Hereditary angioedema agents
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Orladeyo Prescribing Information

Drug Detail:Orladeyo (Berotralstat [ ber-oh-tral-stat ])

Drug Class: Hereditary angioedema agents

Contents
Uses Warnings Before Taking Dosage Side effects Interactions

Highlights of Prescribing Information

These highlights do not include all the information needed to use ORLADEYO® safely and effectively. See full prescribing information for ORLADEYO.

ORLADEYO (berotralstat) capsules, for oral use
Initial U.S. Approval: 2020

Indications and Usage for Orladeyo

ORLADEYO is a 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)

Orladeyo 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)

Dosage Forms and Strengths

Capsules: 150 mg, 110 mg (3)

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/Side Effects

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 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)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 3/2022

Related/similar drugs

Firazyr, Haegarda, Cinryze, Berinert, Ruconest, Kalbitor

Full Prescribing Information

6. Adverse Reactions/Side Effects

The following clinically significant adverse reaction is described elsewhere in the labeling:

  • QT Prolongation [see Warnings and Precautions (5.1)]

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.

The safety of ORLADEYO is primarily based on 24-week (Part 1) data from a 3-part, double-blind, parallel-group, placebo-controlled study (Trial 1) in 120 patients with Type I 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, 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 Caucasian 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 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 1 shows adverse reactions occurring in ≥10% of patients in any ORLADEYO treatment group that also occurred at a 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)		ORLADEYO
110 mg
(N=41)		150 mg
(N=40)		Total
(N=81)
n (%)n (%)n (%)n (%)
*
includes Abdominal pain, Abdominal discomfort, Abdominal pain upper, and Abdominal tenderness
†
includes Diarrhea and Frequent bowel movements
Abdominal Pain*4 (10)4 (10)9 (23)13 (16)
Vomiting1 (3)4 (10)6 (15)10 (12)
Diarrhea†04 (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 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% and <10% at a higher incidence in ORLADEYO-treated patients compared to placebo 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 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 1 (Part 1).

Laboratory Abnormalities

Transaminase elevations

In Part 1 of Trial 1, a single 150 mg ORLADEYO-treated patient discontinued treatment due to asymptomatic elevated transaminases (ALT >8× the upper limit of normal [ULN] and AST >3× ULN). Total bilirubin was normal. No subject receiving 110 mg or placebo developed transaminase levels >3× ULN. In addition to this patient, 2 ORLADEYO-treated patients developed laboratory-related hepatic adverse events compared to 1 placebo-treated patient. No patient reported serious adverse reactions of elevated transaminases.

8. Use In Specific Populations

8.1 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 (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 Data

In 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 2 times, respectively, the MRHDD in adults (on an AUC basis at maternal doses of 75 and 100 mg/kg/day, respectively). In a 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 2 times of the MRHDD on a mg/m2 basis) did not cause fetal structural alterations either. Berotralstat concentrations in the fetal blood were approximately 5-11% of the maternal blood.

12. Orladeyo - Clinical Pharmacology

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 ng*hr/mL (range: 1880 to 3790 ng*hr/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 ng*hr/mL (range: 950 to 4170 ng*hr/mL), respectively.

Berotralstat exposure (Cmax and AUC) increases greater than proportionally with dose and steady state is reached by days 6 to 12. After once-daily administration, exposure of berotralstat at steady state is approximately 5 times that after a single dose.

The pharmacokinetics of berotralstat are similar between healthy adult subjects and in patients with HAE.

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).

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 [see Use in Specific Populations (8.5)].

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)].

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 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). 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 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, 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 Drugs

Berotralstat 150 mg once daily is a moderate inhibitor of CYP2D6 and CYP3A4, and a weak inhibitor of CYP2C9 and CYP2C19.

Berotralstat at a 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 1 [see Drug Interactions (7.2)].

Figure 1: Effect of ORLADEYO on Concomitant Medications

Figure 1

14. Clinical Studies

Trial 1 (NCT3485911)

The efficacy of ORLADEYO for the prevention of angioedema attacks in patients 12 years of age and older with Type I or II HAE was demonstrated in Part 1 of a 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 8 weeks of the run-in period and took at least one dose of study treatment. Patients were randomized into 1 of 3 parallel treatment arms, stratified by baseline attack rate, in a 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 a baseline attack rate of ≥2 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 Population
OutcomeORLADEYOPlacebo
110 mg QD150 mg QD
N = 41N = 40N = 40*
*
One patient in the ITT analysis was randomized to placebo but was not treated.
†
Statistical analysis based on a 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.
‡
Percent reduction relative to placebo.
HAE Attack Rate, rate per 28 days †1.651.312.35
% Rate Reduction ‡ (95% CI)30.0%
(4.6, 48.7)		44.2%
(23.0, 59.5)		-
p-value0.024<0.001-

Reductions 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 Population

Figure 2

Pre-defined exploratory endpoints included the proportion of responders to study drug, defined as at least a 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 a ≥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 a ≥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.

