FAVLYXA

1 INDICATIONS AND USAGE FAVLYXA is indicated for the treatment of patients with: FAVLYXA is a nucleoside metabolic inhibitor indicated for the treatment of patients with: Adenocarcinoma of the Colon and Rectum ( 1.1 ) Adenocarcinoma of the Breast ( 1.2 ) Gastric Adenocarcinoma ( 1.3 ) Pancreatic Adenocarcinoma ( 1.4 ) 1.1 Adenocarcinoma of the Colon and Rectum 1.2 Adenocarcinoma of the Breast 1.3 Gastric Adenocarcinoma 1.4 Pancreatic Adenocarcinoma

2 DOSAGE AND ADMINISTRATION FAVLYXA is recommended for administration either as an intravenous bolus or as an intravenous infusion. ( 2.1 ) Adenocarcinoma of the Colon and Rectum In combination with leucovorin or as a component of a multidrug chemotherapy regimen that includes leucovorin (infusional regimen): 400 mg/m 2 for one dose, followed by 2,400 mg/m 2 to 3,000 mg/m 2 over 46 hours on day 1 of each 2-week cycle or In combination with leucovorin (bolus regimen): 500 mg/m 2 on days 1, 8, 15, 22, 29 and 36 of each 8-week cycle. ( 2.2 ) Adenocarcinoma of the Breast in combination with a cyclophosphamide-based multidrug regimen: 500 mg/m 2 or 600 mg/m 2 on days 1 and 8 of each 28-day cycle (bolus regimen). ( 2.2 ) Gastric Adenocarcinoma in combination with a platinum-containing multidrug regimen: 200 mg/m 2 to 1,000 mg/m 2 over 24 hours (infusional regimen). ( 2.2 ) Pancreatic Adenocarcinoma in combination with leucovorin or as a component of a multidrug chemotherapy regimen that includes leucovorin: 400 mg/m 2 on day 1, followed by 2,400 mg/m 2 over 46 hours every 2 weeks (infusional regimen). ( 2.2 ) Refer to Section 2.3 for dosage modifications due to adverse reactions. 2.1 Evaluation and Testing for DPD Deficiency Before Initiating FAVLYXA Prior to initiating FAVLYXA, test patients for genetic variants of the DPYD gene unless immediate treatment is necessary. An FDA-authorized test for the detection of the DPYD gene to identify patients at risk of serious adverse reactions with FAVLYXA is not currently available. Currently available tests used to identify DPYD variants may vary in accuracy and design (e.g., which DPYD variant(s) they identify). Avoid use of FAVLYXA in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency . No FAVLYXA dose has been proven safe for patients with complete DPD deficiency. For patients with partial DPD deficiency, individualize the dosage and modify based on tolerability and intent of treatment [see Warnings and Precautions (5.1) ] . 2.2 Recommended Dosage FAVLYXA is recommended for administration either as an intravenous bolus or as an intravenous infusion. Dosage recommendations are in Table 1. Table 1: Recommended dosage of FAVLYXA Indication Recommended Dosage Duration of Treatment Adenocarcinoma of the Colon and Rectum In combination with leucovorin or as a component of a multidrug chemotherapy regimen that includes leucovorin 400 mg/m 2 for one dose, followed by 2,400 mg/m 2 to 3,000 mg/m 2 over 46 hours on day 1 of each 2-week cycle Until disease progression or unacceptable toxicity. In combination with leucovorin alone (bolus regimen) 500 mg/m 2 on days 1, 8, 15, 22, 29 and 36 of each 8-week cycle Until disease progression or unacceptable toxicity. Adenocarcinoma of the Breast In combination with cyclophosphamide-based multidrug regimen (bolus regimen) 500 mg/m 2 or 600 mg/m 2 on days 1 and 8 of each 28-day cycle Until disease progression or unacceptable toxicity or 6 cycles Gastric Adenocarcinoma In combination with a platinum-containing multidrug regimen 200 mg/m 2 to 1,000 mg/m 2 over 24 hours Frequency in each cycle and length of each cycle depend on dose of FAVLYXA and specific regimen Pancreatic Adenocarcinoma In combination with leucovorin or as a component of a multidrug chemotherapy regimen that includes leucovorin 400 mg/m 2 on day 1, followed by 2,400 mg/m 2 over 46 hours every 2 weeks Until disease progression or unacceptable toxicity. 2.3 Dosage Modifications for Adverse Reactions Withhold FAVLYXA for the following adverse reactions. Depending on the severity of the adverse reaction, either discontinue or resume FAVLYXA at a reduced dosage upon resolution or improvement to Grade 1: Grade 3 or 4 diarrhea [see Warnings and Precautions (5.5) ] Grade 2 or 3 palmar-plantar erythrodysesthesia (hand-foot syndrome) [see Warnings and Precautions (5.6) ] Grade 3 or 4 mucositis [see Warnings and Precautions (5.8) ] Gra…

