ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reaction is described elsewhere in the labeling:QT Prolongation [see Warnings and Precautions (5.1)] QT 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.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety of ORLADEYO is primarily based on 24-week (Part 1) data from 3-part, double-blind, parallel-group, and placebo-controlled study (Trial 1) in 120 patients with Type or II HAE 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, 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 Caucasian with 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 110 mg and 150 mg ORLADEYO, 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 shows adverse reactions occurring in >=10% of patients in any ORLADEYO treatment group that also occurred at higher rate than in the placebo treatment group in Trial 1.Table 1: Adverse Reactions Observed in >=10% of Patients in any ORLADEYO Treatment Group (Trial 1) Adverse ReactionPlacebo(N=39)ORLADEYO110 mg(N=41)150 mg(N=40)Total(N=81)n (%)n (%)n (%)n (%)Abdominal Painincludes Abdominal pain, Abdominal discomfort, Abdominal pain upper, and Abdominal tenderness (10)4 (10)9 (23)13 (16)Vomiting1 (3)4 (10)6 (15)10 (12)Diarrheaincludes Diarrhea and Frequent bowel movements04 (10)6 (15)10 (12)Back Pain1 (3)1 (2)4 (10)5 (6)Gastroesophageal Reflux Disease04 (10)2 (5)6 (7)Gastrointestinal reactions, including abdominal pain, vomiting, and diarrhea occurred more frequently in patients receiving ORLADEYO 150 mg versus ORLADEYO 110 mg or placebo. These 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 patient in the ORLADEYO 110 mg dose group discontinued treatment due to gastrointestinal adverse reaction.. Less Common Adverse ReactionsOther adverse reactions that occurred in Part of Trial with an incidence between 5% and <10% at higher incidence in ORLADEYO-treated patients compared to placebo included headache (9% versus 5%), fatigue (6% versus 3%), and flatulence (6% versus 3%). maculopapular drug rash was reported in less than 1% of patients treated with ORLADEYO. The rash resolved, including in subjects 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 (Part 1).. Laboratory Abnormalities. Transaminase elevationsIn Part of Trial 1, single 150 mg ORLADEYO-treated patient discontinued treatment due to asymptomatic elevated transaminases (ALT >8x the upper limit of normal [ULN] and AST >3x ULN). Total bilirubin was normal. No subject receiving 110 mg or placebo developed transaminase levels >3x ULN. In addition to this patient, ORLADEYO-treated patients developed laboratory-related hepatic adverse events compared to placebo-treated patient. No patient reported serious adverse reactions of elevated transaminases.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCarcinogenicity of berotralstat was evaluated in 2-year study in Wistar rats and 26-week study in Tg.rasH2 transgenic mice. The berotralstat doses (oral gavage) were up to 20 and 50 mg/kg/day in rats and mice (approximately and 10 times the MRHDD on plasma AUC basis, respectively). No evidence of tumorigenicity was observed in either species. MutagenesisBerotralstat tested negative in the in vitro bacterial reverse mutation assay (Ames test), the in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and the in vivo rat micronucleus assay.. Impairment of FertilityIn fertility study in rats, berotralstat at oral doses up to 45 mg/kg/day (approximately times the MRHDD on mg/m2 basis) showed no effect on fertility in males or females.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Berotralstat is plasma kallikrein inhibitor that binds to plasma kallikrein and inhibits its proteolytic activity. Plasma kallikrein is protease that cleaves high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK) and bradykinin, potent vasodilator that increases vascular permeability resulting in swelling and pain associated with HAE. In patients with HAE due to C1-inhibitor (C1-INH) deficiency or dysfunction, normal regulation of plasma kallikrein activity is not present, which leads to uncontrolled increases in plasma kallikrein activity and results in angioedema attacks. Berotralstat decreases plasma kallikrein activity to control excess bradykinin generation in patients with HAE.. 12.2 Pharmacodynamics. Concentration-dependent inhibition of plasma kallikrein, measured as reduction from baseline of specific enzyme activity, was demonstrated after oral administration of ORLADEYO once daily in patients with HAE.. Cardiac ElectrophysiologyAt the recommended dose of 150 mg once daily, ORLADEYO does not prolong the QT interval to any clinically relevant extent. At 3-times the recommended dose, the mean (upper 90% confidence interval) increase in QTcF was 15.9 msec (23.5 msec). The observed increase in QTcF was concentration-dependent.. 