ORLADEYO 150mg capsules medication leaflet

Orladeyo 150 mg hard capsules

Each hard capsule contains 150 mg berotralstat (as dihydrochloride).

For the full list of excipients, see section 6.1.

Hard capsule (capsule).

Capsule (19.4 mm × 6.9 mm) with white opaque body imprinted with “150” and light blue opaque capimprinted with “BCX”.

Orladeyo is indicated for routine prevention of recurrent attacks of hereditary angioedema (HAE) inadult and adolescent patients aged 12 years and older.

The recommended dose for adults and adolescents aged 12 years and older weighing ≥ 40 kg is150 mg berotralstat once daily.

If a dose of berotralstat is missed, the patient should take the forgotten dose as soon as possiblewithout exceeding one dose per day.

Orladeyo is not intended for treatment of acute HAE attacks (see section 4.4).

No dose adjustment is required for patients above 65 years of age (see sections 4.4 and 5.2).

No dose adjustment is required for patients with mild or moderate renal impairment. In patients withsevere renal impairment, it is preferable to avoid the use of berotralstat. If treatment is required,appropriate monitoring (e.g. ECGs) should be considered (see section 4.4).

There are no available clinical data for the use of berotralstat in patients with end stage renal disease(ESRD) requiring haemodialysis. As a precautionary measure, it is preferable to avoid the use ofberotralstat in patients with ESRD (see section 5.2).

No dose adjustment is required for patients with mild hepatic impairment. Use of berotralstat inpatients with moderate or severe hepatic impairment (Child-Pugh Class B or C) should be avoided(see section 5.2).

The safety and efficacy of berotralstat in children under 12 years of age have not yet been established.

No data are available.

Orladeyo is for oral use. The capsule can be taken at any time of the day, with food (see section 5.2).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Orladeyo is not intended for treatment of acute HAE attacks, individualised treatment should beinitiated with an approved rescue medicinal product.

There are no available clinical data on the use of berotralstat in HAE patients with normal C1 esteraseinhibitor (C1-INH) activity.

There are no available data on the use of berotralstat in patients weighing less than 40 kg and use ofberotralstat in these patients should be avoided.

An increase in QT prolongation may be observed with higher concentrations of berotralstat (seesection 5.1).

Patients with moderate or severe hepatic impairment may develop increased serum berotralstatconcentrations that are associated with a risk of prolonged QT. Use of berotralstat in these patientsshould be avoided.

Patients with severe renal impairment may be at risk of prolonged QT. It is preferable to avoid the useof berotralstat in these patients. If treatment is required, appropriate monitoring (e.g. ECGs) should beconsidered.

There are no data available for the use of berotralstat in patients with independent risk factors for QTprolongation such as electrolyte disturbances, known pre-existing QT prolongation (either acquired orfamilial), advancing age (see section 4.2), or concomitant use of other medicinal products known toprolong the QT. It is preferable to avoid the use of berotralstat in these patients. If treatment isrequired, appropriate monitoring (e.g. ECGs) should be considered.

Berotralstat is a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate.

Effects of other medicinal products on berotralstat

P-gp and BCRP inhibitors

Ciclosporine, a P-gp and BCRP inhibitor, decreased the maximum concentration (Cmax) of a single 150mg dose of berotralstat by 7% and increased the AUC by 27%. No dose adjustment of berotralstat isrecommended for concomitant use with P-gp and BCRP inhibitors.

P-gp and BCRP inducers

Berotralstat is a substrate of P-gp and BCRP. P-gp and BCRP inducers (e.g. rifampicin, St. John’swort) may decrease berotralstat plasma concentration, leading to reduced efficacy of berotralstat. Theuse of P-gp inducers is not recommended with berotralstat.

Effects of berotralstat on other medicinal products

Berotralstat is a moderate inhibitor of CYP3A4, increasing the Cmax and AUC of oral midazolam by45% and 124%, respectively, and the Cmax and AUC of amlodipine by 45% and 77%, respectively.

Concomitant administration may increase concentrations of other medicinal products that are CYP3A4substrates. Refer to the SmPC for concomitant medicinal products that are predominantly metabolisedby CYP3A4, particularly those with a narrow therapeutic index (e.g. ciclosporine, fentanyl). Doseadjustments of these medicinal products may be required (see section 5.2).

Berotralstat is a moderate inhibitor of CYP2D6, increasing the Cmax and AUC of dextromethorphan by196% and 177%, respectively, and the Cmax and AUC of desipramine by 64% and 87%, respectively.