For more information, visit www.ORLADEYO.com

ORLADEYO® is a registered trademark of BioCryst Pharmaceuticals, Inc.

Manufactured for:
BioCryst Pharmaceuticals, Inc.
Durham, NC 27703

214094-BC-001

PATIENT INFORMATION
ORLADEYO® (or-luh-DAY-oh)
(berotralstat)
capsules, for oral use
This Patient Information has been approved by the U.S. Food and Drug Administration.03/2022
What is ORLADEYO?
  • ORLADEYO is a 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 a 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 a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take ORLADEYO?
  • Take ORLADEYO exactly as your healthcare provider tells you to take it.
  • Take 1 capsule, by mouth, 1 time every day with food.
What are the possible side effects of ORLADEYO?
Taking more than one capsule of ORLADEYO a day may cause serious side effects, including:
  • heart rhythm problems. A heart rhythm problem called QT prolongation can happen in people who take more than one capsule of ORLADEYO a day. This condition can cause an abnormal heart beat. Do not take more than one capsule of ORLADEYO a day.
The most common side effects of ORLADEYO include:
  • abdominal pain
  • vomiting
  • diarrhea
  • back pain
  • heartburn
Less common side effects include increases in liver function tests. Rarely, some patients had a 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 I store ORLADEYO?
  • Store ORLADEYO at room temperature between 68ºF to 77ºF (20ºC to 25ºC).
  • Each carton contains a 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 a Patient Information leaflet. Do not use ORLADEYO for a 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 ORLADEYO?
Active ingredient: berotralstat dihydrochloride
Inactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, and pregelatinized starch
Manufactured for: BioCryst Pharmaceuticals, Inc., Durham, NC 27703
ORLADEYO® is a registered trademark of BioCryst Pharmaceuticals, Inc.
© 2022 BioCryst. All rights reserved.
For more information, visit www.ORLADEYO.com or call 1-833-633-2279.

PRINCIPAL DISPLAY PANEL - 110 mg Capsule Blister Card Shellpack Carton

NDC 72769-102-01
RX only

orladeyo®
(berotralstat) capsules 110 mg

FOR ORAL USE ONLY

28 capsules
Contains a 28-day supply
4 shellpacks each containing a 7-capsule blister card

bio cryst®

PRINCIPAL DISPLAY PANEL - 110 mg Capsule Blister Card Shellpack Carton
ORLADEYO
berotralstat hydrochloride capsule
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:72769-101
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
Berotralstat hydrochloride (UNII: 88SH1NBL2B) (Berotralstat - UNII:XZA0KB1BDQ) Berotralstat hydrochloride150 mg
Inactive Ingredients
Ingredient NameStrength
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
Crospovidone (UNII: 2S7830E561)
Magnesium Stearate (UNII: 70097M6I30)
STARCH, CORN (UNII: O8232NY3SJ)
Product Characteristics
ColorWHITE, BLUE (light blue) Scoreno score
ShapeCAPSULESize19mm
FlavorImprint Code150;BCX
Contains
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:72769-101-014 in 1 CARTON12/04/2020
11 in 1 DOSE PACK
17 in 1 BLISTER PACK; Type 0: Not a Combination Product
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA21409412/04/2020
ORLADEYO
berotralstat hydrochloride capsule
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:72769-102
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
Berotralstat hydrochloride (UNII: 88SH1NBL2B) (Berotralstat - UNII:XZA0KB1BDQ) Berotralstat hydrochloride110 mg
Inactive Ingredients
Ingredient NameStrength
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
Crospovidone (UNII: 2S7830E561)
Magnesium Stearate (UNII: 70097M6I30)
STARCH, CORN (UNII: O8232NY3SJ)
Product Characteristics
ColorBLUE (light blue) Scoreno score
ShapeCAPSULESize18mm
FlavorImprint Code110;BCX
Contains
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:72769-102-014 in 1 CARTON12/04/2020
11 in 1 DOSE PACK
17 in 1 BLISTER PACK; Type 0: Not a Combination Product
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA21409412/04/2020
Labeler - BioCryst Pharmaceuticals Inc. (618194609)
Establishment
NameAddressID/FEIBusiness Operations
Cambrex Charles City782974257API MANUFACTURE(72769-101, 72769-102)
Establishment
NameAddressID/FEIBusiness Operations
Catalent CTS, LLC962674474MANUFACTURE(72769-101, 72769-102) , ANALYSIS(72769-101, 72769-102)
Establishment
NameAddressID/FEIBusiness Operations
Catalent Pharma Solutions LLC014904112PACK(72769-101, 72769-102)
Establishment
NameAddressID/FEIBusiness Operations
Patheon Pharmaceuticals, Inc.005286822MANUFACTURE(72769-101, 72769-102) , ANALYSIS(72769-101, 72769-102)
Establishment
NameAddressID/FEIBusiness Operations
AndersonBrecon Inc. A PCI Pharma Services Company053217022PACK(72769-101, 72769-102) , LABEL(72769-101, 72769-102)

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