DRUG INTERACTIONS-(detals)

1. Potential for Other Drugs to Affect ORLADEYO P-gp or BCRP inhibitors-

ORLADEYO is a P-gp and BCRP substrate. A dose of 110 mg ORLADEYO is recommended for patients with chronic administration of P-gp or BCRP inhibitors (e.g., cyclosporine)

. P-gp Inducers Berotralstat is a substrate of P-gp and BCRP. P-gp inducers (e.g., rifampin, St. John’s wort) may decrease berotralstat plasma concentration, leading to reduced efficacy of ORLADEYO.

The use of P-gp inducers is not recommended with ORLADEYO.

2. Potential for ORLADEYO to Affect Other Drugs CYP2D6 and CYP3A4 Substrates-                                                                                                                ORLADEYO at a dose of 150 mg is a moderate inhibitor of CYP2D6 and CYP3A4. For concomitant medications with a 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.

 P-gp Substrates ORLADEYO at a dose of 300 mg is a P-gp inhibitor. Appropriate monitoring and dose titration is recommended for P-gp substrates (e.g. digoxin) when co-administering with ORLADEYO.

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  48

---------------------------CONTRAINDICATIONS----------------------------- None (4) ---------------------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) ----------------------------ADVERSE REACTIONS--------------------------- 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. ----------------------------DRUG INTERACTIONS---------------------------- P-gp or BCRP inhibitors – Reduce ORLADEYO dosage when coadministered. (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

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. Reference ID: 4711629 12 BioCryst Pharmaceuticals, Inc.

Drug Interactions- Advise patients that ORLADEYO may interact with other drugs.

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 Attacks

Advise 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

. For more information, visit www.ORLADEYO.com

ORLADEYOTM is a trademark of BioCryst Pharmaceuticals, Inc. Manufactured for: BioCryst Pharmaceuticals, Inc. Durham, NC 27703 214094-BC-000

CLINICAL PHARMACOLOGY

1. Mechanism of Action-

Berotralstat is a plasma kallikrein inhibitor that binds to plasma kallikrein and inhibits its proteolytic activity.

2. Pharmacodynamics-                                                                                          Concentration-dependent inhibition of plasma kallikrein, measured as a reduction from baseline of specific enzyme activity, was demonstrated after oral administration of ORLADEYO once daily in patients with HAE.

Cardiac Electrophysiology-                                                                             

 At 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.

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 ng*hr/mL (range: 1880 to 3790 ng*hr/mL), respectively.

Absorption- The median time to maximum plasma concentration (Tmax) of berotralstat when administered with food is 5 hours (range: 1 to 8 hours).

Effect of Food-                                                                                                                      No differences in the Cmax and AUC of berotralstat were observed following administration with a high-fat meal, however the median Tmax 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 300 mg, the blood to plasma ratio was approximately 0.92.

Elimination-                                                                                                                   The median elimination half-life of berotralstat was approximately 93 hours (range: 39 to 152 hours). Reference ID: 4711629 8 BioCryst Pharmaceuticals, Inc.

Metabolism-                                                                                                               Berotralstat is metabolized by CYP2D6 and by CYP3A4 with low turnover in vitro.

After a single oral radiolabeled berotralstat 300 mg dose, 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 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 Populations-                                                                                                        Body weight, age, gender, and race did not have a clinically meaningful influence on the systemic exposure of berotralstat.

Geriatric Patients-                                                                                                             Based on the population pharmacokinetic analyses that included elderly patients (= 65 to 74 years, N=25), age does not have a clinically meaningful impact on the systemic exposure of berotralstat.

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 adolescents is not considered to be clinically meaningful.

Patients with Renal Impairment-                                                                                         The pharmacokinetics of a single 200 mg oral dose of berotralstat were studied in subjects with severe renal impairment (CLCR less than 30 mL/min).

When compared to a 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)].

Patients with Hepatic Impairment-                                                                                  The pharmacokinetics of a 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).

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, increased berotralstat Cmax by 25%, AUC0-last by 55%, and AUC0-inf by 69% .

8 USE IN SPECIFIC POPULATIONS-

1 Pregnancy Risk Summary-

There 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 2 times, respectively, the maximum recommended human daily dose (MRHDD) in adults on an AUC basis

(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.

8.2 Lactation Risk Summary-

There 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 a drug is present in animal milk, it is likely that the drug will be present in human milk.

3. 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.

The safety and effectiveness of ORLADEYO in pediatric patients < 12 years of age have not been established.

4.Geriatric Use -

The safety and effectiveness of ORLADEYO were evaluated in a subgroup of patients (N=9) aged = 65 years in Trial 1.

5. Renal Impairment-                                                                                                     No dosage adjustment of ORLADEYO is recommended for patients with mild, moderate or severe renal impairment [see Clinical Pharmacology (12.3)].

6.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 B or C), the recommended dose of ORLADEYO is 110 mg once daily with food [see Dosage and Administration .

.