Concomitant administration may increase exposure of other medicinal products that are CYP2D6substrates. Refer to the SmPC for concomitant medicinal products that are predominantly metabolisedby CYP2D6, particularly those with a narrow therapeutic index (e.g. thioridazine, pimozide) or whoseprescribing information recommends therapeutic monitoring (e.g. tricyclic antidepressants). Doseadjustments of these medicinal products may be required (see section 5.2).

Berotralstat is a weak inhibitor of CYP2C9 increasing the Cmax and AUC of tolbutamide by 19% and73%, respectively. No dose adjustment is recommended for concomitant use of medicinal productsthat are predominantly metabolised by CYP2C9 (e.g. tolbutamide) (see section 5.2).

The effect of berotralstat on the CYP2C9 conversion of desogestrel to etonogestrel (active metabolite)was negligible. No dose adjustment is recommended for concomitant use of desogestrel.

CYP2C19 substrates

Berotralstat is not an inhibitor of CYP2C19, as Cmax and AUC of omeprazole were increased by only21% and 24%, respectively. No dose adjustment is recommended for concomitant use of medicinalproducts that are predominantly metabolised by CYP2C19 (e.g. omeprazole) (see section 5.2).

Berotralstat is a weak inhibitor of P-gp and increased the Cmax and AUC of the P-gp substrate digoxinby 58% and 48%, respectively. Refer to the SmPC for concomitant medicinal products that are P-gpsubstrates, particularly those with a narrow therapeutic index (e.g. digoxin) or whose prescribinginformation recommends therapeutic monitoring (e.g. dabigatran etexilate). Dose adjustments of thesemedicinal products may be required (see section 5.2).

As a moderate inhibitor of CYP3A4, berotralstat may increase concentrations of oral contraceptivesmetabolised by CYP3A4. The coadministration of berotralstat with desogestrel increased the AUC ofetonogestrel (active metabolite) by 58%, Cmax was not affected. The effect of berotralstat on the

CYP2C9 conversion of desogestrel to etonogestrel was negligible. No dose adjustment isrecommended for concomitant use of desogestrel.

Women of childbearing potential must use effective contraception during treatment with berotralstatand for at least 1 month following the last dose. Berotralstat is not recommended in women ofchildbearing potential not using contraception.

There are no or limited amount of data from the use of berotralstat in pregnant women. Animal studiesare insufficient with respect to reproductive toxicity (see section 5.3).

Berotralstat is not recommended during pregnancy.

Available pharmacodynamic/toxicological data in animals have shown excretion of berotralstat inmilk (see section 5.3).

A risk to the suckling child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from

Orladeyo therapy taking into account the benefit of breast-feeding for the child and the benefit oftherapy for the woman.

No effect on fertility was observed in animal studies (see section 5.3).

Orladeyo has no or negligible influence on the ability to drive and use machines.

The most common adverse reactions are abdominal pain (all locations) (reported by 21% of patients),diarrhoea (reported by 15% of patients), and headache (reported by 13% of patients). Thegastrointestinal events were reported primarily in the first 1-3 months of Orladeyo use (median day ofonset was day 66 for abdominal pain and day 45 for diarrhoea) and resolved without medicinalproduct while Orladeyo treatment was continued. Almost all events (99%) of abdominal pain weremild or moderate with a median duration of 3.5 days (95% CI 2-8 days). Almost all events (98%) ofdiarrhoea were mild or moderate with a median duration of 3.2 days (95% CI 2-8 days).

The safety of Orladeyo has been evaluated in long term clinical studies in patients with HAE (bothuncontrolled, open-label and placebo-controlled, blinded) in 381 patients. Adverse reactions obtainedfrom clinical studies and post-marketing surveillance are listed below by MedDRA system organ classand by frequency. Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to< 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); notknown (cannot be estimated from the available data). Within each frequency grouping, adversereactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions observed in clinical studies and post-marketing surveillance

System organ class Frequency Adverse reactions

Nervous system disorders Very common Headachea

Gastrointestinal disorders Very common Abdominal painb, Diarrhoeac

Common Vomiting, Gastroesophageal reflux,

Flatulence

Not known Nausea

Skin and subcutaneous tissue disorders Common Rash

Investigationsd Common ALT increased, AST increaseda Includes the events of Headache, Sinus headacheb Includes the events of Abdominal pain, Abdominal discomfort, Abdominal pain upper, Abdominalpain lower, Epigastric discomfort, Abdominal tendernessc Includes the events of Diarrhoea, Faeces soft, Frequent bowel movementsd LFT elevations, which generally improved with or without discontinuation of berotralstat, wereobserved in some patients, primarily in those who discontinued androgen therapy within 14 days ofinitiating Orladeyo treatment. Abrupt discontinuation of androgens immediately prior to initiating

Orladeyo should be avoided.

