ORZEYFUL Tablet Ref.[116888] Active ingredients: Oveporexton

5.1 Insomnia

In two pooled 12-week placebo-controlled phase 3 studies (Studies 1 and 2) [see Clinical Studies (14)] in patients with narcolepsy type 1, 60%, 55%, and 1% of patients in the ORZEYFUL 2 mg twice daily, ORZEYFUL 1 mg twice daily, and placebo groups, respectively, developed insomnia.

Prior to ORZEYFUL treatment initiation, inform patients about the risk of insomnia at initiation of treatment. If insomnia persists beyond 7 days and significantly impacts daytime functioning or quality of life, consider ORZEYFUL dosage reduction or discontinuation [see Adverse Reactions (6.1)].

5.2 Urinary Frequency and Urgency

ORZEYFUL may cause or worsen urinary frequency and urgency. In two pooled 12-week placebo-controlled phase 3 studies (Studies 1 and 2) [see Clinical Studies (14)] in patients with narcolepsy type 1:

• 58%, 53%, and 5% of patients in the ORZEYFUL 2 mg twice daily, ORZEYFUL 1 mg twice daily, and placebo groups, respectively, developed urinary frequency.
• 16%, 15%, and 1% of patients in the ORZEYFUL 2 mg twice daily, ORZEYFUL 1 mg twice daily, and placebo groups, respectively, developed urinary urgency.

These lower urinary tract symptoms are consistent with ORZEYFUL's mechanism of action through agonism of the orexin receptor 2 (OX2R) on central micturition pathways [see Clinical Pharmacology (12.1)].

Prior to initiation of ORZEYFUL treatment, inform patients about the risk of urinary frequency and urgency and screen patients for lower urinary tract symptoms. Monitor ORZEYFUL-treated patients with a history of overactive bladder for worsening urinary tract symptom.

5.3 Creatine Phosphokinase Elevations

In two pooled 12-week placebo-controlled phase 3 studies (Studies 1 and 2) [see Clinical Studies (14)] in patients with narcolepsy type 1, asymptomatic creatine phosphokinase elevations >5x ULN were observed in 11% (21/196) of ORZEYFUL-treated patients and 5% (4/76) of placebo-treated patients. Two of these cases were characterized by markedly elevated CPK and transaminase levels; both patients discontinued treatment. None of the cases were associated with myoglobinuria or renal impairment.

Advise patients to report unexplained muscle pain, weakness, or dark urine, particularly when engaging in vigorous physical activity or taking concomitant drugs associated with myotoxicity.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of ORZEYFUL was evaluated in two 12-week placebo-controlled phase 3 studies (Studies 1 and 2) [see Clinical Studies (14)] in 196 ORZEYFUL-treated patients with narcolepsy type 1. Patients in the ORZEYFUL group received doses of 1 mg or 2 mg twice in the morning (the two doses were taken at least 3 hours apart with the second dose taken no later than 1 PM) for 12 weeks.

In these studies, the:

• Discontinuation rate due to an adverse reaction was 2.6% in ORZEYFUL-treated patients and 1.3% in placebo-treated patients.
• Most common adverse reactions (incidence ≥5% and greater than placebo) in ORZEYFUL-treated patients were insomnia, pollakiuria, micturition urgency, and salivary hypersecretion.

Table 1 describes the adverse reactions that occurred at a rate of ≥2% in ORZEYFUL-treated patients and more frequently than in placebo-treated patients in Studies 1 and 2.

Table 1. Adverse Reactions Reported in ≥2% of ORZEYFUL-Treated Patients and Greater than Rate of Placebo in Patients with Narcolepsy Type 1 (Studies 1 and 2):

^* The two ORZEYFUL doses were taken at least 3 hours apart with the second dose taken no later than 1 PM
^** Includes Insomnia, Middle Insomnia, and Initial Insomnia

Insomnia

In Studies 1 and 2, insomnia occurred in 58% of ORZEYFUL-treated patients and severe insomnia occurred in 1.5% of ORZEYFUL-treated patients. Regarding the insomnia events in ORZEYFUL-treated patients:

• Approximately 90% started within the first 2 days of therapy initiation, and 4% began between days 2 and 7 of therapy initiation.
• Approximately 63% resolved within 1 week of onset, and approximately 17% were ongoing at study completion.
• None led to study discontinuation or were classified as serious adverse reactions.

Urinary Adverse Reactions

In Studies 1 and 2, urinary adverse reactions occurred in 63% of ORZEYFUL-treated patients and severe urinary adverse reactions occurred in 1% of ORZEYFUL-treated patients. Two ORZEYFUL-treated patients discontinued treatment, one due to frequent urination and the other due to urinary incontinence.

Vital Sign Changes

In Studies 1 and 2, increases of in-clinic blood pressure (BP) and heart rate (HR) were noted on day 1 with higher frequency in ORZEYFUL-treated patients compared to placebo-treated patients. Increases in systolic and diastolic BP (>20 mm Hg) occurred in 22% and 9% of ORZEYFUL-treated patients and 13% and 7% of placebo-treated patients, respectively and increases in HR (>15 bpm) occurred in 30% of ORZEYFUL-treated patients and 22% of placebo-treated patients. The placebo adjusted mean changes in BP and HR from baseline in ORZEYFUL-treated patients were <5 mm Hg and <2 bpm by Week 12, respectively.

No significant differences in BP or HR were observed at Week 10 compared to baseline with 24-hour ambulatory blood pressure and heart rate monitoring.

