Orladeyo
Plasma Kallikrein Inhibitor for Hereditary Angioedema Prevention
Quick Facts About Orladeyo
Key Takeaways About Orladeyo
- First oral prophylactic for HAE: Orladeyo is the first and only oral once-daily medication specifically approved to prevent hereditary angioedema attacks, offering a convenient alternative to injectable therapies
- Proven efficacy in clinical trials: In the pivotal APeX-2 trial, berotralstat 150 mg reduced HAE attack rates by approximately 44% compared to placebo over 24 weeks
- Not for acute attacks: Orladeyo is a preventive medication only and should not be used to treat breakthrough HAE attacks – always keep your rescue medication available
- Gastrointestinal side effects are most common: Abdominal pain, diarrhoea, and headache are the most frequently reported side effects, but they typically improve with continued use
- Important drug interactions: Orladeyo interacts with several medications including thioridazine, pimozide, cyclosporine, and certain antidepressants – always inform your doctor about all medicines you take
What Is Orladeyo and What Is It Used For?
Orladeyo (berotralstat) is a plasma kallikrein inhibitor used to prevent angioedema attacks in adults and adolescents aged 12 years and older with hereditary angioedema (HAE). It is the first oral medication approved for long-term prophylaxis of HAE, offering patients a convenient once-daily capsule instead of regular injections.
Hereditary angioedema is a rare genetic disorder that affects approximately 1 in 50,000 people worldwide. The condition is caused by a deficiency or dysfunction of C1-esterase inhibitor (C1-INH), a protein that normally regulates the complement and contact activation systems in the blood. When C1-INH is absent or does not function properly, the enzyme plasma kallikrein becomes overactive, leading to excessive production of bradykinin – a peptide that causes blood vessels to become leaky and fluid to accumulate in surrounding tissues.
This excess bradykinin results in the characteristic recurrent episodes of angioedema – sudden, unpredictable swelling that can affect the hands, feet, face, eyelids, lips, tongue, larynx (throat), genitals, and gastrointestinal tract. HAE attacks can be painful, debilitating, and in the case of laryngeal (throat) swelling, potentially life-threatening due to airway obstruction. The frequency and severity of attacks vary considerably between patients, ranging from occasional mild episodes to multiple severe attacks per month that significantly impair quality of life.
How Orladeyo Works
Berotralstat, the active substance in Orladeyo, works by directly inhibiting the activity of plasma kallikrein. By blocking this key enzyme in the contact activation pathway, berotralstat reduces the generation of excess bradykinin. With lower bradykinin levels, the vascular leakage that causes swelling is prevented, thereby reducing both the frequency and severity of HAE attacks.
Unlike some older treatments for HAE that replace the missing C1-INH protein through intravenous infusions, Orladeyo acts downstream in the biochemical pathway by targeting the overactive kallikrein enzyme itself. This mechanism allows it to be effective regardless of whether the patient has reduced C1-INH levels (Type I HAE) or dysfunctional C1-INH protein (Type II HAE).
The clinical efficacy of Orladeyo was demonstrated in the APeX-2 trial, a pivotal Phase 3, randomised, double-blind, placebo-controlled study involving 121 patients with HAE. Patients receiving berotralstat 150 mg once daily experienced a statistically significant reduction in the rate of HAE attacks compared to placebo. The median attack rate was reduced by approximately 44% over the 24-week treatment period, with many patients experiencing substantial further reductions during the open-label extension phase. These results led to regulatory approval by the European Medicines Agency (EMA) in 2021 and by the U.S. Food and Drug Administration (FDA) in 2020.
Orladeyo is specifically a prophylactic (preventive) treatment. It is designed to be taken every day to reduce the number of HAE attacks over time. It is not intended for the treatment of acute HAE attacks. If you experience a breakthrough attack while taking Orladeyo, you should use your prescribed rescue medication (such as icatibant, C1-inhibitor concentrate, or ecallantide) without taking an additional dose of Orladeyo.
What Should You Know Before Taking Orladeyo?
Before starting Orladeyo, inform your doctor about all medical conditions, especially liver or kidney problems and any risk of heart rhythm disturbances (QT prolongation). Orladeyo is contraindicated in patients with known hypersensitivity to berotralstat and is not recommended in moderate-to-severe hepatic impairment or severe renal impairment.
Contraindications
You should not take Orladeyo if you are allergic to berotralstat or any of the other ingredients contained in the capsule (listed in the composition section below). Signs of an allergic reaction may include skin rash, itching, swelling of the face or throat, or difficulty breathing. If you suspect an allergic reaction, stop taking Orladeyo and seek medical attention immediately.