The safety of Orladeyo was evaluated in clinical studies in a subgroup of 28 adolescent patients aged12 to < 18 years of age and weighing at least 40 kg. The safety profile was similar to that observed inadults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No case of overdose has been reported in clinical studies. There is no available information to identifypotential signs and symptoms of overdose. If symptoms should occur, symptomatic treatment isrecommended. There is no antidote available.

Pharmacotherapeutic group: Other haematological agents, drugs used in hereditary angioedema, ATCcode: B06AC06

Berotralstat is an inhibitor of plasma kallikrein. Plasma kallikrein is a serine protease that cleaveshigh-molecular-weight-kininogen (HMWK), releasing bradykinin, a potent vasodilator that increasesvascular permeability. In patients with HAE due to C1-INH deficiency or dysfunction, normalregulation of plasma kallikrein activity is impaired, which leads to uncontrolled increases in plasmakallikrein activity and bradykinin release, resulting in HAE attacks consisting of swelling(angioedema).

At the steady state Cmax of berotralstat at the recommended dose of 150 mg once daily, the meancorrected QT interval increased by 3.4 msec (90% upper CI bound of 6.8 msec), which is below the10 msec threshold for concern. At a supratherapeutic dose of 450 mg once daily, steady stateexposures were 4-fold higher than at the recommended 150 mg dose, and the corrected QT intervalincreased by a mean of 21.9 msec.

Efficacy of berotralstat was studied in a multicentre, randomised, double-blind, placebo-controlled,parallel-group study NCT 03485911.

Study NCT 03485911

This study included 120 patients (114 adults and 6 children 12 years and over) with type I or II HAEwho experienced at least two investigator-confirmed attacks within the first 8 weeks of the run-inperiod and took at least one dose of study treatment. Nine patients were aged ≥ 65 years. Patients wererandomised 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) forthe 24-week treatment period.

A total of 81 patients received at least one dose of berotralstat in the 24-week treatment period.

Overall, 66% of patients were female and 93% of patients were Caucasian with a mean age of 41.6years. A history of laryngeal angioedema attacks was reported in 74% of patients and 75% reportedprior use of long-term prophylaxis. The median attack rate during the prospective run-in period(baseline attack rate) was 2.9 per month. Of patients enrolled, 70% had a baseline attack rate of ≥ 2attacks per month.

Patients discontinued other prophylactic HAE medicinal products prior to entering the study; however,all patients were allowed to use rescue medicinal products for treatment of breakthrough HAE attacks.

In berotralstat-treated patients, 51.4% of breakthrough attacks were treated with C1-INH (see section4.4). Concomitant use of C1-INH and berotralstat did not result in any identifiable adverse reactions.

Orladeyo 150 mg produced a statistically significant and clinically meaningful reduction in the rate of

HAE attacks compared to placebo through 24 weeks in the primary endpoint Intent-to-Treat (ITT)population as shown in Table 2. The percent reduction in HAE attack rate was greater with Orladeyo150 mg compared to placebo, regardless of attack rate during the run-in period.

Table 2: Reduction in HAE attack rate in the berotralstat 150 mg ITT population

Outcome Berotralstat 150 mg Placebo(n=40) (n=40a)

Rate per Percent reduction p-value Rate per28 days from placebo 28 days(95% CI)

HAE attack rate 1.31 44.2% (23.0, 59.5) < 0.001 2.35a One patient in the ITT analysis was randomised to placebo but was not treated.

Reduction in attack rates was sustained through 24 weeks, as shown in Figure 1.

Figure 1: HAE attack rate per month through 24 weeks treatment with berotralstat 150 mg(n=40) or placebo (n=40)berotralstat 150 mgplacebo

Baseline 1 2 3 4 5 6

Monthberotralstat 150 mg N= 40 37 37 37 37 37 37

Placebo N= 39 39 38 37 36 34 34

SEM: standard error of the mean

Of patients receiving 150 mg berotralstat, 58% had a ≥ 50% reduction in their HAE attack ratescompared to baseline versus 25% of placebo patients.

Orladeyo 150 mg reduced the rate of HAE attacks requiring treatment with standard of care acuteattack treatments by 49.2% (95% CI: 25.5%, 65.4%) compared to placebo (rate per 28 days: 1.04 vs.

