4.1. Therapeutic indications

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

4.2. Posology and method of administration

Posology

The recommended dose for adults and adolescents aged 12 years and older weighing ≥ 40 kg is 150 mg berotralstat once daily.

Missed doses

If a dose of berotralstat is missed, the patient should take the forgotten dose as soon as possible without exceeding one dose per day.

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

Special populations

Elderly population

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

Renal impairment

No dose adjustment is required for patients with mild or moderate renal impairment. In patients with severe 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 of berotralstat in patients with ESRD (see section 5.2).

Hepatic impairment

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

Paediatric population

The safety and efficacy of berotralstat in children under 12 years of age have not yet been established. No data are available.

Method of administration

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

4.3. Contraindications

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

4.4. Special warnings and precautions for use

General

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

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

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

QT prolongation

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

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

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

There are no data available for the use of berotralstat in patients with independent risk factors for QT prolongation such as electrolyte disturbances, known pre-existing QT prolongation (either acquired or familial), advancing age (see section 4.2), or concomitant use of other medicinal products predominantly metabolised by CYP2D6, CYP3A4, or P-gp substrates with a narrow therapeutic index (see section 4.5) or other medicinal products known to prolong the QT (e.g. citalopram, escitalopram, amitriptyline, ondansetron). It is preferable to avoid the use of berotralstat in these patients. If treatment is required, appropriate monitoring (e.g. ECGs) and dose adjustment of these medicinal products should be considered.

4.5. Interaction with other medicinal products and other forms of interaction

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 150 mg dose of berotralstat by 7% and increased the AUC by 27%. No dose adjustment of berotralstat is recommended 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's wort) may decrease berotralstat plasma concentration, leading to reduced efficacy of berotralstat. The use of P-gp inducers is not recommended with berotralstat.

Effects of berotralstat on other medicinal products

CYP3A4 substrates

Berotralstat is a moderate inhibitor of CYP3A4, increasing the Cmax and AUC of oral midazolam by 45% 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 CYP3A4 substrates. Refer to the SmPC for concomitant medicinal products that are predominantly metabolised by CYP3A4, particularly those with a narrow therapeutic index (e.g. ciclosporine, fentanyl). Dose adjustments of these medicinal products may be required (see sections 4.4 and 5.2).

CYP2D6 substrates

Berotralstat is a moderate inhibitor of CYP2D6, increasing the Cmax and AUC of dextromethorphan by 196% 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 CYP2D6 substrates. Refer to the SmPC for concomitant medicinal products that are predominantly metabolised by CYP2D6, particularly those with a narrow therapeutic index (e.g. thioridazine, pimozide) or whose prescribing information recommends therapeutic monitoring (e.g. tricyclic antidepressants). Dose adjustments of these medicinal products may be required (see sections 4.4 and 5.2).

CYP2C9 substrates

Berotralstat is a weak inhibitor of CYP2C9 increasing the Cmax and AUC of tolbutamide by 19% and 73%, respectively. No dose adjustment is recommended for concomitant use of medicinal products that 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 only 21% and 24%, respectively. No dose adjustment is recommended for concomitant use of medicinal products that are predominantly metabolised by CYP2C19 (e.g. omeprazole) (see section 5.2).

P-gp substrates

Berotralstat is a weak inhibitor of P-gp and increased the Cmax and AUC of the P-gp substrate digoxin by 58% and 48%, respectively. Refer to the SmPC for concomitant medicinal products that are P-gp substrates, particularly those with a narrow therapeutic index (e.g. digoxin) or whose prescribing information recommends therapeutic monitoring (e.g. dabigatran etexilate). Dose adjustments of these medicinal products may be required (see sections 4.4 and 5.2).

Oral contraceptives

As a moderate inhibitor of CYP3A4, berotralstat may increase concentrations of oral contraceptives metabolised by CYP3A4. The coadministration of berotralstat with desogestrel increased the AUC of etonogestrel (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 is recommended for concomitant use of desogestrel.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

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

Berotralstat is not recommended during pregnancy.

Breast-feeding

Available pharmacodynamic/toxicological data in animals have shown excretion of berotralstat in milk (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 of therapy for the woman.

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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). The gastrointestinal events were reported primarily in the first 1-3 months of Orladeyo use (median day of onset was day 66 for abdominal pain and day 45 for diarrhoea) and resolved without medicinal product while Orladeyo treatment was continued. Almost all events (99%) of abdominal pain were mild or moderate with a median duration of 3.5 days (95% CI 2-8 days). Almost all events (98%) of diarrhoea were mild or moderate with a median duration of 3.2 days (95% CI 2-8 days).

Tabulated list of adverse reactions

The safety of Orladeyo has been evaluated in long term clinical studies in patients with HAE (both uncontrolled, open-label and placebo-controlled, blinded) in 381 patients. Adverse reactions obtained from clinical studies and post-marketing surveillance are listed below by MedDRA system organ class and 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions 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 increased

a Includes the events of Headache, Sinus headache

b Includes the events of Abdominal pain, Abdominal discomfort, Abdominal pain upper, Abdominal pain lower, Epigastric discomfort, Abdominal tenderness

c Includes the events of Diarrhoea, Faeces soft, Frequent bowel movements

d LFT elevations, which generally improved with or without discontinuation of berotralstat, were observed in some patients, primarily in those who discontinued androgen therapy within 14 days of initiating Orladeyo treatment. Abrupt discontinuation of androgens immediately prior to initiating Orladeyo should be avoided.

Paediatric population

The safety of Orladeyo was evaluated in clinical studies in a subgroup of 28 adolescent patients aged 12 to < 18 years of age and weighing at least 40 kg. The safety profile was similar to that observed in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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