12.3 Pharmacokinetics. Following oral administration of berotralstat 150 mg once daily, the steady state Cmax and area under the curve over the dosing interval (AUCtau) are 158 ng/mL (range: 110 to 234 ng/mL) and 2770 nghr/mL (range: 1880 to 3790 nghr/mL), respectively. Following oral administration of berotralstat 110 mg once daily, the steady-state Cmax and AUCtau are 97.8 ng/mL (range: 63 to 235 ng/mL) and 1600 nghr/mL (range: 950 to 4170 nghr/mL), respectively.Berotralstat exposure (Cmax and AUC) increases greater than proportionally with dose and steady state is reached by days to 12. After once-daily administration, exposure of berotralstat at steady state is approximately times that after single dose.The pharmacokinetics of berotralstat are similar between healthy adult subjects and in patients with HAE.. AbsorptionThe median time to maximum plasma concentration (Tmax) of berotralstat when administered with food is hours (range: to hours).. Effect of FoodNo differences in the Cmax and AUC of berotralstat were observed following administration with high-fat meal, however the median Tmax was delayed by hours, from hours (fasted) to hours (fed).. DistributionPlasma protein binding is approximately 99%. After single dose of radiolabeled berotralstat 300 mg, the blood to plasma ratio was approximately 0.92.. EliminationThe median elimination half-life of berotralstat was approximately 93 hours (range: 39 to 152 hours).. MetabolismBerotralstat is metabolized by CYP2D6 and by CYP3A4 with low turnover in vitro. After single oral radiolabeled berotralstat 300 mg dose, berotralstat represented 34% of the total plasma radioactivity, with metabolites, each accounting for between 1.8 and 7.8% of the total radioactivity. ExcretionAfter single oral radiolabeled berotralstat 300 mg dose, approximately 9% was excreted in urine (3.4% unchanged; range 1.8 to 4.7%) and 79% was excreted in feces.. Specific PopulationsBody weight, age, gender, and race did not have clinically meaningful influence on the systemic exposure of berotralstat.. Geriatric PatientsBased on the population pharmacokinetic analyses that included elderly patients (>= 65 to 74 years, N=25), age does not have clinically meaningful impact on the systemic exposure of berotralstat [see Use in Specific Populations (8.5)].. Pediatric PatientsBased 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 adolescents is not considered to be clinically meaningful.. Patients with Renal ImpairmentThe pharmacokinetics of single 200 mg oral dose of berotralstat were studied in subjects with severe renal impairment (CLCR less than 30 mL/min). When compared to concurrent cohort with normal renal function (CLCR greater than 90 mL/min), no clinically relevant differences were observed; Cmax was increased by 47%, while AUC0-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 (CLCR less than 15 mL/min or eGFR less than 15 mL/min/1.73 m2 or patients requiring hemodialysis).. Patients with Hepatic ImpairmentThe pharmacokinetics of single 150 mg oral dose of berotralstat were studied in 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; Cmax was increased by 77%, while AUC0-inf was increased by 78%. In subjects with severe hepatic impairment, Cmax was increased by 27%, while AUC0-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 mean of 1.2% in healthy subjects to 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 ORLADEYOBerotralstat is P-gp and BCRP substrate. Cyclosporine, P-gp and BCRP inhibitor, increased berotralstat Cmax by 25%, AUC0-last by 55%, and AUC0-inf by 69% [see Drug Interactions (7.1)].. Effect of ORLADEYO on the Pharmacokinetics of Other DrugsBerotralstat 150 mg once daily is moderate inhibitor of CYP2D6 and CYP3A4, and weak inhibitor of CYP2C9 and CYP2C19.Berotralstat at 300 mg dose is an inhibitor of P-gp and is not an inhibitor of BCRP (rosuvastatin exposure was decreased by approximately 20%).The effect of berotralstat on the pharmacokinetics of other drugs are presented in Figure [see Drug Interactions (7.2)]. Figure 1: Effect of ORLADEYO on Concomitant Medications. Figure 1.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Trial (NCT3485911)The efficacy of ORLADEYO for the prevention of angioedema attacks in patients 12 years of age and older with Type or II HAE was demonstrated in Part of multicenter, randomized, double-blind, placebo-controlled, parallel-group study (Trial 1).The study included 120 adult and adolescent patients who experienced at least two investigator-confirmed attacks within the first weeks of the run-in period and took at least one dose of study treatment. Patients were randomized into of parallel treatment arms, stratified by baseline attack rate, in 1:1:1 ratio (berotralstat 110 mg, berotralstat 150 mg, or placebo by oral administration once daily, with food) for the 24-week treatment period (Part 1).Patients discontinued other prophylactic HAE medications prior to entering the study; however, all patients were allowed to use rescue medications for treatment of breakthrough HAE attacks.A history of laryngeal angioedema attacks was reported in 74% of patients and 75% reported prior use of long-term prophylaxis. The median attack rate during the prospective run-in period (baseline attack rate) was 2.9/month. Seventy percent of patients enrolled had baseline attack rate of >= attacks/month.ORLADEYO 150 mg and 110 mg produced statistically significant reductions in the rate of HAE attacks compared to placebo for the primary endpoint in the Intent-to-Treat (ITT) population as shown in Table 2. The percent reductions in HAE attack rate were greater with ORLADEYO 150 mg and 110 mg relative to placebo regardless of attack rate during the run-in period.Table 2. Primary Efficacy Endpoint (Trial 1): Reduction in HAE Attack Rate- ITT PopulationOutcomeORLADEYOPlacebo110 mg QD150 mg QDN 41N 40N 40One patient in the ITT analysis was randomized to placebo but was not treated. HAE Attack rate, rate per 28 days Statistical analysis based on negative binomial regression model; number of attacks included as dependent variable, treatment included as fixed effect, baseline attack rate included as covariate, and logarithm of duration on treatment included as offset variable. 