2.05).

Patients receiving berotralstat 150 mg experienced an improvement in Angioedema Quality of Life

Questionnaire (AE-QoL) total score and domain scores (functioning, fatigue/mood, fear/shame andnutrition) compared to the placebo group as shown in Table 3. A reduction of 6 points is considered aclinically meaningful improvement. The largest improvement was observed in the functioning score.

Table 3: Change in AE-QoL score*- berotralstat compared to placebo at week 24

LS mean change (SE) from baseline at LS mean differenceweek 24 from placebo

Berotralstat (95% CI)

Placebo150 mg

- 4.90

AE-QoL total score -14.6 (2.6) -9.7 (2.6)(-12.23, 2.43)

- 9.10

Functioning score -19.5 (3.4) -10.4 (3.4)(-18.58, 0.38)

- 2.16

Fatigue/Mood score -11.3 (3.2) -9.2 (3.3)(-11.35, 7.03)

- 4.96

Fear/Shame score -15.4 (3.2) -10.5 (3.3)(-14.05, 4.13)

- 2.68

Nutrition score -8.8 (3.0) -6.1 (3.1)(-11.27, 5.92)

AE-QoL=Angioedema Quality of Life Questionnaire; CI=confidence interval; LS=least squares;

SE=standard error

*Lower scores indicate improved quality of life (lower impairment)

Mean (+/-SEM) Investigator-Confirmed Attack Rate(attacks/month)

The safety and effectiveness of Orladeyo were evaluated in 28 adolescent patients aged 12 to< 18 years across both studies. The safety profile and attack rate on study were similar to thoseobserved in adults.

The safety and efficacy of berotralstat in paediatric patients under 12 years have not been established.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Orladeyo in one or more subsets of the paediatric population in the treatment of hereditaryangioedema for the prevention of attacks in patients with hereditary angioedema (see section 4.2 forinformation on paediatric use).

Following oral administration of berotralstat 150 mg once daily, Cmax and area under the curve overthe dosing interval (AUCtau) are 158 ng/mL (range: 110 to 234 ng/mL) and 2770 ng*h/mL (range:

1880 to 3790 ng*h/mL), respectively. The pharmacokinetics of berotralstat in patients with HAE aresimilar to those of healthy people.

Berotralstat exposure (Cmax and AUC) increases greater than proportionally with dose and steady stateis reached by days 6 to 12.

No differences in the Cmax and AUC of berotralstat were observed following administration with ahigh-fat meal. However the median tmax was delayed by 3 hours, from 2 hours (fasted) to 5 hours (fed,range: 1 to 8 hours). Berotralstat is to be administered with food to minimise gastrointestinal adverseevents.

Plasma protein binding is approximately 99%. After a single dose of radiolabelled berotralstat 300 mg,the blood to plasma ratio was approximately 0.92. At steady state, the geometric mean (%CV) Vd/Fwas 3123 L (40%) for berotralstat 150 mg once daily.

Berotralstat is metabolised by CYP2D6 and by CYP3A4 with low turnover in vitro. After a single oralradiolabelled 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. Structures for5 of the 8 metabolites are known. It is unknown whether any metabolites are pharmacologically active.

Berotralstat 150 mg once daily is a moderate inhibitor of CYP2D6 and CYP3A4, and a weak inhibitorof CYP2C9. Berotralstat is not an inhibitor of CYP2C19.

Berotralstat at double the recommended dose is a weak inhibitor of P-gp and is not an inhibitor of

BCRP.

After a single dose of 150 mg, the median half-life of berotralstat was approximately 93 hours (range:

39 to 152 hours).

After a single oral radiolabelled berotralstat 300 mg dose, approximately 9% was excreted in urine(3.4% unchanged; range 1.8 to 4.7%) and 79% was excreted in faeces. Additional analyses indicatedapproximately 50% of the fraction recovered in the faeces was unchanged berotralstat.

Population pharmacokinetic analyses showed that age, gender and race did not meaningfully influencethe pharmacokinetics of berotralstat. Body weight was identified as a covariate describing thevariability of clearance and volume of distribution, resulting in higher exposure (AUC and Cmax) inpatients weighing less. However, this difference is not considered to be clinically relevant and no doseadjustments are recommended for any of these demographics.

Based on population pharmacokinetic analyses that included paediatric patients 12 to < 18 years andweighing at least 40 kg, exposure at steady state following oral administration of berotralstat 150 mgonce daily was slightly higher (29% higher) than adult exposure, with an estimated geometric mean(CV%) AUCtau of 2515 (38.6) ng*h/mL. However, this difference is not considered to be clinicallyrelevant, and no dose adjustments are recommended in paediatric patients 12 to < 18 years of ageweighing 40 kg or more.

