BEROTRALSTAT: 548 Adverse Event Reports & Safety Profile

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

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) ] .

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&apos;s body weight as provided in Table 1. Take ORLADEYO orally with food (a meal should be consumed just before or after dosing) <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span> .

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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ]</span> .

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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.

2.5 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.

None. None. ( 4 )

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 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.

6.2 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

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 )

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2) and Clinical Pharmacology (12.2) ]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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.