Orladeyo patient education
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Dosage & administration
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Orladeyo prescribing information
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.
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
- 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 |
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.
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) ] .
| 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 |
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) ] .
Dosage Modification in Patients with Persistent GI Adverse Reactions
Gastrointestinal (GI) reactions may occur in patients receiving ORLADEYO [see Adverse Reactions (6.1) ] .
- For adults and pediatric patients 12 years of age and older, if GI adverse reactions persist, consider a lower ORLADEYO capsules dosage of 110 mg once daily with food.
- For pediatric patients 2 to less than 12 years of age with persistent GI adverse reactions, consider the risks and benefits of continuing treatment with ORLADEYO.
Administration Instructions for Oral Pellets
Do not chew or crush ORLADEYO oral pellets because this will affect the film coating (taste masking) and result in bitter taste. Administer one packet of oral pellets as follows:
- Pour the entire contents of one packet directly into the mouth and swallow immediately with non-acidic liquid (e.g., water or milk).
OR
- Sprinkle the entire contents of one packet over approximately one tablespoon (15 mL) of soft, non-acidic food and consume immediately. Food should be at or below room temperature. Examples of soft, non-acidic foods include pudding, mashed potatoes, creamed corn, pureed peas, pureed bananas, and pureed carrots. Acidic foods such as yogurt and applesauce should not be used because they can dissolve the film coating (taste masking) and result in a bitter taste . The film coating (taste masking) remains intact for 10 minutes. If the pellets are not consumed within 10 minutes of sprinkling over food, they should be discarded.
DOSAGE FORMS AND STRENGTHS
Capsules:
- 150 mg: a white opaque body with a black imprint "150" and a light blue opaque cap with a black imprint "BCX".
- 110 mg: light blue opaque body and cap with a white imprint "110" on body and a white imprint "BCX" on cap.
Oral Pellets:
- 72 mg, 96 mg, 108 mg, or 132 mg, white to off-white film-coated pellets in unit-dose packets.
USE IN SPECIFIC POPULATIONS
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.
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. 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 mother's clinical need for ORLADEYO and any potential adverse effects on the breastfed infant from ORLADEYO or from the underlying maternal condition.
Data
Animal Data
In 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 2-times of the MRHDD on a mg/m 2 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 a mg/m 2 basis).
Pediatric Use
The safety and effectiveness of ORLADEYO for prophylaxis to prevent attacks of hereditary angioedema have been established in pediatric patients aged 2 and older. The use of ORLADEYO in pediatric patients aged 12 to <18 years with HAE is supported by evidence from an adequate and well-controlled trial (Trial 1) that included adults and a total of 6 pediatric patients aged 12 to <18 years. The safety profile and attack rate in the study were similar to those observed in adults [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14) ] . An additional 10 pediatric patients aged 12 to <18 years were enrolled in the open-label study (Trial 2).
The use of ORLADEYO in pediatric patients aged 2 to <12 years with HAE is supported by efficacy data from an adequate and well-controlled study in adults and pediatric patients aged 12 years and older (Trial 1), and pharmacokinetic and safety data from 29 pediatric patients aged 2 to less than 12 years enrolled in a multicenter, single-arm, open-label study with additional support from population pharmacokinetic analyses. Pediatric patients aged 2 to less than 12 years received a dosage of ORLADEYO based on the patient's body weight, which showed no clinically significant difference in drug exposures from those observed in adults treated with ORLADEYO 150 mg [see Clinical Pharmacology (12.3) ] . Pediatric patients aged 2 to less than 12 years were treated for at least 12 weeks, with 17 patients completing 48 weeks of treatment. No new safety signals were observed in pediatric patients aged 2 to less than 12 years [see Adverse Reactions (6.1) ] .
The safety and effectiveness of ORLADEYO have not been established in pediatric patients younger than 2 years of age.
Geriatric Use
Of the total number of patients in clinical studies of ORLADEYO, 9 patients were 65 years of age and over in Trial 1, and 5 patients were 65 years of age and over in Trial 2 (open-label safety study). No overall differences in safety or effectiveness of ORLADEYO have been observed between patients 65 years of age and older and younger adult patients [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14) ] .
Renal Impairment
Mild to Moderate Renal Impairment :
Adult and Pediatric Patients Aged 2 Years and Older
- No dosage modification of ORLADEYO is recommended [see Clinical Pharmacology (12.3) ] .
Severe Renal Impairment :
Adult and Pediatric Patients Aged 12 Years and Older
- No dosage modification of ORLADEYO is recommended.
Pediatric Patients Aged 2 to Less than 12 Years
- Avoid use of ORLADEYO.