1.651.312.35% Rate Reduction Percent reduction relative to placebo. (95% CI)30.0%(4.6, 48.7)44.2%(23.0, 59.5)p-value0.024<0.001Reductions in attack rates were observed in the first month of treatment with ORLADEYO 150 mg and 110 mg and were sustained through 24 weeks as shown in Figure 2.Figure 2. Mean (+/- SEM) HAE Attack Rate/month Through 24 Weeks (Trial 1)- ITT PopulationPre-defined exploratory endpoints included the proportion of responders to study drug, defined as at least 50% relative reduction in HAE attacks during treatment compared with the baseline attack rate; 58% of patients receiving 150 mg ORLADEYO and 51% of patients receiving 110 mg ORLADEYO had >= 50% reduction in their HAE attack rates compared to baseline versus 25% of placebo patients. In post-hoc analyses, 50% and 23% of patients receiving 150 mg ORLADEYO, and 27% and 10% of patients receiving 110 mg ORLADEYO, had >= 70% or >= 90% reduction in their HAE attack rates compared to baseline versus 15% and 8% of placebo patients, respectively. The rate of attacks rated as moderate or severe was reduced by 40% and 10% in patients receiving 150 mg ORLADEYO and 110 mg ORLADEYO, respectively, versus placebo.. Figure 2.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety of ORLADEYO is primarily based on 24-week (Part 1) data from 3-part, double-blind, parallel-group, and placebo-controlled study (Trial 1) in 120 patients with Type or II HAE 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, 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 Caucasian with 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 110 mg and 150 mg ORLADEYO, 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 shows adverse reactions occurring in >=10% of patients in any ORLADEYO treatment group that also occurred at higher rate than in the placebo treatment group in Trial 1.Table 1: Adverse Reactions Observed in >=10% of Patients in any ORLADEYO Treatment Group (Trial 1) Adverse ReactionPlacebo(N=39)ORLADEYO110 mg(N=41)150 mg(N=40)Total(N=81)n (%)n (%)n (%)n (%)Abdominal Painincludes Abdominal pain, Abdominal discomfort, Abdominal pain upper, and Abdominal tenderness (10)4 (10)9 (23)13 (16)Vomiting1 (3)4 (10)6 (15)10 (12)Diarrheaincludes Diarrhea and Frequent bowel movements04 (10)6 (15)10 (12)Back Pain1 (3)1 (2)4 (10)5 (6)Gastroesophageal Reflux Disease04 (10)2 (5)6 (7)Gastrointestinal reactions, including abdominal pain, vomiting, and diarrhea occurred more frequently in patients receiving ORLADEYO 150 mg versus ORLADEYO 110 mg or placebo. These 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 patient in the ORLADEYO 110 mg dose group discontinued treatment due to gastrointestinal adverse reaction.. Less Common Adverse ReactionsOther adverse reactions that occurred in Part of Trial with an incidence between 5% and <10% at higher incidence in ORLADEYO-treated patients compared to placebo included headache (9% versus 5%), fatigue (6% versus 3%), and flatulence (6% versus 3%). maculopapular drug rash was reported in less than 1% of patients treated with ORLADEYO. The rash resolved, including in subjects 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 (Part 1).. Laboratory Abnormalities. Transaminase elevationsIn Part of Trial 1, single 150 mg ORLADEYO-treated patient discontinued treatment due to asymptomatic elevated transaminases (ALT >8x the upper limit of normal [ULN] and AST >3x ULN). Total bilirubin was normal. No subject receiving 110 mg or placebo developed transaminase levels >3x ULN. In addition to this patient, ORLADEYO-treated patients developed laboratory-related hepatic adverse events compared to placebo-treated patient. No patient reported serious adverse reactions of elevated transaminases.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None. None (4).

DESCRIPTION SECTION.

11 DESCRIPTION. ORLADEYO (berotralstat) capsules is plasma kallikrein inhibitor. Berotralstat is presented as the dihydrochloride salt with the chemical name 1-[3-(aminomethyl)phenyl]-N-(5-(R)-(3-cyanophenyl)[(cyclopropylmethyl)amino]methyl-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide dihydrochloride. The chemical structure is:Berotralstat dihydrochloride is white to off-white powder that is soluble in water at pH <= 4. The molecular formula is C30H26F4N6O 2HCl and the molecular weight is 635.49 (dihydrochloride).ORLADEYO is supplied as 150 mg (equivalent to 169.4 mg berotralstat dihydrochloride) and 110 mg (equivalent to 124.2 mg berotralstat dihydrochloride) hard gelatin capsules for oral administration. Each capsule contains the active ingredient berotralstat dihydrochloride and the inactive ingredients colloidal silicon dioxide, crospovidone, magnesium stearate, and pregelatinized starch.. Chemical Structure.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).Inform patients of the risks and benefits of ORLADEYO before prescribing or administering to the patient.. Drug InteractionsAdvise patients that ORLADEYO may interact with other drugs [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products.. Not for Acute Treatment of HAE AttacksAdvise patients to take their usual rescue medication to treat an acute attack of HAE. Inform patients that the safety and effectiveness of ORLADEYO has not been established as an acute treatment for HAE attacks. Advise patients that they should not take daily doses higher than 150 mg once daily or additional doses of ORLADEYO to treat an acute attack of HAE due to risk of QT prolongation [see Limitations of Use (1) and Warnings and Precautions (5.1)].

