Orzeyful

Orzeyful is used to treat narcolepsy type 1 (narcolepsy with cataplexy) in adults. Narcolepsy type 1 (NT1) is a chronic neurological disease caused by the loss of orexin, a brain chemical that helps keep you awake. People with NT1 can have excessive daytime sleepiness, cataplexy (a sudden, temporary loss of muscle tone), cognitive symptoms, and disrupted nighttime sleep.

Orzeyful (oveporexton) is an orexin receptor 2 (OX2R) agonist. It works by stimulating OX2R to help restore the orexin signaling that is missing in narcolepsy type 1. By activating these receptors, Orzeyful promotes wakefulness and reduces cataplexy, helping with both daytime and nighttime symptoms.

Orzeyful (oveporexton) received FDA approval on August 5, 2026. It is the first orexin receptor 2 (OX2R) agonist approved for narcolepsy type 1 and is taken as two oral doses in the morning.

Orzeyful is not yet available to fill. Its controlled substance classification is still under review by the U.S. Drug Enforcement Administration (DEA), and the drug cannot be supplied until the DEA assigns a schedule. Pending that decision, Orzeyful is expected to become available by November 2026 through a specialty pharmacy.

Do not take Orzeyful if you take a strong CYP3A inhibitor, such as itraconazole or ketoconazole, which can raise Orzeyful to unsafe levels in your body.

Orzeyful can cause or worsen insomnia and can cause urinary frequency and urgency. It can also raise a muscle enzyme called creatine phosphokinase (CPK) and may increase LDL ("bad") cholesterol. Tell your healthcare provider right away about trouble sleeping that does not improve, new or worsening bladder symptoms, or unexplained muscle pain, weakness, or dark urine.

Orzeyful (oveporexton) has the potential for abuse and misuse. Its controlled substance schedule will be determined by the DEA. Tell your healthcare provider if you have ever misused or been addicted to alcohol, prescription medicines, or street drugs.

• Take Orzeyful exactly as your healthcare provider tells you to.
• Take Orzeyful as two doses in the morning, at about the same time each day.
• The recommended dose is either 1 mg after waking followed by another 1 mg three to five hours later, or 2 mg after waking followed by another 2 mg three to five hours later. The maximum total dose is 4 mg per day. In the studies, the second dose was taken no later than early afternoon.
• Swallow Orzeyful tablets whole with water. Do not split, crush, or chew them.
• You can take Orzeyful with or without food.
• If you take a moderate CYP3A inhibitor, your provider will lower your dose (to 0.5 mg after waking and 0.5 mg three to five hours later, up to 1 mg per day).
• If you miss a dose, skip it and take your next dose at the regular time. Do not take two doses at the same time.

If you take too much Orzeyful, there is no specific antidote; treatment is supportive. Contact the Poison Help line (1-800-222-1222) or seek medical care.

Avoid taking Orzeyful with a strong CYP3A inhibitor, because this combination is not allowed. Also avoid strong and moderate CYP3A inducers, which can make Orzeyful less effective. Do not start any new prescription medicine, over-the-counter medicine, or supplement without first checking with your healthcare provider or pharmacist.

Orzeyful is broken down in the body by an enzyme called CYP3A, so medicines that affect CYP3A can change how much Orzeyful is in your body:

• Strong CYP3A inhibitors (for example, itraconazole) raise Orzeyful levels significantly and must not be taken with Orzeyful.
• Moderate CYP3A inhibitors (for example, fluconazole) also raise Orzeyful levels. If you need one, your provider will reduce your Orzeyful dose.
• Strong or moderate CYP3A inducers (for example, phenytoin) lower Orzeyful levels and can make it less effective, so this combination should be avoided.

Ask your healthcare provider or pharmacist if you are not sure whether a medicine you take affects CYP3A. Keep a list of all your medicines to show your healthcare provider and pharmacist.

Do not take Orzeyful if you are taking a strong CYP3A inhibitor.