Warnings and Precautions
Talk to your doctor or pharmacist before taking Orladeyo if any of the following apply to you:
- Moderate or severe liver impairment: Reduced liver function can increase berotralstat blood levels, potentially raising the risk of side effects. Orladeyo is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C).
- Severe kidney impairment or dialysis: If your kidney function is severely reduced, treatment with Orladeyo should generally be avoided. If your doctor determines that Orladeyo is necessary, additional monitoring – including regular electrocardiogram (ECG) assessments of your heart rhythm – may be required. Orladeyo should be avoided in patients who are on dialysis.
- Risk of QT prolongation: Tell your doctor if you have a known risk of a heart rhythm problem called QT prolongation, which can cause irregular heartbeat and is potentially dangerous. This risk may be increased in patients taking other medications that prolong the QT interval.
If you experience an HAE attack while taking Orladeyo, use your prescribed rescue medication as directed. Do not take an extra dose of Orladeyo. The effectiveness of Orladeyo as an acute treatment for HAE attacks has not been established.
Use in Children and Adolescents
Orladeyo is approved for use in adolescents aged 12 years and older who weigh at least 40 kg. The dosage is the same as for adults. Orladeyo has not been studied in children under 12 years of age or in adolescents weighing less than 40 kg, and therefore its safety and efficacy in these groups have not been established. It is not recommended for use in these populations.
Pregnancy and Breastfeeding
There is limited information regarding the use of Orladeyo during pregnancy. As a precautionary measure, Orladeyo should be avoided during pregnancy unless the potential benefit clearly outweighs the risk. If you are pregnant, think you might be pregnant, or are planning to become pregnant, consult your doctor before taking this medication. Your doctor will discuss the benefits and risks with you and may recommend alternative treatments during pregnancy.
It is not known whether berotralstat passes into breast milk. As a precautionary measure, Orladeyo should be avoided during breastfeeding. Your doctor will advise you on whether to continue breastfeeding or to discontinue the medication, taking into account the benefit of breastfeeding for the child and the benefit of therapy for you.
Women of childbearing potential should use effective contraception during treatment with Orladeyo and for at least one month after the last dose. Orladeyo is not recommended for women of childbearing potential who are not using contraception.
Driving and Operating Machinery
Orladeyo has no or negligible effect on the ability to drive and use machines. Based on the known pharmacological properties and the side-effect profile observed in clinical trials, berotralstat is not expected to impair driving ability or the operation of machinery. However, if you experience headache or dizziness while taking Orladeyo, exercise caution until the symptoms resolve.
How Does Orladeyo Interact with Other Drugs?
Orladeyo can interact with several medications, including antipsychotics (thioridazine, pimozide), immunosuppressants (cyclosporine), anticoagulants (dabigatran), and various other drugs metabolised by specific liver enzymes. Rifampicin can significantly reduce Orladeyo's effectiveness. Always tell your doctor about all medications you are taking.
Berotralstat is metabolised primarily by the liver enzymes CYP2D6 and CYP3A4. It also acts as an inhibitor of CYP2D6, CYP3A4, and P-glycoprotein (P-gp), which means it can increase the blood levels of other drugs metabolised by these pathways. Additionally, strong CYP3A4 inducers (such as rifampicin) can significantly reduce berotralstat levels, potentially decreasing its efficacy. The following tables summarise the most clinically important drug interactions.
