Orladeyo

Orladeyo (berotralstat) is a once-daily oral medicine used to prevent attacks of hereditary angioedema (HAE) in adults and children 2 years of age and older. It is a long-term HAE treatment that you take every day to make swelling attacks happen less often. Orladeyo does not treat an HAE attack that has already started.

Orladeyo comes in two forms:

• Capsules, for adults and children 12 years of age and older.
• Oral pellets, for adults and children 2 years of age and older. Children 2 to under 12 years take a pellet dose based on their body weight. Adults and children 12 years and older take one 150 mg pellet packet once a day, the same strength as the 150 mg capsule. The pellets can be swallowed on their own or sprinkled on soft food, which can help people who have trouble swallowing capsules.

Orladeyo is a plasma kallikrein inhibitor. In people with HAE, plasma kallikrein is too active. It releases bradykinin, a natural chemical that makes blood vessels leak fluid into nearby tissue. This leaking fluid causes the swelling of an HAE attack, which can affect the face, hands, feet, throat (airway), and stomach area. Orladeyo blocks plasma kallikrein, so less bradykinin is released and swelling attacks are less likely.

Orladeyo was shown to reduce the number of HAE attacks in the APeX-2 clinical trial (NCT03485911). This study included 120 adults and children 12 years of age and older with HAE.

After 24 weeks of treatment, compared with placebo (a dummy pill):

• People taking Orladeyo 150 mg had about 44% fewer HAE attacks
• People taking Orladeyo 110 mg had about 30% fewer HAE attacks

Their attack rate was also cut by at least half in 58% of people taking 150 mg and 51% taking 110 mg, compared with 25% taking placebo.

For children 2 to under 12 years of age, Orladeyo oral pellets were approved based on the results in older patients plus safety and blood-level data from 29 children in an open-label study.

Take Orladeyo once a day with food. Eat a meal just before or just after your dose.

Capsules

Swallow one capsule once a day with food.

Oral pellets

Do not chew or crush the pellets. Chewing or crushing damages the coating that hides the bitter taste. Use one whole packet in one of these two ways:

• Directly into the mouth: pour the whole packet into the mouth and swallow right away with a non-acidic drink, such as water or milk.
• Sprinkled on food: sprinkle the whole packet over about 1 tablespoon (15 mL) of soft, non-acidic food and eat it right away.

• Food should be at room temperature or cooler.
• Good choices include pudding, mashed potatoes, creamed corn, and pureed peas, bananas, or carrots.
• Do not use acidic foods such as yogurt or applesauce. They can dissolve the coating and make the pellets taste bitter.
• The coating lasts 10 minutes. Throw away pellets that have not been eaten within 10 minutes of sprinkling.

QT prolongation: Higher than recommended doses of Orladeyo can lengthen the QT interval, a measure of the heart's electrical activity. Do not take more than your prescribed daily dose.

To make sure Orladeyo is safe for you, tell your doctor if you have ever had:

• Liver disease
• Kidney disease, or if you are on dialysis
• Heart rhythm problems

Pregnancy

Tell your doctor if you are pregnant or plan to become pregnant. There is not enough information to know whether Orladeyo can harm an unborn baby.

Breastfeeding

Tell your doctor if you are breastfeeding or plan to breastfeed. It is not known whether Orladeyo passes into human breast milk, but it was found in the milk of animals. Talk to your doctor about the best way to feed your baby.

Like all prescription medicines, Orladeyo (berotralstat) can cause side effects.

Common side effects

The most common Orladeyo side effects are:

• Stomach (abdominal) pain
• Vomiting
• Diarrhea
• Back pain
• Heartburn (gastroesophageal reflux disease)

Stomach and bowel (gastrointestinal) side effects happened more often with the 150 mg dose. They usually started soon after beginning treatment, became less frequent over time, and often went away on their own. In the clinical trial, no patients taking 150 mg and 1 patient taking 110 mg stopped treatment because of these side effects.

Serious side effects

Heart rhythm problems (QT prolongation). Taking more Orladeyo than prescribed can cause a heart rhythm change called QT prolongation, which can lead to an abnormal heartbeat. Take only one capsule or one packet of pellets a day, and do not take an extra dose.

This is not a complete list of side effects, and others may occur. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Adults and children 12 years of age and older

One 150 mg capsule taken by mouth once a day with food. Adults and children 12 years and older can instead take one 150 mg packet of oral pellets once a day with food, for example if they have trouble swallowing capsules.

Children 2 to under 12 years of age

The dose of Orladeyo oral pellets is based on body weight:

Dose changes for ongoing stomach side effects

• 12 years and older: your doctor may lower the dose to 110 mg (capsule) once a day with food.
• 2 to under 12 years: your child's doctor will weigh the risks and benefits of continuing treatment.

Dose changes for liver problems

• Mild liver problems (Child-Pugh Class A): no dose change is needed.
• Moderate or severe liver problems (Child-Pugh Class B or C): for people 12 years and older, one 110 mg capsule once a day with food. Orladeyo should not be used in children 2 to under 12 years of age.

Kidney problems

• Mild or moderate kidney problems: no dose change is needed.
• Severe kidney problems: no dose change for people 12 years and older. Orladeyo should not be used in children 2 to under 12 years of age.
• End-stage kidney disease: Orladeyo has not been studied and is not recommended.

• Capsules: 110 mg and 150 mg
• Oral pellets: 72 mg, 96 mg, 108 mg, 132 mg, and 150 mg film-coated pellets in single-dose packets

Take the missed dose as soon as you remember. Skip it if it is almost time for your next dose. Do not take two doses at once.

Call the Poison Help line at 1-800-222-1222 or get emergency medical help right away. Taking too much Orladeyo may cause heart rhythm problems.

Orladeyo can interact with other medicines, including:

• P-gp inducers (medicines that lower Orladeyo levels in the body): avoid using these with Orladeyo.
• Medicines broken down by CYP2D6 or CYP3A4, or carried by P-gp: Orladeyo can raise the levels of these medicines. If small changes in their levels could cause serious side effects, your doctor may monitor you closely or adjust the dose.
• Desogestrel (a birth control hormone): Orladeyo raises levels of etonogestrel (the active form of desogestrel), which may increase its side effects. Your doctor will weigh the benefits and risks of using them together.

Tell your doctor about all the medicines, vitamins, and supplements you take. This is not a complete list of interactions.

• Store at room temperature, 68°F to 77°F (20°C to 25°C). Short periods between 59°F and 86°F (15°C and 30°C) are OK.
• Each carton has a tamper-evident seal. Do not use Orladeyo if the seal is broken or missing.
• Keep out of reach of children.

BioCryst Pharmaceuticals, Inc., Durham, NC 27703.