Berotralstat Hydrochloride
FDA Drug Information • Also known as: Orladeyo
- Brand Names
- Orladeyo
- Route
- ORAL
- Dosage Form
- CAPSULE
- Product Type
- HUMAN PRESCRIPTION DRUG
Description
11 DESCRIPTION ORLADEYO (berotralstat) is a 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)-1 H -pyrazole-5-carboxamide dihydrochloride. The chemical structure is: Berotralstat dihydrochloride is a white to off-white powder that is soluble in water at pH ≤4. The molecular formula is C 30 H 26 F 4 N 6 O ∙ 2HCl and the molecular weight is 635.49 (dihydrochloride). ORLADEYO (berotralstat) capsules contain 150 mg of berotralstat (equivalent to 169.4 mg berotralstat dihydrochloride) or 110 mg of berotralstat (equivalent to 124.3 mg berotralstat dihydrochloride) in 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. ORLADEYO (berotralstat) oral pellets are white to off-white film-coated pellets for oral administration and enclosed in a unit-dose packet containing berotralstat 72 mg (equivalent to 81.3 mg berotralstat dihydrochloride), 96 mg (equivalent to 108.4 mg berotralstat dihydrochloride), 108 mg (equivalent to 122.0 mg berotralstat dihydrochloride), or 132 mg (equivalent to 149.1 mg of berotralstat dihydrochloride). Each unit-dose packet contains the active ingredient berotralstat dihydrochloride and the inactive ingredients colloidal silicon dioxide, crospovidone, magnesium stearate, and pregelatinized starch. The oral pellets film coating contains butylated methacrylate copolymer, silicon dioxide, sodium lauryl sulphate, stearic acid, talc, and titanium dioxide. Chemical Structure
What Is Berotralstat Hydrochloride Used For?
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) ] .
Dosage and Administration
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...
Side Effects (Adverse Reactions)
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...
Drug Interactions
7 DRUG INTERACTIONS P-gp inducers: Avoid use with ORLADEYO. ( 7.1 ) CYP2D6, CYP3A4 or P-gp Substrates: When used concomitantly with ORLADEYO, closely monitor or modify the dosage of the substrates where minimal increases in concentration may lead to serious adverse reactions. ( 7.2 , 12.3 ) 7.1 Effect of Other Drugs on ORLADEYO P-gp Inducers Berotralstat is a substrate of P-gp and BCRP. P-gp inducers may decrease berotralstat plasma concentration, leading to reduced efficacy of ORLADEYO. Avoid concomitant use of P-gp inducers with ORLADEYO. 7.2 Effect of ORLADEYO on Other Drugs CYP2D6 and CYP3A4 Substrates ORLADEYO at a dose of 150 mg is a moderate inhibitor of CYP2D6 and CYP3A4. Concomitant use of ORLADEYO with CYP2D6 or CYP3A4 substrates can increase exposure of the CYP2D6 or CYP3A4 substrates and may increase the risk of adverse reactions associated with the substrates. If ORLADEYO is concomitantly used with CYP2D6 or CYP3A4 substrates where minimal increases in the concentration of the substrates may lead to serious adverse reactions, closely monitor or modify the dosage of the CYP2D6 or CYP3A4 substrate [see Clinical Pharmacology (12.3) ] . Refer to the Prescribing Information of the CYP2D6 or CYP3A4 substrate. Desogestrel Concomitant use of ORLADEYO with desogestrel increases exposure to etonogestrel, the active metabolite of desogestrel, and may increase the risk of desogestrel-associated adverse reactions. Consider the benefits and risks when using ORLADEYO concomitantly with desogestrel [see Clinical Pharmacology (12.3) ] . P-gp Substrates ORLADEYO at 2-times the maximum recommended dose of 150 mg is a P-gp inhibitor and can increase exposure of P-gp substrates, leading to increased risk of adverse reactions associated with the substrates. Higher-than-recommended dosages of ORLADEYO are not recommended [see Warnings and Precautions (5.1) ] . If ORLADEYO is concomitantly used with P-gp substrates where minimal increases in the concentration of the substrates may lead to serious adverse reactions, closely monitor or modify the dosage of the P-gp substrate [see Clinical Pharmacology (12.3) ] . Refer to the Prescribing Information of the P-gp substrate.
Contraindications
4 CONTRAINDICATIONS None. None. ( 4 )
Pregnancy and Breastfeeding
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% to 4% and 15% to 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/m 2 basis) did not cause fetal structural alterations either. Berotralstat concentrations in the fetal blood were approximately 5% to 11% of the maternal blood.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING ORLADEYO (berotralstat) capsules and oral pellets are supplied as follows in Table 4: Table 4. Dosage Form, Strength, and Package Configuration for ORLADEYO Dosage Form Strength Description Package Configuration NDC Capsule 110 mg light blue opaque body and cap with a white imprint "110" on body and a white imprint "BCX" on cap A 28-day supply of ORLADEYO is provided in a carton containing 4 child-resistant shellpacks, each containing a 7-capsule blister card. Each carton contains a tamper-evident seal. Do not use if tamper-evident seal is broken or missing. 72769-102-01 150 mg white opaque body with a black imprint "150" and a light blue opaque cap with a black imprint "BCX" 72769-101-01 Pellets 72 mg white to off-white, film-coated pellets A 28-day supply of ORLADEYO oral pellets is provided in a carton containing 4 wallets, each containing 7 child-resistant unit-dose packets. Each carton contains a tamper-evident seal. Do not use if tamper-evident seal is broken or missing. 72769-111-02 96 mg 72769-112-02 108 mg 72769-113-02 132 mg 72769-114-02 Store at 20°C to 25°C (68°F to 77°F). Excursions permitted between 15°C and 30°C (59°F to 86°F) [see USP Controlled Room Temperature] .
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.