Major Interactions
| Drug | Category | Effect | Recommendation |
|---|---|---|---|
| Thioridazine | Antipsychotic | Berotralstat inhibits CYP2D6, increasing thioridazine levels and risk of QT prolongation and serious cardiac arrhythmias | Concomitant use should be avoided |
| Pimozide | Antipsychotic | Berotralstat inhibits CYP2D6, increasing pimozide levels and risk of QT prolongation | Concomitant use should be avoided |
| Cyclosporine | Immunosuppressant | Berotralstat inhibits P-gp and CYP3A4, potentially increasing cyclosporine levels and risk of nephrotoxicity | Monitor cyclosporine levels closely; dose adjustment may be needed |
| Rifampicin | Antibiotic (CYP3A4 inducer) | Rifampicin strongly induces CYP3A4, significantly reducing berotralstat blood levels and potentially reducing its effectiveness | Concomitant use should be avoided; consider alternative antibiotic |
| Fentanyl | Opioid analgesic | Berotralstat inhibits CYP3A4, potentially increasing fentanyl levels and risk of respiratory depression | Use with caution; monitor for signs of opioid toxicity |
| Midazolam | Benzodiazepine sedative | Berotralstat inhibits CYP3A4, increasing midazolam exposure and risk of prolonged sedation | Use with caution; dose reduction of midazolam may be needed |
Other Notable Interactions
| Drug | Category | Effect | Recommendation |
|---|---|---|---|
| Amlodipine | Calcium channel blocker | Berotralstat may increase amlodipine levels via CYP3A4 inhibition | Monitor blood pressure; dose adjustment may be needed |
| Dabigatran | Anticoagulant | Berotralstat inhibits P-gp, potentially increasing dabigatran levels and bleeding risk | Monitor for signs of bleeding; dose adjustment may be needed |
| Desipramine | Tricyclic antidepressant | Berotralstat inhibits CYP2D6, increasing desipramine levels | Monitor for increased side effects; dose reduction may be needed |
| Digoxin | Cardiac glycoside | Berotralstat inhibits P-gp, potentially increasing digoxin levels | Monitor digoxin levels; adjust dose as necessary |
| Dextromethorphan | Cough suppressant | Berotralstat inhibits CYP2D6, increasing dextromethorphan exposure | Use with caution; consider lower doses of dextromethorphan |
| Oral contraceptives | Hormonal contraception | Berotralstat may affect levels of hormonal contraceptives via CYP3A4 inhibition | Use additional barrier contraception or non-hormonal methods if concerned; consult your doctor |
| St John's Wort | Herbal antidepressant (CYP3A4 inducer) | May reduce berotralstat blood levels via CYP3A4 induction | Avoid concomitant use |
| Tolbutamide | Antidiabetic (sulfonylurea) | Berotralstat may affect tolbutamide metabolism | Monitor blood glucose levels closely |
This includes prescription and over-the-counter medications, vitamins, herbal supplements, and any other products you are taking. Drug interactions with Orladeyo can affect how well it works or increase your risk of side effects. Your doctor or pharmacist can advise you on safe combinations.
What Is the Correct Dosage of Orladeyo?
The recommended dosage of Orladeyo is one 150 mg capsule taken once daily with food, at the same time each day. The capsule should be swallowed whole with a glass of water. The dose is the same for adults and adolescents (12 years and older, weighing at least 40 kg).
Always take Orladeyo exactly as your doctor or pharmacist has told you. If you are unsure about any aspect of your treatment, ask your doctor or pharmacist for clarification. Consistent daily dosing is important for maintaining steady drug levels in the blood and achieving optimal protection against HAE attacks.
Adults and Adolescents (12 years and older, ≥40 kg)
Standard Dosage
Dose: 150 mg (one capsule) once daily
Administration: Take with food and a glass of water
Timing: At the same time each day; the time of day does not matter
Duration: Continue treatment for as long as your doctor prescribes
Children Under 12 Years
Not Recommended
Orladeyo is not recommended for children under 12 years of age because it has not been studied in this age group. Additionally, Orladeyo has not been studied in adolescents weighing less than 40 kg.
Special Populations
Liver Impairment
Orladeyo is not recommended for patients with moderate or severe liver impairment (Child-Pugh B or C). These patients may have increased berotralstat blood levels, which could lead to a higher risk of side effects, including cardiac effects. No dose adjustment is needed for patients with mild liver impairment.
Kidney Impairment
Patients with severe kidney impairment should generally avoid treatment with Orladeyo. If your doctor determines that Orladeyo is necessary, additional monitoring including ECG (electrocardiogram) assessments may be required to check your heart rhythm. Patients on dialysis should not take Orladeyo. No dose adjustment is needed for patients with mild-to-moderate kidney impairment.
Elderly Patients
No specific dose adjustment is required for elderly patients based solely on age. However, older patients are more likely to have reduced kidney or liver function, which should be considered by the prescribing doctor.
Missed Dose
If you forget to take your Orladeyo capsule, take the missed dose as soon as you remember on the same day. However, you must never take more than one capsule per day. Do not take a double dose to compensate for a forgotten capsule. If it is already close to the time for your next dose, skip the missed dose and continue with your regular schedule.
Overdose
If you take more Orladeyo capsules than you should, contact your doctor or go to your nearest emergency department immediately. Take the medication packaging with you so that the healthcare professionals can see what you have taken. In clinical studies, single doses of up to 750 mg have been administered to healthy volunteers; gastrointestinal side effects were the most commonly reported symptoms at higher doses.
It is important to take Orladeyo regularly for as long as your doctor has prescribed. Do not stop taking it without consulting your doctor first. Stopping treatment abruptly may result in a return of HAE attacks to their previous frequency and severity.
What Are the Side Effects of Orladeyo?
