Berotralstat Hydrochloride

1 INDICATIONS AND USAGE ORLADEYO ® is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adults and pediatric patients 2 years of age and older. ORLADEYO is a plasma kallikrein inhibitor indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adults and pediatric patients 2 years and older. ( 1 ) Limitations of Use : ORLADEYO should not be used for treatment of acute HAE attacks. ( 1 ) Limitations of Use : The safety and effectiveness of ORLADEYO for the treatment of acute HAE attacks have not been established. ORLADEYO should not be used for treatment of acute HAE attacks. Additional doses or doses of ORLADEYO higher than the prescribed once-daily dose are not recommended due to the potential for QTc interval prolongation [see Warnings and Precautions (5.1) ] .

2 DOSAGE AND ADMINISTRATION Recommended dosage in adult and pediatric patients aged 12 years and older: 150 mg capsule orally once daily with food. ( 2.1 ) Recommended dosage in pediatric patients aged 2 to less than 12 years is based on body weight as follows ( 2.2 , 2.5 ): Weight Recommended Dosage (oral pellets) Administration Instructions 12 kg to less than 24 kg 72 mg once daily Pour directly in mouth and swallow immediately with non-acidic liquid, or, Sprinkle over 1 tablespoon (15 mL) of non-acidic soft food and consume immediately. A meal should be consumed just before or after administration. 24 kg to less than 32 kg 96 mg once daily 32 kg to less than 40 kg 108 mg once daily 40 kg or greater 132 mg once daily See full prescribing information for recommended dosage in patients with hepatic impairment and dosage modification in patients with persistent gastrointestinal adverse reactions. ( 2.3 , 2.4 ) 2.1 Recommended Dosage in Adults and Pediatric Patients 12 Years of Age and Older The recommended dosage of ORLADEYO capsules for adults and pediatric patients 12 years of age and older is 150 mg taken orally once daily with food. 2.2 Recommended Dosage in Pediatric Patients 2 Years to Less than 12 Years of Age The recommended dosage of ORLADEYO oral pellets for pediatric patients 2 years to less than 12 years of age is based on the patient's body weight as provided in Table 1. Take ORLADEYO orally with food (a meal should be consumed just before or after dosing) [see Dosage and Administration (2.5) ] . Table 1: Recommended Dosage of ORLADEYO Oral Pellets by Body Weight in Pediatric Patients 2 Years to Less than 12 Years of Age Body Weight (kg) Recommended Dosage of ORLADEYO Oral Pellets 12 kg to less than 24 kg 72 mg (one packet) once daily 24 kg to less than 32 kg 96 mg (one packet) once daily 32 kg to less than 40 kg 108 mg (one packet) once daily 40 kg or greater 132 mg (one packet) once daily 2.3 Recommended Dosage in Patients with Hepatic Impairment Mild Hepatic Impairment (Child-Pugh Class A) Adult and Pediatric Patients 2 Years of Age and Older No dosage modification of ORLADEYO is recommended [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . Moderate or Severe Hepatic Impairment (Child-Pugh Class B or C) Adult and Pediatric Patients 12 Years of Age and Older Recommended dosage of ORLADEYO capsules is 110 mg taken orally once daily with food [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . Pediatric Patients 2 Years to Less than 12 Years of Age Avoid use of ORLADEYO [see Use in Specific Populations (8.7) ] . 2.4 Dosage Modification in Patients with Persistent GI Adverse Reactions Gastrointestinal (GI) reactions may occur in patients receiving ORLADEYO [see Adverse Reactions (6.1) ] . For adults and pediatric patients 12 years of age and older, if GI adverse reactions persist, consider a lower ORLADEYO capsules dosage of 110 mg once daily with food. For pediatric patients 2 to less than 12 years of age with persistent GI adverse reactions, consider the risks and benefits of continuing treatment with ORLADEYO. 2.5 Administration Instructions for Oral Pellets Do not chew or crush ORLADEYO oral pellets because this will affect the film coating (taste masking) and result in bitter taste. Administer one packet of oral pellets as follows: Pour the entire contents of one packet directly into the mouth and swallow immediately with non-acidic liquid (e.g., water or milk). OR Sprinkle the entire contents of one packet over approximately one tablespoon (15 mL) of soft, non-acidic food and consume immediately. Food should be at or below room temperature. Examples of soft, non-acidic foods include pudding, mashed potatoes, creamed corn, pureed peas, pureed bananas, and pureed carrots. Acidic foods such as yogurt and applesauce should not be used because they can dissolve the film coating (taste masking) and result in a bitter taste . The film coating (taste masking) remains intact for 10 minutes. If the pellets are not consumed within 10 minutes of sprinkling over food, they should be discarded.

