• Orladeyo is a brand (trade) name for berotralstat which may be used to prevent attacks of hereditary angioedema (HAE) in adults and children aged 12 years and older. HAE is a rare genetic condition that occurs in people with low levels of certain proteins (C1-INH and C4) in their bodies.
• The main purpose of the C1 inhibitor protein is to regulate the coagulation pathway (the process that causes our blood to clot), the fibrinolytic system (the process that removes and degrades clots after blood vessels are repaired), and to control the production of bradykinin, which is a protein fragment that increases the movement of fluid through blood vessel walls, resulting in swelling and inflammation.
• Orladeyo (berotralstat) works by controlling excessive bradykinin production. It does this by binding to plasma kallikrein and preventing it from breaking down high-molecular-weight-kininogen (HMWK) to cleaved HMWK and bradykinin. By reducing bradykinin production, Orladeyo decreases the permeability of blood vessels which reduces swelling and pain associated with HAE.
• Orladeyo belongs to the class of medicines known as plasma kallikrein inhibitors. It may also be called a hereditary angioedema agent.

• May be used to prevent angioedema attacks in adults and adolescents aged 12 years and older with hereditary angioedema (HAE).
• Reduces swelling in the limbs, face, intestinal tract, and airway.
• The usual dosage is 150mg (one capsule) taken once daily with food. The dosage needs to be reduced in those with moderate-to-severe liver disease (Child-Pugh B or C) or on regular P-gp or BCRP inhibitors (such as cyclosporine) to 110mg once daily.
• Orladeyo is the only oral HAE prevention agent. Other HAE prevention agents. such as Haegarda and Ruconest, have to be given by injection.
• Available as 150mg and 110mg capsules.
• Additional dosages greater than 150mg once daily are not recommended due to the potential for QT prolongation.
• No dosage adjustment is required for people with kidney disease.
• Severe hypersensitivity reactions have not been reported with Orladeyo.
• There are no contraindications documented in the product information.

If you are between the ages of 18 and 60, take no other medication or have no other medical conditions, side effects you are more likely to experience include:

• Abdominal pain, vomiting, diarrhea, back pain, and gastroesophageal reflux disease are the most common side effects reported with Orladeyo. Headaches, fatigue, and flatulence were also reported in some people. Less than 1% of people experienced a rash that resolved in all, including people who continued treatment with Orladeyo.
• There is a risk of QT prolongation with a higher than the recommended dose of 150mg/day. Do not use more than 150mg/day or use Orladeyo for acute attacks of HAE.
• May cause gastrointestinal (GI) side effects such as vomiting, diarrhea, or abdominal pain. Consider reducing the dosage to 110mg once daily. In clinical trials, nobody discontinued Orleydo because of GI side effects.
• Does not treat attacks of HAE. Other medications, such as Berinert or Ruconest do this.
• The safety of Orladeyo in children under the age of 12 has not been established.
• There is no data regarding the use of Orladeyo in pregnant women. Animal studies in rats and rabbits revealed no evidence of structural alterations when Orladeyo was administered at 10 and 2 times (respectively) the recommended dose during organogenesis. It is unknown if Orladeyo can cause fetal harm or affect reproduction capacity. Only give to pregnant women if needed. There is no data regarding the presence of Orladeyo in human milk or its effects on milk production. Animal studies have revealed the concentration of Orladeyo in breastmilk was 2% of that of maternal plasma.
• No generic is available.

Note: In general, seniors or children, people with certain medical conditions (such as liver or kidney problems, heart disease, diabetes, seizures) or people who take other medications are more at risk of developing a wider range of side effects. View complete list of side effects

• Take once a day with food. You can take it in the morning or at night but try to take it at the same time each day.
• Orladeyo is not a treatment for acute attacks of HAE. Do not take more Orladeyo than recommended because this could give you heart rhythm problems.
• Orladeyo may cause gastrointestinal side effects, such as abdominal pain, vomiting, and diarrhea. These are more likely to occur when you start treatment and resolve by themselves the longer you are on treatment. You could talk to your doctor about a dosage reduction if symptoms persist.
• Orladeyo may interact with other medications, including those brought from a supermarket or drugstore. Always talk to your pharmacist or doctor before taking other medications because of the potential for drug interactions.
• Before you start taking Orladeyo, tell your doctor if you have any liver or kidney problems.
• Orladeyo has not been studied in pregnant or breastfeeding women. Talk to your healthcare provider about the risk of taking this drug during pregnancy or breastfeeding especially if you are considering trying to become pregnant. Tell your doctor if you inadvertently become pregnant.

• Research has shown that Orladeyo can reduce the risk of HAE attacks by an average of about 30% (with 110mg/day) and 44.2% (150mg/day).
• 58% of patients receiving Orladeyo 150mg and 51% receiving Orladeyo 110mg had a 50% reduction in their HAE attack rates. The rate of attacks rated as moderate to severe was reduced by 40% in those receiving Orladeyo 150mg and 10% in those receiving Orladeyo 110mg.

Medicines that interact with Orladeyo may either decrease its effect, affect how long it works, increase side effects, or have less of an effect when taken with Orladeyo. An interaction between two medications does not always mean that you must stop taking one of the medications; however, sometimes it does. Speak to your doctor about how drug interactions should be managed.

More than 420 other medications interact with Orladeyo, and most of these interactions are considered major or moderate. Some examples of common medications that may interact with Orladeyo include:

• antibiotics, such as azithromycin, clarithromycin, or erythromycin
• anticoagulants, such as dabigatran or rivaroxaban
• antifungals, such as ketoconazole or itraconazole
• antihistamines, such as chlorpheniramine or fexofenadine
• antipsychotics such as amitriptyline, haloperidol, or thioridazine
• antiseizure medications, such as carbamazepine or phenytoin
• benzodiazepines such as alprazolam, clonazepam, or midazolam
• beta-blockers, such as carvedilol
• bromocriptine
• Cannabis
• chemotherapy agents such as vincristine
• chloroquine
• cisapride
• colchicine
• corticosteroids such as budesonide or dexamethasone
• CYP2D6 substrates, such as thioridazine and pimozide: Monitor and reduce the dosage of the substrate if necessary
• CYP3A4 substrates with a narrow therapeutic index, such as cyclosporine and fentanyl: Monitor and reduce the dosage of the substrate if necessary
• digoxin - monitor digoxin concentrations and adjust as necessary
• dihydroergotamine and ergotamine
• estrogens or progesterones
• granisetron
• heart medications such as diltiazem, doxazosin, or nifedipine
• HIV medications, such as amprenavir, cobicistat, or ritonavir
• opioids, such as alfentanil, fentanyl, hydrocodone, or oxycodone
• pimozide
• quinidine
• oxybutynin
• P-gp or BCRP inhibitors (such as cyclosporine): Can increase the concentration of Orladeyo
• P-gp or BCRP inducers (such as rifampin or St. John's wort)
• rifampin
• sildenafil
• tacrolimus
• tamoxifen
• Tyrosine kinase inhibitors, such as afatinib
• zolpidem.

Orladeyo is a P-gp and BCRP substrate, a moderate inhibitor of CYP2D6 and CYP3A4, and a weak inhibitor of CYP2C9 and CYP2C19. No dosage adjustment is necessary for CYP2C9 substrates, such as tolbutamide nor CYP2C19 substrates, such as omeprazole. Rosuvastatin, a BCRP substrate, does not require dosage adjustment.

Note that this list is not all-inclusive and includes only common medications that may interact with Orladeyo. You should refer to the prescribing information for Orladeyo for a complete list of interactions.