The most common side effects of Orladeyo are gastrointestinal in nature: headache, abdominal pain, diarrhoea, and frequent bowel movements affect more than 1 in 10 patients. These side effects are generally mild to moderate and tend to improve over time with continued use. Serious side effects are rare.
Like all medicines, Orladeyo can cause side effects, although not everybody gets them. The side effects observed in clinical trials were generally mild to moderate and were most frequently gastrointestinal in nature. Most gastrointestinal symptoms occurred during the first few weeks of treatment and tended to diminish as the body adjusted to the medication. Below is a detailed breakdown of side effects by frequency category.
Very Common
May affect more than 1 in 10 patients
- Headache – typically mild and may resolve within the first weeks of treatment
- Abdominal pain – including stomach discomfort and abdominal bloating
- Diarrhoea and frequent bowel movements – the most common gastrointestinal effect; usually transient
Common
May affect up to 1 in 10 patients
- Vomiting – occasional episodes, usually not persistent
- Heartburn (gastroesophageal reflux) – burning sensation in the chest or upper abdomen
- Flatulence (gas) – increased intestinal gas production
- Elevated liver enzymes (ALT and AST) – detected in blood tests; usually reversible and not associated with symptoms
- Skin rash – mild skin reactions that typically resolve spontaneously
Frequency Not Known
Cannot be estimated from the available data
- Nausea – a feeling of sickness or urge to vomit
The gastrointestinal side effects associated with Orladeyo are thought to be related to the mechanism of action of plasma kallikrein inhibition, as the kallikrein-kinin system plays a role in gastrointestinal function. Importantly, these side effects were the primary reason for discontinuation in a small proportion of patients during clinical trials (approximately 5–10% of patients in the APeX-2 study).
It is important to note that elevated liver enzymes (ALT and AST) were observed in some patients. Your doctor may recommend periodic blood tests to monitor your liver function, particularly during the first months of treatment. In most cases, the elevations were mild, transient, and resolved without discontinuation of the medication.
Contact your doctor if you experience persistent or severe abdominal pain, diarrhoea, vomiting, or any symptoms of liver problems such as yellowing of the skin or eyes (jaundice), dark urine, or unusual tiredness. If you experience a severe allergic reaction (difficulty breathing, swelling of the face or throat), seek emergency medical help immediately.
How Should You Store Orladeyo?
Store Orladeyo at room temperature with no special storage conditions required. Keep the capsules in the original blister packaging until ready to use, and always store out of sight and reach of children.
Orladeyo does not require any special storage conditions. It can be kept at normal room temperature. However, as with all medications, you should follow these general storage guidelines:
- Keep out of reach and sight of children – store in a safe location where children cannot access the medication
- Check the expiry date – do not use Orladeyo after the expiry date printed on the carton and blister pack after "EXP". The expiry date refers to the last day of that month
- Keep in original packaging – store the capsules in their blister packs until you are ready to take them
- Do not dispose of in wastewater or household waste – ask your pharmacist how to dispose of medicines you no longer use. These measures help protect the environment
What Does Orladeyo Contain?
Each Orladeyo capsule contains 150 mg of berotralstat (as dihydrochloride) as the active ingredient. The capsules have a white opaque body marked with "150" and a light blue opaque cap marked with "BCX".
Active Ingredient
Each hard capsule contains 150 mg berotralstat (as berotralstat dihydrochloride). Berotralstat is the active substance responsible for the therapeutic effect of the medication.
Inactive Ingredients (Excipients)
The other ingredients that make up the capsule and its contents are:
- Capsule contents: pregelatinised starch, crospovidone (type A), colloidal anhydrous silica, magnesium stearate
- Capsule shell: gelatin, titanium dioxide (E 171)
- Colourants: indigo carmine (E 132), black iron oxide (E 172), red iron oxide (E 172)
- Printing ink: black iron oxide (E 172), potassium hydroxide, shellac, propylene glycol (E 1520)
Appearance and Pack Sizes
Orladeyo capsules have a white opaque body marked with "150" and a light blue opaque cap marked with "BCX". The capsules measure approximately 19.4 mm × 6.9 mm. They are packaged in plastic/aluminium blister packs, with 7 capsules per blister strip, contained in a cardboard carton. Available pack sizes are 28 hard capsules (4 weeks' supply) and 98 hard capsules (14 weeks' supply).
The marketing authorisation holder is BioCryst Ireland Limited, Dublin, Ireland. The manufacturer is Millmount Healthcare Limited, Stamullen, Co. Meath, Ireland.
Frequently Asked Questions About Orladeyo
Orladeyo (berotralstat) is used to prevent angioedema attacks in adults and adolescents aged 12 years and older with hereditary angioedema (HAE). It is taken as a once-daily capsule to reduce the frequency and severity of HAE attacks. It is important to understand that Orladeyo is a preventive medication and is not intended for the treatment of acute HAE attacks – patients should always have their rescue medication available for breakthrough episodes.