5 WARNINGS AND PRECAUTIONS Cardiotoxicity: FAVLYXA can cause cardiotoxicity, including angina, myocardial infarction/ischemia, arrhythmia, and heart failure. Withhold FAVLYXA for cardiac toxicity. ( 5.2 ) Hyperammonemic Encephalopathy: Altered mental status, confusion, disorientation, coma, or ataxia with elevated serum ammonia level can occur within 72 hours of initiation of FAVLYXA. Withhold FAVLYXA and initiate ammonia-lowering therapy. ( 5.3 ) Neurologic Toxicity: FAVLYXA can cause acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances. Withhold FAVLYXA for neurologic toxicity. ( 5.4 ) Diarrhea: FAVLYXA can cause severe diarrhea. Withhold FAVLYXA for severe diarrhea until resolved. ( 5.5 ) Palmar-Plantar Erythrodysesthesia Syndrome: Based on severity, withhold FAVLYXA until resolved or decreased to Grade 1, then resume at a reduced dose. ( 5.6 ) Myelosuppression: FAVLYXA can cause severe and fatal myelosuppression. Withhold FAVLYXA until severe myelosuppression resolves, then resume at a reduced dose. ( 5.7 ) Mucositis: FAVLYXA can cause severe mucositis. Withhold FAVLYXA until resolved or decreased to Grade 1, then resume at a reduced dose. ( 5.8 ) Increased Risk of Bleeding with Concomitant Use of Warfarin: Concurrent administration with warfarin can result in clinically significant increases in coagulation parameters: Closely monitor INR and prothrombin time. ( 5.9 ) Embryofetal Toxicity: Can cause fetal harm. Advise females and males of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.10 , 8.1 , 8.3 ) 5.1 Serious Adverse Reactions or Death from Dihydropyrimidine Dehydrogenase (DPD) Deficiency Patients with certain homozygous or compound heterozygous variants in the DPYD gene known to result in complete or near complete absence of DPD activity (complete DPD deficiency) are at increased risk for acute early-onset toxicity and serious, including fatal adverse reactions due to FAVLYXA (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity (partial DPD deficiency) may also have increased risk of serious or fatal adverse reactions. Prior to initiating FAVLYXA, test patients for genetic variants of the DPYD gene unless immediate treatment is necessary [see Clinical Pharmacology (12.5) ] . Serious adverse reactions may still occur even if no DPYD variants are identified. Avoid use of FAVLYXA in patients with certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency. Withhold or permanently discontinue FAVLYXA based on clinical assessment of the onset, duration, and severity of adverse events in patients with evidence of acute early-onset or unusually severe reactions. No fluorouracil dose has been proven safe for patients with complete DPD deficiency. For patients with partial DPD deficiency, individualize the dosage and modify based on tolerability and intent of treatment. An FDA-authorized test for the detection of genetic variants of the DPYD gene to identify patients at risk of serious adverse reactions with FAVLYXA treatment is not currently available. Currently available tests used to identify DPYD variants may vary in accuracy and design (e.g., which DPYD variant(s) they identify). 5.2 Cardiotoxicity FAVLYXA can cause cardiotoxicity, including angina, myocardial infarction/ischemia, arrhythmia, and heart failure, based on postmarketing reports. Reported risk factors for cardiotoxicity are administration by continuous infusion rather than intravenous bolus and presence of coronary artery disease. Withhold FAVLYXA for cardiotoxicity. The risks of resumption of FAVLYXA in patients with cardiotoxicity that has resolved have not been established [see Dosage and Administration (2.3) ]. 5.3 Hyperammonemic Encephalopathy FAVLYXA can cause hyperammonemic encephalopathy in the absence of liver disease or other identifiable cause, based on postmarketing reports. Signs or sympt…

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS 7.1 Effect of FAVLYXA on Other Drugs Vitamin K Antagonists Monitor INR and PT more frequently in patients receiving FAVLYXA and warfarin. Elevated INR and PT have been reported in patients taking fluorouracil concomitantly with warfarin.

