXATA TM (carboplatin) injection is supplied as clear to pale yellow solution in the following presentations: Unit of Sale Strength NDC 83831-140-02 Carton containing 1 multiple-dose vial (Light Blue flip-off seals) 20 mg/2 mL (10 mg/mL) NDC 83831-141-08 Carton containing 1 multiple-dose vial (Green flip-off seals) 80 mg/8 mL (10 mg/mL) NDC 83831-142-50 Carton containing 1 multiple-dose vial (Grey flip-off seals) 500 mg/50 mL (10 mg/mL) Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. KYXATA is a hazardous drug. Follow applicable special handling and disposal procedures. 1