Before taking Orzeyful, tell your healthcare provider about all of your medical conditions, including if you:

• have liver problems. Orzeyful has not been studied in severe liver impairment (Child-Pugh C) and should be avoided in this group
• have kidney problems. Orzeyful has not been studied in severe kidney impairment requiring dialysis (eGFR less than 15 mL/minute) and should be avoided in this group
• have bladder problems or a history of overactive bladder, as Orzeyful may cause or worsen urinary frequency and urgency
• have ever misused or been dependent on alcohol, prescription medicines, or street drugs, especially stimulants
• are pregnant or plan to become pregnant. There is not enough information to know whether Orzeyful is safe to use during pregnancy. A pregnancy exposure registry monitors outcomes in people who take Orzeyful while pregnant; to enroll or get information, call 1-877-371-0309
• are breastfeeding or plan to breastfeed. It is not known whether Orzeyful passes into human milk; it was found in the milk of animals. Talk with your healthcare provider about the best way to feed your baby during treatment.

The safety and effectiveness of Orzeyful in children have not been established. Clinical studies did not include enough patients aged 65 and older to know whether they respond differently from younger adults.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements, because some can interact with Orzeyful.

Warnings and important risks

Orzeyful may cause:

• Insomnia (trouble sleeping). Insomnia was common in clinical studies. It usually began within the first few days of treatment and often eased within a week, though it sometimes continued. In the studies, insomnia events did not lead anyone to stop treatment and were not classified as serious. If insomnia lasts more than 7 days and significantly affects your daytime functioning or quality of life, your healthcare provider may lower your dose or stop treatment.
• Urinary frequency and urgency. Orzeyful may cause or worsen a frequent or urgent need to urinate. Your healthcare provider should check for bladder symptoms before you start and monitor you during treatment, especially if you have a history of overactive bladder.
• Creatine phosphokinase (CPK) elevations. Orzeyful can raise this muscle enzyme in the blood. Tell your healthcare provider about unexplained muscle pain, weakness, or dark urine, particularly with vigorous physical activity or when taking other medicines that can affect the muscles.
• Increased LDL cholesterol. In studies, more people taking Orzeyful had raised LDL ("bad") cholesterol than those taking placebo. Your healthcare provider may check your cholesterol during treatment.

Common side effects

The most common side effects of Orzeyful are:

• trouble sleeping (insomnia)
• frequent urination
• urgent need to urinate
• increased saliva

Other side effects reported more often than with placebo included influenza, sinus infection (sinusitis), abdominal pain, sore throat, tingling (paresthesia), and rash. Small increases in blood pressure and heart rate were also seen on the first day of treatment and generally settled over time.

Tell your healthcare provider about any side effects that bother you or that do not go away. These are not all the possible side effects of Orzeyful. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Orzeyful was studied in two 12-week, randomized, double-blind, placebo-controlled Phase 3 trials in adults with narcolepsy type 1: Study 1 (NCT06470828) and Study 2 (NCT06505031), also known as the FirstLight and RadiantLight studies. Study 1 included 168 patients and Study 2 included 105 patients.

The main measure was how long people could stay awake during the day on the Maintenance of Wakefulness Test (MWT). At the start of the studies, patients could stay awake only about 4 to 5 minutes on average. After 12 weeks, people taking Orzeyful were able to stay awake far longer, on the order of 12 to 19 additional minutes on average, while those taking placebo did not improve.

People taking Orzeyful also had statistically significant improvements compared with placebo in daytime sleepiness (measured by the Epworth Sleepiness Scale), in how often they had cataplexy (roughly 60% to 75% fewer weekly cataplexy episodes than placebo), and in their overall impression of how their narcolepsy symptoms had changed. Both the 1 mg and 2 mg twice-daily doses were more effective than placebo.

For Orzeyful to work best, take it exactly as your healthcare provider tells you.

Store Orzeyful at room temperature, 68°F to 77°F (20°C to 25°C). Brief exposure to 59°F to 86°F (15°C to 30°C) is permitted. Keep Orzeyful and all medicines out of the reach of children and pets.

Active ingredient: oveporexton

Inactive ingredients: hydroxypropyl cellulose, magnesium stearate, mannitol, microcrystalline cellulose, and sodium starch glycolate (type A). The tablet coating contains calcium carbonate, ferric oxide red, ferric oxide yellow, hypromellose 2910, and polyethylene glycol 8000.