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended Dosage: One capsule (150 mg) taken orally once daily with food. (2.1)See Full Prescribing Information for:Dosage adjustment in patients with moderate or severe hepatic impairment. (2.2)Dosage adjustment in patients with chronic administration of P-gp or BCRP inhibitors. (2.3)Dosage adjustment in patients with persistent gastrointestinal reactions. (2.4). Recommended Dosage: One capsule (150 mg) taken orally once daily with food. (2.1). Dosage adjustment in patients with moderate or severe hepatic impairment. (2.2). Dosage adjustment in patients with chronic administration of P-gp or BCRP inhibitors. (2.3). Dosage adjustment in patients with persistent gastrointestinal reactions. (2.4). 2.1 Recommended Dosage. The recommended dosage of ORLADEYO is one 150 mg capsule taken orally once daily with food.. 2.2 Recommended Dosage in Patients with Hepatic Impairment. No dosage adjustment of ORLADEYO is recommended for patients with mild hepatic impairment (Child-Pugh Class A) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].In patients with moderate or severe hepatic impairment (Child-Pugh or C), the recommended dosage of ORLADEYO is one 110 mg capsule taken orally once daily with food [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].. 2.3 Recommended Dosage for Concomitant Use with P-gp or BCRP Inhibitors. In patients with chronic administration of P-gp or BCRP inhibitors (e.g., cyclosporine), the recommended dosage of ORLADEYO is one 110 mg capsule taken orally once daily with food [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].. 2.4 Dosage Adjustment in Patients with Persistent GI Reactions. Gastrointestinal (GI) reactions may occur in patients receiving ORLADEYO [see Adverse Reactions (6.1)]. If GI events persist, reduced dose of 110 mg once daily with food may be considered.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Capsules: 150 mg, 110 mg (3). Capsules:150 mg: white opaque body with black imprint 150 and light blue opaque cap with black imprint BCX.110 mg: light blue opaque capsules with white imprint 110 on body and white imprint BCX on cap.. 150 mg: white opaque body with black imprint 150 and light blue opaque cap with black imprint BCX.. 110 mg: light blue opaque capsules with white imprint 110 on body and white imprint BCX on cap.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. This section describes clinically relevant drug interactions with ORLADEYO. Drug interaction studies are described elsewhere in the labeling [see Clinical Pharmacology (12.3)]. P-gp or BCRP inhibitors Reduce ORLADEYO dosage when co-administered. (7.1, 12.3)P-gp inducers Avoid use with ORLADEYO. (7.1)CYP2D6, CYP3A4 or P-gp Substrates: Appropriately monitor or dose titrate narrow therapeutic index drugs that are predominantly metabolized by CYP2D6, CYP3A4 or are P-gp substrates when co-administered with ORLADEYO. (7.2, 12.3). 7.1Potential for Other Drugs to Affect ORLADEYO. P-gp or BCRP inhibitorsORLADEYO is P-gp and BCRP substrate. dose of 110 mg ORLADEYO is recommended for patients with chronic administration of P-gp or BCRP inhibitors (e.g., cyclosporine) [see Clinical Pharmacology (12.3)]. P-gp InducersBerotralstat is substrate of P-gp and BCRP. P-gp inducers (e.g., rifampin, St. Johns wort) may decrease berotralstat plasma concentration, leading to reduced efficacy of ORLADEYO. The use of P-gp inducers is not recommended with ORLADEYO.. 7.2Potential for ORLADEYO to Affect Other Drugs. CYP2D6 and CYP3A4 SubstratesORLADEYO at dose of 150 mg is moderate inhibitor of CYP2D6 and CYP3A4. For concomitant medications with narrow therapeutic index that are predominantly metabolized by CYP2D6 (e.g., thioridazine, pimozide) or CYP3A4 (e.g., cyclosporine, fentanyl), appropriate monitoring and dose titration is recommended [see Clinical Pharmacology (12.3)].. P-gp Substrates. ORLADEYO at dose of 300 mg is P-gp inhibitor. Appropriate monitoring and dose titration is recommended for P-gp substrates (e.g. digoxin) when co-administering with ORLADEYO [see Clinical Pharmacology (12.3)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. The safety and effectiveness of ORLADEYO were evaluated in subgroup of patients (N=9) aged >= 65 years in Trial 1. Results of the subgroup analysis by age were consistent with overall study results. The safety profile from an additional elderly patients aged >= 65 years enrolled in the open-label, long-term safety study (Trial 2) was consistent with data from Trial [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)].