6 ADVERSE REACTIONS The following clinically significant adverse reaction is described elsewhere in the labeling: QTc Interval Prolongation [see Warnings and Precautions (5.1) ] . Most common adverse reactions (≥10%) are abdominal pain, vomiting, diarrhea, back pain, and gastroesophageal reflux disease. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact BioCryst Pharmaceuticals, Inc. at 1-833-633-2279 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 practice. Adverse Reactions in Adult and Pediatric Patients 12 Years of Age and Older The safety of ORLADEYO is primarily based on 24-week (Part 1) data from a 3-part, double-blind, parallel-group, placebo-controlled trial (Trial 1) in 120 patients with Type I or II HAE who were randomized and dosed with either ORLADEYO 110 mg, 150 mg, or placebo, once daily with food. After Week 24, patients who continued in the study received active treatment through 48 weeks. In Trial 1, a total of 81 patients aged 12 years and older with HAE received at least one dose of ORLADEYO in Part 1. Overall, 66% of patients were female and 93% of patients were White with a mean age of 41.6 years. The proportion of patients who discontinued study drug prematurely due to adverse reactions was 7% and 3% for patients treated with ORLADEYO 110 mg and 150 mg, respectively, and 3% for placebo-treated patients. No deaths occurred in the trial. The safety profile of ORLADEYO was generally similar across all subgroups of patients, including analysis by age, sex, and geographic region. Table 2 shows adverse reactions occurring in ≥10% of adult and pediatric patients aged 12 years and older in any ORLADEYO treatment group that also occurred at a higher rate than in the placebo treatment group in Trial 1. Table 2: Adverse Reactions Observed in ≥10% of Adult and Pediatric Patients Aged 12 Years and Older with HAE in Any ORLADEYO Treatment Group (Trial 1) Adverse Reaction Placebo (N=39) ORLADEYO 110 mg (N=41) 150 mg (N=40) Total (N=81) n (%) n (%) n (%) n (%) Abdominal Pain includes Abdominal pain, Abdominal discomfort, Abdominal pain upper, and Abdominal tenderness 4 (10) 4 (10) 9 (23) 13 (16) Vomiting 1 (3) 4 (10) 6 (15) 10 (12) Diarrhea includes Diarrhea and Frequent bowel movements 0 4 (10) 6 (15) 10 (12) Back Pain 1 (3) 1 (2) 4 (10) 5 (6) Gastroesophageal Reflux Disease 0 4 (10) 2 (5) 6 (7) Gastrointestinal adverse reactions, including abdominal pain, vomiting, and diarrhea occurred more frequently in patients receiving ORLADEYO 150 mg versus ORLADEYO 110 mg or placebo. These adverse reactions generally occurred early after initiation of treatment with ORLADEYO, became less frequent with time, and typically self-resolved. No patients in the ORLADEYO 150 mg dose group and 1 patient in the ORLADEYO 110 mg dose group discontinued treatment due to a gastrointestinal adverse reaction. Less Common Adverse Reactions Other adverse reactions that occurred in Part 1 of Trial 1 with an incidence between 5% to <10% and at a higher incidence in ORLADEYO-treated patients compared to placebo-treated patients included headache (9% versus 5%), fatigue (6% versus 3%), and flatulence (6% versus 3%). A maculopapular drug rash was reported in less than 1% of patients treated with ORLADEYO. The rash resolved, including in patients who continued dosing. Safety data are also available from 227 patients enrolled in an ongoing, open-label, long-term safety study (Trial 2) who received ORLADEYO 110 mg (N=100) or 150 mg (N=127) once daily with food and are consistent with the 24-week controlled safety data from Trial 1 (Part 1). Laboratory Abnormalities Transaminase Elevations In Part 1 of Trial 1, one patient treated with ORLADEYO 