Leaflet ORLADEYO 150mg capsules
- Product code:
- W69633001
- Quantity:
- 28
- Indicated for:
- hereditary angioedema
- Route of administration:
- oral
- Substance:
- berotralstat (enzyme inhibitor)
- ATC
- B06AC06 — Blood and blood forming organs | Other hematological agents | Other hematological agents | Drugs used in hereditary angioedema
The medication is taken orally, usually once daily, as directed by a doctor. It is important for patients to strictly adhere to the treatment regimen to prevent HAE attacks. The treatment is intended solely for prevention and should not be used for managing acute attacks.
Common side effects include abdominal pain, diarrhea, nausea, fatigue, and headache. In rare cases, severe allergic reactions or elevated liver enzyme levels may occur, necessitating regular monitoring of liver function.
Berotralstat is not recommended for pregnant or breastfeeding women unless the benefits outweigh the risks. Patients should inform their doctor about all medications they are taking to avoid drug interactions. Additionally, patients should be aware of the symptoms of an acute attack and have appropriate treatment available for such situations.
General data about ORLADEYO 150mg
- Substance:
- berotralstat
- Date of latest medicines list:
- 01-09-2026
- Product code:
- W69633001
- Concentration:
- 150mg
- Pharmaceutical form:
- capsules
- Quantity:
- 28
- Product type:
- Original
- Price:
- 62097.14 RON
- Prescription status:
- P-RF — Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Official documents
- Added to database:
- 01/06/2021
- Source record updated:
- 31/08/2026
Contents of the package leaflet for the medicine ORLADEYO 150mg capsules
Find in leaflet
Leaflet ORLADEYO 150mg
1. NAME OF THE MEDICINAL PRODUCT
Orladeyo 150 mg hard capsules
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each hard capsule contains 150 mg berotralstat (as dihydrochloride).
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Hard capsule (capsule).
Capsule (19.4 mm × 6.9 mm) with white opaque body imprinted with “150” and light blue opaque capimprinted with “BCX”.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Orladeyo is indicated for routine prevention of recurrent attacks of hereditary angioedema (HAE) inadult and adolescent patients aged 12 years and older weighing at least 40 kg.
4.2 Posology and method of administration
The recommended dose for adults and adolescents aged 12 years and older weighing ≥ 40 kg is150 mg Orladeyo (one capsule) once daily.
Consideration should be given to discontinuing treatment in patients with normal C1 esterase inhibitor
HAE (nC1-INH) who have shown insufficient reduction in attacks after 3 months of treatment (seesections 4.4 and 5.1).
For adolescent patients aged 12 years and older weighing < 40 kg, reference should be made to the
Summary of Product Characteristics for Orladeyo granules.
Missed dosesIf a dose of Orladeyo is missed, the patient should take the forgotten dose as soon as possible withoutexceeding one dose per day.
Orladeyo is not intended for treatment of acute HAE attacks (see section 4.4).
Special populationsElderly population
No dose adjustment is required for patients above 65 years of age (see sections 4.4 and 5.2).
Renal impairmentNo 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).
Hepatic impairmentNo 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).
Paediatric populationThe safety and efficacy of berotralstat in children aged 2 to less than 12 years has been establishedusing weight-based dosing. The recommended doses for children aged 2 to less than 12 years areprovided in the Summary of Product Characteristics for Orladeyo granules. Orladeyo 150 mg capsulesare not intended for use in children less than 12 years of age.
Method of administrationOral 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
Berotralstat is not intended for treatment of acute HAE attacks, individualised treatment should beinitiated 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 donot include plasma kallikrein activation. In this population, it is recommended to perform genetictesting, if available, according to the current HAE guidelines and to discontinue the treatment ifclinical response is not observed (see sections 4.2 and 5.1).
QT prolongationAn increased risk of 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.
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 single150 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-gpand 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
CYP3A4 substratesBerotralstat 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).
CYP2D6 substratesBerotralstat 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).
CYP2C9 substratesBerotralstat 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).
P-gp substratesBerotralstat 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).
Oral contraceptivesAs 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.
4.6 Fertility, pregnancy and lactation
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.
PregnancyThere 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 recommendedduring pregnancy.
Breast-feedingAvailable 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 madewhether to discontinue breast-feeding or to discontinue/abstain from berotralstat therapy taking intoaccount the benefit of breast-feeding for the child and the benefit of therapy for the woman.
FertilityNo effect on fertility was observed in animal studies (see section 5.3).
4.7 Effects on ability to drive and use machines
Berotralstat has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
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 berotralstat use (median dayof onset was day 66 for abdominal pain and day 45 for diarrhoea) and resolved without medicinalproduct while berotralstat 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).
Tabulated list of adverse reactionsThe safety of berotralstat has been evaluated in long term clinical studies in patients with HAE (bothuncontrolled, open-label and placebo-controlled, blinded) in 381 adult and adolescent patients and29 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 beestimated from the available data). Within each frequency grouping, adverse reactions are presented inorder 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
Hepatobiliary disorders 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 movements
Description of selected adverse reactionsTransaminase elevations
Liver function tests (LFT) elevations, which generally improved with or without discontinuation ofberotralstat, were observed in some patients, primarily in those who discontinued androgen therapywithin 14 days of initiating berotralstat treatment. Abrupt discontinuation of androgens immediatelyprior to initiating berotralstat should be avoided.
Paediatric populationAdolescents aged 12 to less than 18 years
The safety of berotralstat was evaluated in clinical studies in a subgroup of 28 adolescent patients aged12 to < 18 years 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 andweighing at least 14.9 kg. The safety profile was similar to that observed in adults.
Reporting of suspected adverse reactionsReporting 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.
4.9 Overdose
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.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other haematological agents, drugs used in hereditary angioedema, ATCcode: B06AC06
Mechanism of actionBerotralstat 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).