8.1 Pregnancy Risk Summary Based on mechanism of action and animal reproduction studies, FAVLYXA can cause fetal harm when administered during pregnancy [see Clinical Pharmacology (12.1) ]. Available data from observational studies with intravenous administration of fluorouracil during pregnancy are insufficient to identify a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Administration of fluorouracil to rats and mice during selected periods of organogenesis, at doses lower than a human dose of 12 mg/kg, caused embryolethality and teratogenicity. Malformations included cleft palate and skeletal defects. In monkeys, maternal doses of fluorouracil higher than an approximate human dose of 12 mg/kg resulted in abortion (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data Malformations including cleft palate, skeletal defects and deformed appendages (paws and tails) were observed when fluorouracil was administered by intraperitoneal injection to mice at doses at or above 10 mg/kg (approximately 0.06 times a human dose of 12 mg/kg on a mg/m 2 basis) for 4 days during the period of organogenesis. Similar results were observed in hamsters administered fluorouracil intramuscularly at doses lower than those administered in commonly used clinical treatment regimens. In rats, administration of fluorouracil by intraperitoneal injection at doses greater than 15 mg/kg (approximately 0.2 times a human dose of 12 mg/kg on a mg/m 2 basis) for a single day during organogenesis resulted in delays in growth and malformations including micro-anophthalmos. In monkeys, administration of fluorouracil during organogenesis at doses approximately equal to a human dose of 12 mg/kg on a mg/m 2 basis resulted in abortion; at a 50% lower dose, resorptions and decreased fetal body weights were reported.

8.2 Lactation Risk Summary There are no data on the presence of fluorouracil or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients not to breastfeed during treatment with FAVLYXA and for 1 week after the last dose.

12.5 Pharmacogenomics The DPYD gene encodes the enzyme DPD, which is responsible for the catabolism of >80% of fluorouracil. Approximately 3 to 5% of White populations have partial DPD deficiency and 0.2% of White populations have complete DPD deficiency, which may be due to certain genetic no function or decreased function variants in DPYD resulting in partial to complete or near complete absence of enzyme activity. DPD deficiency is estimated to be more prevalent in Black or African American populations compared to White populations. Insufficient information is available to estimate the prevalence of DPD deficiency in other populations. Patients who are homozygous or compound heterozygous for no function DPYD variants (i.e., carry two DPYD variants that result in no DPD enzyme activity) or are compound heterozygous for a no function DPYD variant plus a decreased function DPYD variant have complete DPD deficiency and are at increased risk for acute early-onset of toxicity and serious life-threatening, or fatal adverse reactions due to increased systemic exposure to fluorouracil. Partial DPD deficiency can result from the presence of either two decreased function DPYD variants or one normal function plus either a decreased function or a no function DPYD variant. Patients with partial DPD deficiency may also be at an increased risk for toxicity from fluorouracil. Several DPYD variants observed with variability across populations have been associated with reduced or no DPD activity, especially when present as homozygous or compound heterozygous variants. These include c.1905+1G>A ( DPYD *2A), c.1679T>G ( DPYD *13), c.2846A>T, and c.1129-5923C>G (Haplotype B3). DPYD *2A and DPYD *13 are no function variants, and c.2846A>T, c.1129-5923C>G, and c557A>G are decreased function variants. This is not a complete listing of all DPYD variants that may result in DPD deficiency [see Warnings and Precautions (5.1) ] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Serious adverse reactions or death from Dihydropyrimidine Dehydrogenase (DPD) deficiency [see Warnings and Precautions (5.1) ] Cardiotoxicity [see Warnings and Precautions (5.2) ] Hyperammonemic encephalopathy [see Warnings and Precautions (5.3) ] Neurologic toxicity [see Warnings and Precautions (5.4) ] Diarrhea [see Warnings and Precautions (5.5) ] Palmar-plantar erythrodysesthesia (hand-foot syndrome) [see Warnings and Precautions (5.6) ] Myelosuppression [see Warnings and Precautions (5.7) ] Mucositis [see Warnings and Precautions (5.8) ] Increased risk of bleeding with concomitant use of warfarin [see Warnings and Precautions (5.9) ] 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of fluorouracil. 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. Hematologic: pancytopenia [see Warnings and Precautions (5.7) ] Gastrointestinal: gastrointestinal ulceration, nausea, vomiting Allergic Reactions: anaphylaxis and generalized allergic reactions Neurologic: nystagmus, headache Dermatologic: dry skin; fissuring; photosensitivity, as manifested by erythema or increased pigmentation of the skin; vein pigmentation Ophthalmic: lacrimal duct stenosis, visual changes, lacrimation, photophobia Psychiatric: euphoria Miscellaneous: thrombophlebitis, epistaxis, nail changes (including loss of nails)