150 mg discontinued treatment due to asymptomatic elevated transaminases (ALT >8x the upper limit of normal [ULN] and AST >3x ULN). Total bilirubin was normal. No patient receiving ORLADEYO 110 mg or placebo developed transaminase levels >3x ULN. In addition to this patient, 2 ORLADEYO-treated patients developed laboratory-related hepatic adverse reactions compared to 1 placebo-treated patient. No patient reported serious adverse reactions of elevated transaminases. Adverse Reactions in Pediatric Patients 2 to Less than 12 Years of Age The safety of ORLADEYO was evaluated in 29 pediatric patients aged 2 to <12 years with HAE in a multicenter, single-arm, open-label safety and pharmacokinetic study (Trial 3). Patients received ORLADEYO based on patient's body weight for at least 12 weeks, with 17 patients completing 48 weeks of treatment. No new safety signals were observed in these patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ORLADEYO. 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. Gastrointestinal Disorders: nausea

12.3 Pharmacokinetics Following oral administration of berotralstat 150 mg once daily in adults, the geometric mean steady-state C max is 158 ng/mL (range: 110 to 234 ng/mL) and steady-state area under the curve over the dosing interval (AUC tau ) is 2770 ng*hr/mL (range: 1880 to 3790 ng*hr/mL). Following oral administration of berotralstat 110 mg once daily, the geometric mean steady-state C max is 97.8 ng/mL (range: 63 to 235 ng/mL) and steady-state AUC tau is 1600 ng*hr/mL (range: 950 to 4170 ng*hr/mL). Berotralstat exposure (C max and AUC) increases in a greater than dose-proportional manner and steady state is reached in approximately 6 to 12 days. Berotralstat accumulation at steady state is approximately 5-fold at the recommended dosage. No clinically significant difference in the pharmacokinetics of berotralstat was observed between healthy adult subjects and patients with HAE. Absorption The median time to maximum plasma concentration (T max ) of berotralstat when administered with food is 5 hours (range: 1 to 8 hours). No clinically significant difference in ORLADEYO exposure was observed following oral administration of either the pellets or capsules at the recommended adult dosage for 7 days. Effect of Food No clinically significant differences in the C max and AUC of berotralstat were observed following administration with a high-fat meal, however the median T max was delayed by 3 hours, from 2 hours (fasted) to 5 hours (fed). Distribution Plasma protein binding is approximately 99%. After a single dose of radiolabeled berotralstat at 2-times the maximum recommended dosage of 150 mg, the blood to plasma ratio was approximately 0.92. Elimination The median elimination half-life of berotralstat is approximately 93 hours (range: 39 to 152 hours). Metabolism Berotralstat is metabolized by CYP2D6 and by CYP3A4 with low turnover in vitro . After a single oral dose of radiolabeled berotralstat at 2-times the maximum recommended dosage of 150 mg, berotralstat represented 34% of the total plasma radioactivity, with 8 metabolites, each accounting for between 1.8 and 7.8% of the total radioactivity. Excretion After a single oral dose of radiolabeled berotralstat at 2-times the maximum recommended dosage of 150 mg, approximately 9% was excreted in urine (3.4% unchanged; range: 1.8 to 4.7%) and 79% was excreted in feces. Specific Populations In adults and pediatric patients 12 to <18 years of age, no clinically significant differences in the pharmacokinetics of ORLADEYO were observed based on age (12 to 74 years), sex, race, and body weight. Pediatric Patients Based on population pharmacokinetic analyses