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. No dosage adjustment of ORLADEYO is recommended for patients with mild hepatic impairment (Child-Pugh Class A) [see Clinical Pharmacology (12.3)].In patients with moderate or severe hepatic impairment (Child-Pugh or C), the recommended dose of ORLADEYO is 110 mg once daily with food [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. ORLADEYO (berotralstat) capsules:150 mg: white opaque body with black imprint 150 and light blue opaque cap with black imprint BCX. NDC 72769-101-01.110 mg: light blue opaque capsules with white imprint 110 on body and white imprint BCX on cap. NDC 72769-102-01.A 28-day supply of ORLADEYO is provided in carton containing four child-resistant shellpaks, each containing 7-capsule blister card.Each carton contains tamper evident seal.Do not use if tamper evident seal is broken or missing.. 150 mg: white opaque body with black imprint 150 and light blue opaque cap with black imprint BCX. NDC 72769-101-01.. 110 mg: light blue opaque capsules with white imprint 110 on body and white imprint BCX on cap. NDC 72769-102-01.. 28-day supply of ORLADEYO is provided in carton containing four child-resistant shellpaks, each containing 7-capsule blister card.. Each carton contains tamper evident seal.. Do not use if tamper evident seal is broken or missing.. Store at 20C to 25C (68F to 77F). Excursions permitted between 15C and 30C (59F to 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. ORLADEYO(TM) is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years of age and older.. ORLADEYO is plasma kallikrein inhibitor indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 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 150 mg once daily are not recommended due to the potential for QT prolongation [see Warnings and Precautions (5.1)].

STORAGE AND HANDLING SECTION.

Store at 20C to 25C (68F to 77F). Excursions permitted between 15C and 30C (59F to 86F) [see USP Controlled Room Temperature].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are insufficient data in pregnant women available to inform drug-related risks with ORLADEYO use in pregnancy. Based on animal reproduction studies, no evidence of structural alterations was observed when berotralstat was administered orally to pregnant rats and rabbits during organogenesis at doses up to approximately 10 and times, respectively, the maximum recommended human daily dose (MRHDD) in adults on an AUC basis (see Data).The background risk of major birth defects and miscarriage for the indicated population is unknown. 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 DataIn animal reproduction studies, oral administration of berotralstat to pregnant rats and rabbits during the period of organogenesis did not cause fetal structural alterations. The berotralstat dose in rats and rabbits was up to approximately 10 and times, respectively, the MRHDD in adults (on an AUC basis at maternal doses of 75 and 100 mg/kg/day, respectively). In pre- and postnatal development study in rats, oral administration of berotralstat to pregnant rats during the period of organogenesis and until delivery at doses up to 45 mg/kg/day (approximately times of the MRHDD on mg/m2 basis) did not cause fetal structural alterations either. Berotralstat concentrations in the fetal blood were approximately 5-11% of the maternal blood. 8.2 Lactation. Risk SummaryThere are no data on the presence of berotralstat in human milk, its effects on the breastfed infant, or its effects on milk production. However, when drug is present in animal milk, it is likely that the drug will be present in human milk. Low levels of berotralstat were detected in the plasma of rat pups when dams were dosed with the drug orally during the lactation period. The berotralstat concentration in the pup plasma was approximately 2% of the maternal plasma (see Data).The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ORLADEYO and any potential adverse effects on the breastfed infant from ORLADEYO or from the underlying maternal condition.. Data. Animal DataIn the pre- and post-natal development study in rats, berotralstat was administered to dams during the pregnancy and lactation periods at doses up to 45 mg/kg/day (approximately times of the MRHDD on mg/m2 basis). Berotralstat was detected in the plasma of pups during the lactation period. The berotralstat concentration in the pup plasma was approximately 2% of the maternal plasma. Both dams and pups at 45 mg/kg/day showed statistically significant decreases in body weight gain (p 0.05). No treatment-related effects were observed at 25 mg/kg/day (approximately equal to the MRHDD on mg/m2 basis).. 8.4 Pediatric Use. The safety and effectiveness of ORLADEYO for prophylaxis to prevent attacks of hereditary angioedema have been established in pediatric patients aged 12 and older. Use of ORLADEYO in this population is supported by evidence from an adequate and well-controlled study (Trial 1) that included adults and total of adolescent patients aged 12 to <18 years of age. The safety profile and attack rate on study were similar to those observed in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)]. An additional 10 adolescent patients aged 12 to <18 years were enrolled in the open-label study (Trial 2).The safety and effectiveness of ORLADEYO in pediatric patients 12 years of age have not been established.. 8.5 Geriatric Use. The safety and effectiveness of ORLADEYO were evaluated in subgroup of patients (N=9) aged >= 65 years in Trial 1. Results of the subgroup analysis by age were consistent with overall study results. The safety profile from an additional elderly patients aged >= 65 years enrolled in the open-label, long-term safety study (Trial 2) was consistent with data from Trial [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)].. 