Orladeyo works by inhibiting an enzyme called plasma kallikrein. In people with hereditary angioedema, deficient or dysfunctional C1-inhibitor protein leads to overactivation of plasma kallikrein, which generates excess bradykinin. Bradykinin makes blood vessels leaky, causing fluid to accumulate in tissues and resulting in the swelling characteristic of HAE. By blocking plasma kallikrein, Orladeyo reduces bradykinin levels and prevents the swelling episodes.
The most common side effects of Orladeyo are gastrointestinal: headache, abdominal pain (including stomach discomfort and bloating), diarrhoea, and frequent bowel movements. These affect more than 1 in 10 patients. Common side effects (affecting up to 1 in 10 patients) include vomiting, heartburn, flatulence, elevated liver enzymes (ALT and AST), and skin rash. Most of these side effects are mild to moderate and tend to improve over time as the body adjusts to the medication.
There is limited information about the safety of Orladeyo during pregnancy and breastfeeding. As a precaution, Orladeyo should be avoided during both pregnancy and breastfeeding unless the potential benefits clearly outweigh the risks. Women of childbearing potential should use effective contraception during treatment and for at least one month after the last dose. Always discuss your options with your doctor, who can help you weigh the risks and benefits and consider alternative treatments if necessary.
If you miss a dose of Orladeyo, take it as soon as you remember on the same day. Do not take a double dose to make up for a missed one. Never take more than one capsule (150 mg) per day. To help prevent missed doses, try taking Orladeyo at the same time each day with a meal. If it is almost time for your next regular dose, skip the missed dose and continue with your normal schedule.
Orladeyo can interact with several other medications. In particular, it should not be used together with thioridazine or pimozide (antipsychotic drugs) due to the risk of serious heart rhythm problems. Other medications that require careful monitoring include cyclosporine, dabigatran, digoxin, fentanyl, midazolam, desipramine, and hormonal contraceptives. Rifampicin and St John's Wort can reduce Orladeyo's effectiveness and should be avoided. Always provide your doctor with a complete list of all medications, supplements, and herbal products you are taking.
References and Sources
- Zuraw B, Lumry WR, Johnston DT, et al. Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial (APeX-2). Journal of Allergy and Clinical Immunology. 2021;148(1):164-172. doi:10.1016/j.jaci.2020.10.017
- European Medicines Agency (EMA). Orladeyo (berotralstat) – Summary of Product Characteristics. EMA/CHMP Assessment Report. First published 2021, last updated 2024.
- U.S. Food and Drug Administration (FDA). Orladeyo (berotralstat) Prescribing Information. BioCryst Pharmaceuticals. Approved December 2020.
- Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema – The 2021 revision and update. World Allergy Organization Journal. 2022;15(1):100627. doi:10.1016/j.waojou.2021.100627
- Wedner HJ. Hereditary angioedema: Pathophysiology and current management approaches. Immunology and Allergy Clinics of North America. 2021;41(3):377-392. doi:10.1016/j.iac.2021.04.003
- Craig T, Zuraw B, Edwards N, et al. Long-term outcomes with berotralstat for prevention of hereditary angioedema attacks: APeX-2 open-label extension study. Annals of Allergy, Asthma & Immunology. 2023;130(5):619-626. doi:10.1016/j.anai.2023.01.029
- World Health Organization (WHO). WHO Model List of Essential Medicines – 23rd List, 2023. Geneva: World Health Organization; 2023.
- British National Formulary (BNF). Berotralstat. NICE Evidence Services. Last accessed February 2026.
Evidence Level: All medical claims in this article are based on Level 1A evidence (systematic reviews and meta-analyses of randomised controlled trials) where available, supplemented by official regulatory assessment reports from the EMA and FDA. Content follows the GRADE evidence framework and adheres to international HAE management guidelines (WAO/EAACI 2021).
Editorial Team
Medical Author
iMedic Medical Editorial Team
Specialists in immunology, allergy, and clinical pharmacology with expertise in rare diseases and hereditary angioedema management.
Medical Reviewer
iMedic Medical Review Board
Independent panel of board-certified physicians who verify accuracy, completeness, and adherence to international medical guidelines (WAO, EAACI, EMA, FDA).
Editorial Standards: This article follows iMedic's editorial standards. All content is evidence-based, peer-reviewed, and written in accordance with international medical guidelines. We have no commercial funding and accept no pharmaceutical advertising. Read more about our medical team.