Orladeyo Drug Information

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: ORLADEYO should not be used for treatment of acute HAE attacks. Limitations of Use: The safety and effectiveness of ORLADEYO for the treatment of acute HAE attacks have not been established.

Additional doses or doses of ORLADEYO higher than the prescribed once-daily dose are not recommended due to the potential for QTc interval prolongation.

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).

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. 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. Pediatric Patients 2 Years to Less than 12 Years of Age Avoid use of ORLADEYO.

Dosage Modification in Patients with Persistent GI Adverse Reactions Gastrointestinal (GI) reactions may occur in patients receiving ORLADEYO. 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.

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.

Overall, 66% of patients were female and 93% of patients were White with a mean age of 41.6 years. 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 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. A maculopapular drug rash was reported in less than 1% of patients treated with ORLADEYO. The rash resolved, including in patients who continued dosing.

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 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. 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

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.

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.

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. Refer to the Prescribing Information of the P-gp substrate.

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 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.

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 safety profile and attack rate in the study were similar to those observed in adults. 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. No new safety signals were observed in pediatric patients aged 2 to less than 12 years. The safety and effectiveness of ORLADEYO have not been established in pediatric patients younger than 2 years of age.