that included pediatric patients 12 to <18 years of age, exposure at steady state following oral administration of berotralstat 150 mg once daily was approximately 20% higher compared to adults. The higher exposure in pediatric patients 12 to <18 years of age is not considered to be clinically significant. Based on population pharmacokinetics analyses that included pediatric patients 2 to <12 years of age, body weight was the only covariate with a clinically significant impact on the systemic exposure of berotralstat. In pediatric patients 2 to <12 years of age at the recommended dosage based on body weight, median C max at steady state is expected to be up to 24% higher compared to adults. However, this difference is not considered to be clinically significant [see Dosage and Administration (2.2) and Use in Special Populations (8.4) ] . Patients with Renal Impairment The pharmacokinetics of a single oral dose of berotralstat at 1.33-times the highest recommended dosage of 150 mg were studied in adult subjects with severe renal impairment (CL CR less than 30 mL/min, estimated by Cockcroft-Gault). When compared to a concurrent cohort with normal renal function (CL CR greater than 90 mL/min, estimated by Cockcroft-Gault), no clinically significant difference was observed; C max was increased by 47%, while AUC 0-last was increased by 14% [see Use in Specific Populations (8.6) ] . The pharmacokinetics of berotralstat has not been studied in patients with End-Stage Renal Disease (CL CR less than 15 mL/min or eGFR less than 15 mL/min/1.73 m 2 or patients requiring hemodialysis). Patients with Hepatic Impairment The pharmacokinetics of a single 150 mg oral dose of berotralstat were studied in adult subjects with mild, moderate, and severe hepatic function (Child-Pugh Class A, B, and C, respectively). The pharmacokinetics of berotralstat were unchanged in subjects with mild hepatic impairment compared to subjects with normal hepatic function. In subjects with moderate hepatic impairment, C max was increased by 77%, while AUC 0-inf was increased by 78%. In subjects with severe hepatic impairment, C max was increased by 27%, while AUC 0-last was decreased by 5%. The median half-life of berotralstat was increased by 37% and 22% in patients with moderate and severe hepatic impairment, respectively, in comparison to healthy subjects. The percent of unbound berotralstat increased 2-fold from a mean of 1.2% in healthy subjects to a mean of 2.4% in subjects with severe hepatic impairment [see Use in Specific Populations (8.7) ] . Drug Interaction Studies Effect of Other Drugs on the Pharmacokinetics of ORLADEYO Berotralstat is a P-gp and BCRP substrate. Cyclosporine, a P-gp and BCRP inhibitor, decreased berotralstat 150 mg C max by 7%, while AUC 0-last and AUC 0-inf increased by 27% and 24%, respectively. Effect of ORLADEYO on the Pharmacokinetics of Other Drugs Berotralstat 150 mg once daily is a moderate inhibitor of CYP2D6 and CYP3A4, and a weak inhibitor of CYP2C9 and CYP2C19. At 2-times the maximum recommended dosage of 150 mg, berotralstat is an inhibitor of P-gp and is not an inhibitor of BCRP (rosuvastatin exposure was decreased by approximately 20%). In a drug interaction study conducted in healthy females of reproductive potential (N=22), concomitant administration of berotralstat 150 mg once daily with 0.15 mg/0.03 mg desogestrel/ethinyl estradiol led to a 2.6-fold increase in the AUC 0-last of etonogestrel, the active metabolite of desogestrel. The effect of berotralstat on the pharmacokinetics of other drugs are presented in Figure 1 [see Drug Interactions (7.2) ] . Figure 1: Effect of ORLADEYO on Concomitant Medications Figure 1