8.6 Renal Impairment. No dosage adjustment of ORLADEYO is recommended for patients with mild, moderate or severe renal impairment [see Clinical Pharmacology (12.3)].ORLADEYO has not been studied in patients with End-Stage Renal Disease (CLCR 15 mL/min or eGFR 15 mL/min/1.73 m2 or patients requiring hemodialysis), and, therefore is not recommended for use in these patient populations [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment. No dosage adjustment of ORLADEYO is recommended for patients with mild hepatic impairment (Child-Pugh Class A) [see Clinical Pharmacology (12.3)].In patients with moderate or severe hepatic impairment (Child-Pugh or C), the recommended dose of ORLADEYO is 110 mg once daily with food [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of berotralstat in human milk, its effects on the breastfed infant, or its effects on milk production. However, when drug is present in animal milk, it is likely that the drug will be present in human milk. Low levels of berotralstat were detected in the plasma of rat pups when dams were dosed with the drug orally during the lactation period. The berotralstat concentration in the pup plasma was approximately 2% of the maternal plasma (see Data).The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ORLADEYO and any potential adverse effects on the breastfed infant from ORLADEYO or from the underlying maternal condition.. Data. Animal DataIn the pre- and post-natal development study in rats, berotralstat was administered to dams during the pregnancy and lactation periods at doses up to 45 mg/kg/day (approximately times of the MRHDD on mg/m2 basis). Berotralstat was detected in the plasma of pups during the lactation period. The berotralstat concentration in the pup plasma was approximately 2% of the maternal plasma. Both dams and pups at 45 mg/kg/day showed statistically significant decreases in body weight gain (p 0.05). No treatment-related effects were observed at 25 mg/kg/day (approximately equal to the MRHDD on mg/m2 basis).

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Berotralstat is plasma kallikrein inhibitor that binds to plasma kallikrein and inhibits its proteolytic activity. Plasma kallikrein is protease that cleaves high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK) and bradykinin, potent vasodilator that increases vascular permeability resulting in swelling and pain associated with HAE. In patients with HAE due to C1-inhibitor (C1-INH) deficiency or dysfunction, normal regulation of plasma kallikrein activity is not present, which leads to uncontrolled increases in plasma kallikrein activity and results in angioedema attacks. Berotralstat decreases plasma kallikrein activity to control excess bradykinin generation in patients with HAE.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCarcinogenicity of berotralstat was evaluated in 2-year study in Wistar rats and 26-week study in Tg.rasH2 transgenic mice. The berotralstat doses (oral gavage) were up to 20 and 50 mg/kg/day in rats and mice (approximately and 10 times the MRHDD on plasma AUC basis, respectively). No evidence of tumorigenicity was observed in either species. MutagenesisBerotralstat tested negative in the in vitro bacterial reverse mutation assay (Ames test), the in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and the in vivo rat micronucleus assay.. Impairment of FertilityIn fertility study in rats, berotralstat at oral doses up to 45 mg/kg/day (approximately times the MRHDD on mg/m2 basis) showed no effect on fertility in males or females.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 150 mg Capsule Blister Card Shellpack Carton. NDC 72769-101-01RX onlyorladeyo(TM)(berotralstat) capsules 150 mgFOR ORAL USE ONLY28 capsulesContains 28-day supply4 shellpacks each containing 7-capsule blister cardbio cryst(TM). PRINCIPAL DISPLAY PANEL 150 mg Capsule Blister Card Shellpack Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of ORLADEYO for prophylaxis to prevent attacks of hereditary angioedema have been established in pediatric patients aged 12 and older. Use of ORLADEYO in this population is supported by evidence from an adequate and well-controlled study (Trial 1) that included adults and total of adolescent patients aged 12 to <18 years of age. The safety profile and attack rate on study were similar to those observed in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)]. An additional 10 adolescent patients aged 12 to <18 years were enrolled in the open-label study (Trial 2).The safety and effectiveness of ORLADEYO in pediatric patients 12 years of age have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Concentration-dependent inhibition of plasma kallikrein, measured as reduction from baseline of specific enzyme activity, was demonstrated after oral administration of ORLADEYO once daily in patients with HAE.. Cardiac ElectrophysiologyAt the recommended dose of 150 mg once daily, ORLADEYO does not prolong the QT interval to any clinically relevant extent. At 3-times the recommended dose, the mean (upper 90% confidence interval) increase in QTcF was 15.9 msec (23.5 msec). The observed increase in QTcF was concentration-dependent.