ORLADEYO Hard capsule Ref.[28003] Active ingredients: Berotralstat

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

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 known to prolong the 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.

Women of childbearing potential

Berotralstat may reduce the effectiveness of oral hormonal contraceptives requiring CYP2C9 for conversion of prodrug to active metabolite, such as desogestrel. Therefore, women using only desogestrel for contraception should switch to an alternative method of effective contraception, such as barrier method, injectable progesterone, or combination oral hormonal contraception (see section 4.5).

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

Cyclosporine, a P-gp and BCRP inhibitor, increased the steady state maximum concentration (C_max) of berotralstat by 25% and the AUC of berotralstat by 55%. Berotralstat exposure may be increased with concomitant administration of P-gp and BCRP inhibitors, but no dose adjustment is necessary. Close monitoring for adverse events 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 medicines that are CYP3A4 substrates. Refer to the SmPC for concomitant medicines that are predominantly metabolised by CYP3A4, particularly those with a narrow therapeutic index (e.g. cyclosporine, fentanyl). Dose adjustments of these medicines 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 medicines that are CYP2D6 substrates. Refer to the SmPC for concomitant medicines 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 medicines 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 medicines that are predominantly metabolised by CYP2C9 (e.g. tolbutamide) (see section 5.2).

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 medicines 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 medicines 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). Dose adjustments of these medicines may be required (see section 5.2).

Oral contraceptives

Administration of berotralstat during use of oral contraceptives has not been studied. As a moderate inhibitor of CYP3A4, berotralstat may increase concentrations of oral contraceptives metabolised by CYP3A4. As a mild inhibitor of CYP2C9, berotralstat may reduce the effectiveness of hormonal contraceptives requiring CYP2C9 for conversion of prodrug to active metabolite, such as desogestrel. Therefore, women using only desogestrel for contraception should switch to an alternative method of effective contraception, such as barrier method, injectable progesterone, or combination oral hormonal contraception (see section 4.4).

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 (see section 4.4).

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).

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

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 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:

^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 national reporting system listed in Appendix V.

Not applicable.