End-Stage Renal Disease :
ORLADEYO has not been studied in patients with End-Stage Renal Disease (CL CR <15 mL/min or eGFR <15 mL/min/1.73 m 2 or patients requiring hemodialysis) and therefore is not recommended for use in these patient populations [see Clinical Pharmacology (12.3) ].
Hepatic Impairment
Mild Hepatic Impairment (Child-Pugh Class A) :
Adult and Pediatric Patients Aged 2 Years and Older
- No dosage modification of ORLADEYO is recommended [see Clinical Pharmacology (12.3) ] .
Moderate or Severe Hepatic Impairment (Child-Pugh B or C) :
Adult and Pediatric Patients Aged 12 Years and Older
- The recommended dosage of ORLADEYO capsules is 110 mg once daily with food [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ].
Pediatric Patients Aged 2 Years and Older
- Avoid use of ORLADEYO.
CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
An increase in QTc interval prolongation can occur at dosages higher than the recommended dosage. Additional doses or doses of ORLADEYO higher than the recommended dosage are not recommended. (5.1 )
Risk of QTc Interval 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 the recommended dosage are not recommended. An increase in QTc interval was observed in adults at dosages higher than 150 mg once daily and was concentration dependent [see Dosage and Administration (2) and Clinical Pharmacology (12.2) ].
ADVERSE REACTIONS
The following clinically significant adverse reaction is described elsewhere in the labeling:
- QTc Interval Prolongation [see Warnings and Precautions (5.1) ]
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.
| Adverse Reaction | Placebo (N=39) | ORLADEYO | ||
|---|---|---|---|---|
| 110 mg (N=41) | 150 mg (N=40) | Total (N=81) | ||
| n (%) | n (%) | n (%) | n (%) | |
| Abdominal Pain includes Abdominal pain, Abdominal discomfort, Abdominal pain upper, and Abdominal tenderness | 4 (10) | 4 (10) | 9 (23) | 13 (16) |
| Vomiting | 1 (3) | 4 (10) | 6 (15) | 10 (12) |
| Diarrhea includes Diarrhea and Frequent bowel movements | 0 | 4 (10) | 6 (15) | 10 (12) |
| Back Pain | 1 (3) | 1 (2) | 4 (10) | 5 (6) |
| Gastroesophageal Reflux Disease | 0 | 4 (10) | 2 (5) | 6 (7) |
Gastrointestinal adverse reactions, including abdominal pain, vomiting, and diarrhea occurred more frequently in patients receiving ORLADEYO 150 mg versus ORLADEYO 110 mg or placebo. These adverse reactions generally occurred early after initiation of treatment with ORLADEYO, became less frequent with time, and typically self-resolved. No patients in the ORLADEYO 150 mg dose group and 1 patient in the ORLADEYO 110 mg dose group discontinued treatment due to a gastrointestinal adverse reaction.
Less Common Adverse Reactions
Other adverse reactions that occurred in Part 1 of Trial 1 with an incidence between 5% to <10% and at a higher incidence in ORLADEYO-treated patients compared to placebo-treated patients included headache (9% versus 5%), fatigue (6% versus 3%), and flatulence (6% versus 3%).
A maculopapular drug rash was reported in less than 1% of patients treated with ORLADEYO. The rash resolved, including in patients who continued dosing.
Safety data are also available from 227 patients enrolled in an ongoing, open-label, long-term safety study (Trial 2) who received ORLADEYO 110 mg (N=100) or 150 mg (N=127) once daily with food and are consistent with the 24-week controlled safety data from Trial 1 (Part 1).
Laboratory Abnormalities
Transaminase Elevations
In Part 1 of Trial 1, one patient treated with ORLADEYO 150 mg discontinued treatment due to asymptomatic elevated transaminases (ALT >8x the upper limit of normal [ULN] and AST >3x ULN). Total bilirubin was normal. No patient receiving ORLADEYO 110 mg or placebo developed transaminase levels >3x ULN. In addition to this patient, 2 ORLADEYO-treated patients developed laboratory-related hepatic adverse reactions compared to 1 placebo-treated patient. No patient reported serious adverse reactions of elevated transaminases.
Adverse Reactions in Pediatric Patients 2 to Less than 12 Years of Age
The safety of ORLADEYO was evaluated in 29 pediatric patients aged 2 to <12 years with HAE in a multicenter, single-arm, open-label safety and pharmacokinetic study (Trial 3). Patients received ORLADEYO based on patient's body weight for at least 12 weeks, with 17 patients completing 48 weeks of treatment. No new safety signals were observed in these patients.
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of ORLADEYO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal Disorders: nausea
DRUG INTERACTIONS
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.