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Following oral administration of berotralstat 150 mg once daily, the steady state Cmax and area under the curve over the dosing interval (AUCtau) are 158 ng/mL (range: 110 to 234 ng/mL) and 2770 nghr/mL (range: 1880 to 3790 nghr/mL), respectively. Following oral administration of berotralstat 110 mg once daily, the steady-state Cmax and AUCtau are 97.8 ng/mL (range: 63 to 235 ng/mL) and 1600 nghr/mL (range: 950 to 4170 nghr/mL), respectively.Berotralstat exposure (Cmax and AUC) increases greater than proportionally with dose and steady state is reached by days to 12. After once-daily administration, exposure of berotralstat at steady state is approximately times that after single dose.The pharmacokinetics of berotralstat are similar between healthy adult subjects and in patients with HAE.. AbsorptionThe median time to maximum plasma concentration (Tmax) of berotralstat when administered with food is hours (range: to hours).. Effect of FoodNo differences in the Cmax and AUC of berotralstat were observed following administration with high-fat meal, however the median Tmax was delayed by hours, from hours (fasted) to hours (fed).. DistributionPlasma protein binding is approximately 99%. After single dose of radiolabeled berotralstat 300 mg, the blood to plasma ratio was approximately 0.92.. EliminationThe median elimination half-life of berotralstat was approximately 93 hours (range: 39 to 152 hours).. MetabolismBerotralstat is metabolized by CYP2D6 and by CYP3A4 with low turnover in vitro. After single oral radiolabeled berotralstat 300 mg dose, berotralstat represented 34% of the total plasma radioactivity, with metabolites, each accounting for between 1.8 and 7.8% of the total radioactivity. ExcretionAfter single oral radiolabeled berotralstat 300 mg dose, approximately 9% was excreted in urine (3.4% unchanged; range 1.8 to 4.7%) and 79% was excreted in feces.. Specific PopulationsBody weight, age, gender, and race did not have clinically meaningful influence on the systemic exposure of berotralstat.. Geriatric PatientsBased on the population pharmacokinetic analyses that included elderly patients (>= 65 to 74 years, N=25), age does not have clinically meaningful impact on the systemic exposure of berotralstat [see Use in Specific Populations (8.5)].. Pediatric PatientsBased 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 adolescents is not considered to be clinically meaningful.. Patients with Renal ImpairmentThe pharmacokinetics of single 200 mg oral dose of berotralstat were studied in subjects with severe renal impairment (CLCR less than 30 mL/min). When compared to concurrent cohort with normal renal function (CLCR greater than 90 mL/min), no clinically relevant differences were observed; Cmax was increased by 47%, while AUC0-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 (CLCR less than 15 mL/min or eGFR less than 15 mL/min/1.73 m2 or patients requiring hemodialysis).. Patients with Hepatic ImpairmentThe pharmacokinetics of single 150 mg oral dose of berotralstat were studied in 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; Cmax was increased by 77%, while AUC0-inf was increased by 78%. In subjects with severe hepatic impairment, Cmax was increased by 27%, while AUC0-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 mean of 1.2% in healthy subjects to 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 ORLADEYOBerotralstat is P-gp and BCRP substrate. Cyclosporine, P-gp and BCRP inhibitor, increased berotralstat Cmax by 25%, AUC0-last by 55%, and AUC0-inf by 69% [see Drug Interactions (7.1)].. Effect of ORLADEYO on the Pharmacokinetics of Other DrugsBerotralstat 150 mg once daily is moderate inhibitor of CYP2D6 and CYP3A4, and weak inhibitor of CYP2C9 and CYP2C19.Berotralstat at 300 mg dose is an inhibitor of P-gp and is not an inhibitor of BCRP (rosuvastatin exposure was decreased by approximately 20%).The effect of berotralstat on the pharmacokinetics of other drugs are presented in Figure [see Drug Interactions (7.2)]. Figure 1: Effect of ORLADEYO on Concomitant Medications. Figure 1.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are insufficient data in pregnant women available to inform drug-related risks with ORLADEYO use in pregnancy. Based on animal reproduction studies, no evidence of structural alterations was observed when berotralstat was administered orally to pregnant rats and rabbits during organogenesis at doses up to approximately 10 and times, respectively, the maximum recommended human daily dose (MRHDD) in adults on an AUC basis (see Data).The background risk of major birth defects and miscarriage for the indicated population is unknown. 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 DataIn animal reproduction studies, oral administration of berotralstat to pregnant rats and rabbits during the period of organogenesis did not cause fetal structural alterations. The berotralstat dose in rats and rabbits was up to approximately 10 and times, respectively, the MRHDD in adults (on an AUC basis at maternal doses of 75 and 100 mg/kg/day, respectively). In pre- and postnatal development study in rats, oral administration of berotralstat to pregnant rats during the period of organogenesis and until delivery at doses up to 45 mg/kg/day (approximately times of the MRHDD on mg/m2 basis) did not cause fetal structural alterations either. Berotralstat concentrations in the fetal blood were approximately 5-11% of the maternal blood.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. No dosage adjustment of ORLADEYO is recommended for patients with mild, moderate or severe renal impairment [see Clinical Pharmacology (12.3)].ORLADEYO has not been studied in patients with End-Stage Renal Disease (CLCR 15 mL/min or eGFR 15 mL/min/1.73 m2 or patients requiring hemodialysis), and, therefore is not recommended for use in these patient populations [see Clinical Pharmacology (12.3)].