The pharmacokinetics of a single 200 mg oral dose of berotralstat were studied in patients with severerenal impairment (eGFR less than 30 mL/min). When compared to a concurrent cohort with normalrenal function (eGFR greater than 90 mL/min); Cmax was increased by 39%, while no difference wasobserved in AUC. No dose adjustment is required for patients with mild or moderate renalimpairment. Patients with severe renal impairment may be at risk of prolonged QT. It is preferable toavoid the use of berotralstat in these patients.

The pharmacokinetics of berotralstat in patients with kidney failure requiring haemodialysis has notbeen studied. Given the high plasma protein binding of berotralstat, it is unlikely to be cleared byhaemodialysis.

The pharmacokinetics of a single 150 mg oral dose of berotralstat were studied in patients with mild,moderate and severe hepatic dysfunction (Child-Pugh Class A, B or C). The pharmacokinetics ofberotralstat were unchanged in patients with mild hepatic impairment compared to patients withnormal hepatic function. In patients with moderate hepatic impairment, Cmax was increased by 77%,while AUC0-inf was increased by 78%. In subjects with severe hepatic impairment, Cmax was increasedby 27%, while AUC0-inf was decreased by 6%. The estimated increase in mean QTcF in patients withmoderate to severe hepatic dysfunction was up to 8.8 msec (2 sided 90% UB 13.1 msec). Use ofberotralstat should be avoided in patients with moderate or severe hepatic impairment (Child-Pugh

Class B or C).

Berotralstat has not been studied in patients above 75 years of age; however, age is not expected toaffect exposure to berotralstat.

In non-clinical chronic repeat-dose toxicity studies, phospholipidosis (presence of foamy vacuolatedmacrophages) was observed in the liver of rats (by electron microscopy) and suspected in the liver,small intestine, lung, spleen and lymphoid tissue in rats and monkeys, at clinically relevant exposures.

The clinical relevance of these findings is unknown.

Skeletal myofiber degeneration/necrosis was observed in the 2-year (lifetime) study in rats. Exposureat the no observed adverse effect level (NOAEL) for these findings in rats was 4.5 times the exposureachieved (on an AUC basis) at the clinical 150 mg berotralstat dose.

Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity.

There was no increase in tumours in a 6-month study in Tg rasH2 transgenic mice. Exposure in thismouse carcinogenicity study was 10 times the exposure achieved (on an AUC basis) at the clinical150 mg berotralstat dose.

Rare stromal sarcomas of the endometrium and undifferentiated sarcomas of the skin were found in a2-year (lifetime) study in rats administered berotralstat at an exposure that was 4.5 times the exposureachieved (on an AUC basis) at the clinical 150 mg berotralstat dose. These findings are inconclusive,with an incidence slightly higher than in control groups. The clinical relevance of these findings isunknown.

Berotralstat crossed the placental barrier in rats and rabbits. An embryo-foetal development studyconducted in pregnant rats administered berotralstat at exposures 9.7 times the exposure achieved (onan AUC basis) at the clinical 150 mg berotralstat dose revealed no evidence of harm to the developingfoetus. A second embryo-foetal development study in a relevant non-rodent species was notconducted.

Berotralstat was detected in the plasma of rat pups on lactation day 14 at approximately 5% of thematernal plasma concentration.

Berotralstat had no effects on mating or fertility in male and female rats at a dose 2.9 times the clinical150 mg berotralstat dose on a mg/m2 basis.

Capsule filling

Crospovidone (type A)

Magnesium stearate

Silica, colloidal anhydrous

Starch, pregelatinised

Gelatin

Titanium dioxide (E 171)

Indigo carmine (E 132)

Black iron oxide (E 172)

Red iron oxide (E 172)

Black iron oxide (E 172)

Potassium hydroxide

Shellac

Propylene glycol (E 1520)

Not applicable.

4 years.

This medicinal product does not require any special storage conditions.

PCTFE/PVC-Alu blisters in a carton with 7 capsules per blister

Pack size: 28 or 98 hard capsules.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

BioCryst Ireland Limited

Block 4, Harcourt Centre, Harcourt Road, DUBLIN 2, D02HW77

Ireland

EU/1/21/1544/001

EU/1/21/1544/002

Date of first authorisation: 30 April 2021

Date of latest renewal:

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.