Cardiac electrophysiologyAt the steady state Cmax of berotralstat at the recommended dose of 150 mg once daily in adults, themean corrected QT interval increased by 3.4 msec (90% upper CI bound of 6.8 msec), which is belowthe 10 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 in adults, and the corrected QTinterval increased by a mean of 21.9 msec.
Clinical efficacy and safetyEfficacy of berotralstat was studied in a multicentre, randomised, double-blind, placebo-controlled,parallel-group study NCT03485911.
Study NCT03485911
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 of41.6 years. A history of laryngeal angioedema attacks was reported in 74% of patients and 75%reported prior use of long-term prophylaxis. The median attack rate during the prospective run-inperiod (baseline attack rate) was 2.9 per month. Of patients enrolled, 70% had a baseline attack rate of≥ 2 attacks 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.
Berotralstat 150 mg produced a statistically significant and clinically meaningful reduction in the rateof 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 berotralstat150 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.
Berotralstat 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).
Health-related quality of lifePatients 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.
Mean (+/-SEM) Investigator-Confirmed Attack Rate(attacks/month)
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)150 mg Placebo
AE-QoL total score -14.6 (2.6) -9.7 (2.6) -4.90(-12.23, 2.43)
Functioning score -19.5 (3.4) -10.4 (3.4) -9.10(-18.58, 0.38)
Fatigue/Mood score -11.3 (3.2) -9.2 (3.3) -2.16(-11.35, 7.03)
Fear/Shame score -15.4 (3.2) -10.5 (3.3) -4.96(-14.05, 4.13)
Nutrition score -8.8 (3.0) -6.1 (3.1) -2.68(-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)
Normal C1-INH HAE population
An analysis of observational clinical data was conducted in 311 adult patients with nC1-INH HAEwho were treated with berotralstat for up to 18 months. HAE type was determined according to C1-
INH levels, C1-INH function, and C4 levels without genetic testing. This observational study suggestsa similar trend in efficacy in patients with nC1-INH HAE.
Paediatric populationAdolescents aged 12 to less than 18 years (Study NCT03485911, Study NCT03472040)
The safety and effectiveness of berotralstat 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.
Children aged 2 to less than 12 years
The safety and effectiveness of berotralstat were evaluated in a multicentre, open-label, sequential,single-arm study that evaluated 29 paediatric patients aged 3 to < 12 years with HAE who received
Orladeyo granules once daily with food (Study NCT05453968). The median attack rate reported atbaseline (Standard of Care period) was 0.96 attacks/month (range: 0 to 5 attacks/month). To achievedrug exposures similar to those observed in adults treated with 150 mg, patients were assigned to oneof 4 dose groups based on baseline body weight: ≥ 40 kg (n=7), 32 to < 40 kg (n=9), 24 to < 32 kg(n=9), and 12 to < 24 kg (n=4).
All 29 patients completed 12 weeks of treatment with berotralstat, with 27 patients completing48 weeks of treatment.
Reduction from baseline in monthly mean attack rate was sustained through 48 weeks (Figure 2).
Figure 2: Adjusted mean HAE attack rate per montha through 48 weeks treatment withberotralstat weight-based dosinga Adjusted mean HAE attack rate per month was not a primary endpoint of the study
The safety and efficacy of berotralstat in paediatric patients under 2 years have not been established.
5.2 Pharmacokinetic properties
Following oral administration of berotralstat 150 mg once daily, Cmax and AUC over the dosinginterval (AUCtau) are 158 ng/mL (range: 110 to 234 ng/mL) and 2770 ng*h/mL (range: 1880 to3790 ng*h/mL), respectively. The pharmacokinetics of berotralstat in patients with HAE are similar tothose of healthy people.
Berotralstat exposure (Cmax and AUC) increases greater than proportionally with dose and steady stateis reached by days 6 to 12.
Food effectNo 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 adversereactions.
DistributionPlasma 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.
BiotransformationBerotralstat 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.
EliminationAfter 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.
Special populationsPopulation 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.
Paediatric populationBased 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.
Berotralstat exposure in paediatric patients aged 2 to < 12 years is provided in the Summary of
Product Characteristics for Orladeyo granules. Orladeyo 150 mg capsules are not intended for use inchildren < 12 years of age.
Renal impairmentThe pharmacokinetics of a single 200 mg oral dose of berotralstat were studied in adult patients withsevere renal impairment (eGFR less than 30 mL/min). When compared to a concurrent cohort withnormal renal function (eGFR greater than 90 mL/min); Cmax was increased by 39%, while nodifference was observed in AUC. No dose adjustment is required for patients with mild or moderaterenal impairment. Patients with severe renal impairment may be at risk of prolonged QT. It ispreferable to avoid 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.
Hepatic impairmentThe pharmacokinetics of a single 150 mg oral dose of berotralstat were studied in adult patients withmild, 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).
ElderlyBerotralstat has not been studied in patients above 75 years of age; however, age is not expected toaffect exposure to berotralstat.
5.3 Preclinical safety data
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.
There were no new findings observed in the definitive juvenile toxicology study in male and femalerats. No adverse effects were observed at doses up to 50 mg/kg/day with AUC0-24 exposures 5.8 to6.5 times the recommended paediatric therapeutic exposures.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Capsule filling
Crospovidone (type A)
Magnesium stearate
Silica, colloidal anhydrous
Starch, pregelatinised
Capsule shellGelatin
Titanium dioxide (E 171)
Indigo carmine (E 132)
Black iron oxide (E 172)
Red iron oxide (E 172)
Printing inkBlack iron oxide (E 172)
Potassium hydroxide
Shellac
Propylene glycol (E 1520)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
4 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
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.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency https://www.ema.europa.eu.