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONORLADEYO(TM) (or-luh-DAY-oh) (berotralstat) capsules, for oral useThis Patient Information has been approved by the U.S. Food and Drug Administration.12/2020 What is ORLADEYOORLADEYO is prescription medicine used to prevent attacks of Hereditary Angioedema (HAE) in adults and children 12 years of age and older. ORLADEYO is not used to treat an acute HAE attack. Do not take more than one capsule of ORLADEYO day because extra doses can cause heart rhythm problems. It is not known if ORLADEYO is safe and effective to treat an acute HAE attack.It is not known if ORLADEYO is safe and effective in children under 12 years of age.Before you take ORLADEYO, tell your healthcare provider about all of your medical conditions, including if you:have liver problems or are on kidney dialysis.are pregnant or planning to become pregnant. It is not known if ORLADEYO can harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if ORLADEYO passes into your breastmilk. Talk to your healthcare provider about the best way to feed your baby while taking ORLADEYO.Tell your healthcare provider about all of the medicines you take, including other medicines for HAE, prescription and over-the-counter medicines, vitamins, and herbal supplements.Taking ORLADEYO with certain other medicines may affect the way other medicines work and other medicines may affect how ORLADEYO works.Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should take ORLADEYOTake ORLADEYO exactly as your healthcare provider tells you to take it.Take capsule, by mouth, time every day with food. What are the possible side effects of ORLADEYOTaking more than one capsule of ORLADEYO day may cause serious side effects, including: heart rhythm problems. heart rhythm problem called QT prolongation can happen in people who take more than one capsule of ORLADEYO day. This condition can cause an abnormal heart beat. Do not take more than one capsule of ORLADEYO day.The most common side effects of ORLADEYO include: abdominal painvomitingdiarrheaback painheartburnLess common side effects include increases in liver function tests. Rarely, some patients had brief, itchy rash.These are not all of the possible side effects of ORLADEYO. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store ORLADEYOStore ORLADEYO at room temperature between 68oF to 77oF (20oC to 25oC).Each carton contains tamper evident seal. Do not use ORLADEYO if the tamper evident seal is broken or missing.Keep ORLADEYO and all medicines out of the reach of children.General information about the safe and effective use of ORLADEYO.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use ORLADEYO for condition for which it was not prescribed. Do not give ORLADEYO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ORLADEYO that is written for health professionals.What are the ingredients in ORLADEYOActive ingredient: berotralstat dihydrochlorideInactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, and pregelatinized starchManufactured for: BioCryst Pharmaceuticals, Inc., Durham, NC 27703 ORLADEYO(TM) and the BioCryst Logo are trademarks or registered trademarks of BioCryst Pharmaceuticals, Inc.(C) 2020 BioCryst. All rights reserved.For more information, visit www.ORLADEYO.com or call 1-833-633-2279.. ORLADEYO is prescription medicine used to prevent attacks of Hereditary Angioedema (HAE) in adults and children 12 years of age and older. ORLADEYO is not used to treat an acute HAE attack. Do not take more than one capsule of ORLADEYO day because extra doses can cause heart rhythm problems. It is not known if ORLADEYO is safe and effective to treat an acute HAE attack.. It is not known if ORLADEYO is safe and effective in children under 12 years of age.. have liver problems or are on kidney dialysis.. are pregnant or planning to become pregnant. It is not known if ORLADEYO can harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if ORLADEYO passes into your breastmilk. Talk to your healthcare provider about the best way to feed your baby while taking ORLADEYO.. Take ORLADEYO exactly as your healthcare provider tells you to take it.. Take capsule, by mouth, time every day with food. heart rhythm problems. heart rhythm problem called QT prolongation can happen in people who take more than one capsule of ORLADEYO day. This condition can cause an abnormal heart beat. Do not take more than one capsule of ORLADEYO day.. abdominal pain. vomiting. diarrhea. back pain. heartburn. Store ORLADEYO at room temperature between 68oF to 77oF (20oC to 25oC).. Each carton contains tamper evident seal. Do not use ORLADEYO if the tamper evident seal is broken or missing.

SPL UNCLASSIFIED SECTION.

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 150 mg once daily are not recommended due to the potential for QT prolongation [see Warnings and Precautions (5.1)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. An increase in QT prolongation can occur at dosages higher than the recommended 150 mg once daily dosage. Additional doses or doses of ORLADEYO higher than 150 mg once daily are not recommended. (5.1). 5.1 Risk of QT Prolongation with Higher-Than-Recommended Dosages. ORLADEYO should not be used for treatment of acute attacks of HAE. Additional doses or doses of ORLADEYO higher than 150 mg once daily are not recommended. An increase in QT was observed at dosages higher than the recommended 150 mg once daily dosage and was concentration dependent [see Clinical Pharmacology (12.2)].