ORLADEYO Film-coated granules in sachet Ref.[116874] Active ingredients: Berotralstat

General

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

There are limited clinical data on the use of berotralstat in HAE patients with nC1-INH activity.

Some categories of nC1-INH HAE may not respond to treatment due to alternative pathways that do not include plasma kallikrein activation. In this population, it is recommended to perform genetic testing, if available, according to the current HAE guidelines and to discontinue the treatment if clinical response is not observed (see sections 4.2 and 5.1).

QT prolongation

An increased risk of QT prolongation may be observed with higher concentrations of berotralstat (see section 5.1). Children should not take doses of berotralstat higher than indicated for their weight.

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, or concomitant use of other medicinal products known to prolong the QT. It is preferrable to avoid the use of berotralstat in these patients. If treatment is required, appropriate monitoring (e.g. ECGs) should be considered.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially 'sodium-free'.

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 (C_max) of a single 150 mg dose of berotralstat by 7% and increased the area under the concentration versus time curve (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 C_max and AUC of oral midazolam by 45% and 124%, respectively, and the C_max 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 section 5.2).

CYP2D6 substrates

Berotralstat is a moderate inhibitor of CYP2D6, increasing the C_max and AUC of dextromethorphan by 196% and 177%, respectively, and the C_max 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 section 5.2).

CYP2C9 substrates

Berotralstat is a weak inhibitor of CYP2C9 increasing the C_max 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 C_max 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 C_max 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 section 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%, C_max 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.

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 berotralstat therapy taking into account the benefit of breast-feeding for the newborn/infant and the benefit of therapy for the woman.

Fertility

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

Berotralstat has no or negligible influence on the ability to drive and use machines. Berotralstat is not anticipated to affect children's alertness or ability to participate in activities.

Summary of the safety profile

The most common adverse reactions in patients 12 years and older 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 berotralstat use (median day of onset was day 66 for abdominal pain and day 45 for diarrhoea) and resolved without medicinal product while berotralstat 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).

The safety profile in patients 2 to <12 years of age was similar to that observed in adults.

Tabulated list of adverse reactions

The safety of berotralstat has been evaluated in long term clinical studies in patients with HAE (both uncontrolled, open-label and placebo-controlled, blinded) in 381 adult and adolescent patients and 29 paediatric patients aged 3 to <12 years. 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 2. Adverse reactions observed in clinical studies and post-marketing surveillance:

^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

Description of selected adverse reactions

Transaminase elevations

Liver function tests (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 berotralstat treatment. Abrupt discontinuation of androgens immediately prior to initiating berotralstat should be avoided.

Paediatric population

Adolescents aged 12 to less than 18 years

The safety of berotralstat 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.

Children aged 3 to less than 12 years

The safety of berotralstat was evaluated in a clinical study of 29 patients aged 3 to <12 years and weighing at least 14.9 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 national reporting system listed in Appendix V.

Not applicable.