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.
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.
CLINICAL PHARMACOLOGY
Mechanism of Action
Berotralstat is a plasma kallikrein inhibitor that binds to plasma kallikrein and inhibits its proteolytic activity. Plasma kallikrein is a protease that cleaves high-molecular-weight kininogen (HMWK) to generate cleaved HMWK (cHMWK) and bradykinin, a 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.
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 maximum recommended dosage of 150 mg once daily in adults, clinically significant QTc interval prolongation was not observed . At 3-times the maximum recommended dosage, 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
Following oral administration of berotralstat 150 mg once daily in adults, the geometric mean steady-state C max is 158 ng/mL (range: 110 to 234 ng/mL) and steady-state area under the curve over the dosing interval (AUC tau ) is 2770 ng•hr/mL (range: 1880 to 3790 ng•hr/mL). Following oral administration of berotralstat 110 mg once daily, the geometric mean steady-state C max is 97.8 ng/mL (range: 63 to 235 ng/mL) and steady-state AUC tau is 1600 ng•hr/mL (range: 950 to 4170 ng•hr/mL).
Berotralstat exposure (C max and AUC) increases in a greater than dose-proportional manner and steady state is reached in approximately 6 to 12 days. Berotralstat accumulation at steady state is approximately 5-fold at the recommended dosage.
No clinically significant difference in the pharmacokinetics of berotralstat was observed between healthy adult subjects and patients with HAE.
Absorption
The median time to maximum plasma concentration (T max ) of berotralstat when administered with food is 5 hours (range: 1 to 8 hours).
No clinically significant difference in ORLADEYO exposure was observed following oral administration of either the pellets or capsules at the recommended adult dosage for 7 days.
Effect of Food
No clinically significant differences in the C max and AUC of berotralstat were observed following administration with a high-fat meal, however the median T max was delayed by 3 hours, from 2 hours (fasted) to 5 hours (fed).
Distribution
Plasma protein binding is approximately 99%. After a single dose of radiolabeled berotralstat at 2-times the maximum recommended dosage of 150 mg, the blood to plasma ratio was approximately 0.92.
Elimination
The median elimination half-life of berotralstat is approximately 93 hours (range: 39 to 152 hours).
Metabolism
Berotralstat is metabolized by CYP2D6 and by CYP3A4 with low turnover in vitro . After a single oral dose of radiolabeled berotralstat at 2-times the maximum recommended dosage of 150 mg, berotralstat represented 34% of the total plasma radioactivity, with 8 metabolites, each accounting for between 1.8 and 7.8% of the total radioactivity.
Excretion
After a single oral dose of radiolabeled berotralstat at 2-times the maximum recommended dosage of 150 mg, approximately 9% was excreted in urine (3.4% unchanged; range: 1.8 to 4.7%) and 79% was excreted in feces.
Specific Populations
In adults and pediatric patients 12 to <18 years of age, no clinically significant differences in the pharmacokinetics of ORLADEYO were observed based on age (12 to 74 years), sex, race, and body weight.
Pediatric Patients
Based on population pharmacokinetic analyses that included pediatric patients 12 to <18 years of age, exposure at steady state following oral administration of berotralstat 150 mg once daily was approximately 20% higher compared to adults. The higher exposure in pediatric patients 12 to <18 years of age is not considered to be clinically significant.
Based on population pharmacokinetics analyses that included pediatric patients 2 to <12 years of age, body weight was the only covariate with a clinically significant impact on the systemic exposure of berotralstat. In pediatric patients 2 to <12 years of age at the recommended dosage based on body weight, median C max at steady state is expected to be up to 24% higher compared to adults. However, this difference is not considered to be clinically significant [see Dosage and Administration (2.2) and Use in Special Populations (8.4) ] .
Patients with Renal Impairment
The pharmacokinetics of a single oral dose of berotralstat at 1.33-times the highest recommended dosage of 150 mg were studied in adult subjects with severe renal impairment (CL CR less than 30 mL/min, estimated by Cockcroft-Gault). When compared to a concurrent cohort with normal renal function (CL CR greater than 90 mL/min, estimated by Cockcroft-Gault), no clinically significant difference was observed; C max was increased by 47%, while AUC 0-last was increased by 14% [see Use in Specific Populations (8.6) ] .
The pharmacokinetics of berotralstat has not been studied in patients with End-Stage Renal Disease (CL CR less than 15 mL/min or eGFR less than 15 mL/min/1.73 m 2 or patients requiring hemodialysis).
Patients with Hepatic Impairment
The pharmacokinetics of a single 150 mg oral dose of berotralstat were studied in adult subjects with mild, moderate, and severe hepatic function (Child-Pugh Class A, B, and C, respectively). The pharmacokinetics of berotralstat were unchanged in subjects with mild hepatic impairment compared to subjects with normal hepatic function. In subjects with moderate hepatic impairment, C max was increased by 77%, while AUC 0-inf was increased by 78%. In subjects with severe hepatic impairment, C max was increased by 27%, while AUC 0-last was decreased by 5%. The median half-life of berotralstat was increased by 37% and 22% in patients with moderate and severe hepatic impairment, respectively, in comparison to healthy subjects. The percent of unbound berotralstat increased 2-fold from a mean of 1.2% in healthy subjects to a mean of 2.4% in subjects with severe hepatic impairment [see Use in Specific Populations (8.7) ] .
Drug Interaction Studies
Effect of Other Drugs on the Pharmacokinetics of ORLADEYO
Berotralstat is a P-gp and BCRP substrate. Cyclosporine, a P-gp and BCRP inhibitor, decreased berotralstat 150 mg C max by 7%, while AUC 0-last and AUC 0-inf increased by 27% and 24%, respectively.
Effect of ORLADEYO on the Pharmacokinetics of Other Drugs
Berotralstat 150 mg once daily is a moderate inhibitor of CYP2D6 and CYP3A4, and a weak inhibitor of CYP2C9 and CYP2C19.
At 2-times the maximum recommended dosage of 150 mg, berotralstat is an inhibitor of P-gp and is not an inhibitor of BCRP (rosuvastatin exposure was decreased by approximately 20%).
In a drug interaction study conducted in healthy females of reproductive potential (N=22), concomitant administration of berotralstat 150 mg once daily with 0.15 mg/0.03 mg desogestrel/ethinyl estradiol led to a 2.6-fold increase in the AUC 0-last of etonogestrel, the active metabolite of desogestrel.
The effect of berotralstat on the pharmacokinetics of other drugs are presented in Figure 1 [see Drug Interactions (7.2) ].
Figure 1: Effect of ORLADEYO on Concomitant Medications
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity of berotralstat was evaluated in a 2-year study in Wistar rats and a 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 5- and 10-times the MRHDD on a plasma AUC basis, respectively). No evidence of tumorigenicity was observed in either species.
Mutagenesis
Berotralstat 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 Fertility
In a fertility study in rats, berotralstat at oral doses up to 45 mg/kg/day (approximately 2-times the MRHDD on a mg/m 2 basis) showed no effect on fertility in males or females.
CLINICAL STUDIES
The efficacy of ORLADEYO for the prevention of angioedema attacks in adult and pediatric 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 trial (Trial 1 [NCT3485911]).
The trial included 120 adults and pediatric patients 12 to <18 years of age 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 (ORLADEYO 110 mg, ORLADEYO 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 trial; 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 3. 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.
| Outcome | ORLADEYO | Placebo | |
|---|---|---|---|
| 110 mg QD | 150 mg QD | ||
| N = 41 | N = 40 | N = 40 One patient in the ITT analysis was randomized to placebo but was not treated. | |
| HAE Attack Rate, rate per 28 days 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. | 1.65 | 1.31 | 2.35 |
| % Rate Reduction Percent reduction relative to placebo. (95% CI) | 30.0% (4.6, 48.7) | 44.2% (23.0, 59.5) | - |
| p-value | 0.024 | <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 (Adult and Pediatric Patients 12 Years of Age and Older)
Pre-defined exploratory endpoints included the proportion of responders to ORLADEYO, defined as at least a 50% relative reduction in HAE attacks during treatment compared with the baseline attack rate; 58% of patients who received ORLADEYO 150 mg and 51% of patients who received ORLADEYO 110 mg 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 who received ORLADEYO 150 mg, and 27% and 10% of patients who received ORLADEYO 110 mg, had a ≥70% or ≥90% reduction in their HAE attack rates compared to baseline versus 15% and 8% of placebo-treated patients, respectively. The rate of HAE attacks rated as moderate or severe was reduced by 40% and 10% in patients who received ORLADEYO 150 mg and 110 mg, respectively, versus placebo-treated patients.
HOW SUPPLIED/STORAGE AND HANDLING
ORLADEYO (berotralstat) capsules and oral pellets are supplied as follows in Table 4:
| 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] .
Mechanism of Action
Berotralstat is a plasma kallikrein inhibitor that binds to plasma kallikrein and inhibits its proteolytic activity. Plasma kallikrein is a protease that cleaves high-molecular-weight kininogen (HMWK) to generate cleaved HMWK (cHMWK) and bradykinin, a 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.