Low-Density Lipoprotein Cholesterol Elevations

In Studies 1 and 2 [see Clinical Studies (14)], LDL values >160 mg/dL were observed in 32% (62/196) of ORZEYFUL-treated patients and 20% (15/76) of placebo-treated patients. Mean (SD) LDL changes from baseline to Week 12 were +17.6 (21.9) mg/dL and +4.4 (17.5) mg/dL for the pooled ORZEYFUL treatment group (1 mg and 2 mg twice daily combined groups) and the placebo group, respectively.

Table 2 describes drug interactions where concomitant use of another drug affects the use of ORZEYFUL.

Table 2. Concomitant Use of Other Drugs that Affect the Use of ORZEYFUL:

Prevention or Management Reduce the ORZEYFUL dosage to 0.5 mg two times daily with concomitant use of
ORZEYFUL with moderate CYP3A inhibitors [see Dosage and Administration (2.3)].
|\2< Strong and Moderate CYP3A Inducers |
|Mechanism and Clinical
Effect(s) |Concomitant use of ORZEYFUL with strong or moderate CYP3A inducers can increase
oveporexton metabolism and decrease plasma levels of oveporexton, which may
decrease the effectiveness of ORZEYFUL [see Clinical Pharmacology (12.3)]. |
|Prevention or Management |Avoid concomitant use with strong or moderate CYP3A inducers.|

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women who are exposed to ORZEYFUL during pregnancy. Patients should be encouraged to enroll in the ORZEYFUL pregnancy registry if they become pregnant. To enroll or obtain information from the registry, patients can call 1-877-371-0309.

Risk Summary

Available data from clinical trials with ORZEYFUL use during pregnancy are insufficient to identify a drug associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Animal reproduction studies did not show evidence of embryofetal toxicity or effects on pre- and post-natal development (see Data).

The background risk of major birth defects and miscarriage in adults with narcolepsy type 1 is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Oveporexton was administered orally to pregnant rats during the period of organogenesis at 10, 100, and 750 mg/kg/day (approximately 118, 346, and 1166 times, respectively, the maximum recommended human dose (MRHD) based on AUC). No adverse embryofetal effects were observed up to 750 mg/kg/day.

Maternal toxicity of decreased body weight/gain, which correlated with decreased food consumption, was observed at 750 mg/kg/day (approximately 1166 times the MRHD based on AUC). Placental transfer of oveporexton was observed in pregnant rats.

Oveporexton was administered orally to pregnant rabbits during the period of organogenesis at 4, 20, and 100 mg/kg/day (approximately 11, 38, and 153 times, respectively the MRHD based on AUC). No adverse embryofetal effects were observed up to 100 mg/kg/day. Maternal toxicity of decreased body weight/gain, which correlated with decreased food consumption, was observed at 100 mg/kg/day (approximately 153 times the MRHD based on AUC).

In a pre- and postnatal development study, oveporexton was administered orally to pregnant rats from gestation day 7 through lactation day 20 at 1, 3, and 10 mg/kg/day (up to approximately 118 times the MRHD based on AUC). No adverse effects were observed up to 10 mg/kg/day.

Risk Summary

There are no data available on the presence of oveporexton in human milk, the effects on the breastfed infant, or the effects on milk production. Animal studies indicate that oveporexton was present in the milk of lactating rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ORZEYFUL and any potential adverse effects on the breastfed infant from ORZEYFUL or from the underlying maternal condition.

Data

Animal Data

Following administration of a single dose of radiolabeled oveporexton (100 mg/kg) in lactating rats, oveporexton was detected in milk.

The safety and effectiveness of ORZEYFUL in pediatric patients have not been established.

In Studies 1 and 2 [see Clinical Studies (14)], 1 (<1%) ORZEYFUL-treated patient was 65 years of age or older. Clinical studies of ORZEYFUL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger adult patients [see Clinical Pharmacology (12.3)].

Avoid use of ORZEYFUL in patients with severe renal impairment (RI) on dialysis (eGFR<15 mL/minute) as it has not been studied in this population [see Clinical Pharmacology (12.3)].

The recommended ORZEYFUL dosage in patients with mild RI (estimated glomerular filtration rate (eGFR) ≥60 to <90 mL/minute), moderate RI (eGFR 30 to <60 mL/minute), or severe RI not requiring dialysis (eGFR ≥15 to <30 mL/minute) is the same in those with normal kidney function [see Clinical Pharmacology (12.3)].

Avoid use of ORZEYFUL in patients with severe hepatic impairment (HI) (Child-Pugh C) as it has not been studied in this population [see Clinical Pharmacology (12.3)].

The recommended ORZEYFUL dosage in patients with mild HI or moderate HI (Child-Pugh A or B, respectively) is the same in those with normal hepatic function [see Clinical Pharmacology (12.3)].

ORZEYFUL contains oveporexton. (Controlled substance schedule to be determined after review by the Drug Enforcement Administration.)

ORZEYFUL has potential for abuse. Abuse of ORZEYFUL may lead to substance use disorder, including addiction. Drug abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

ORZEYFUL can also be misused. Drug misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Misuse, like abuse, is often associated with higher doses and/or more frequent use of the drug, which may lead to adverse reactions similar to those seen in the context of abuse and addiction.

Human Abuse Potential Study

The abuse potential of ORZEYFUL 6 mg, 18 mg, and 30 mg (1.5, 4.5 and 7.5 times the maximum recommended daily dose, respectively) was assessed relative to phentermine 75 mg, (a Schedule IV controlled substance) in a human abuse potential study in individuals experienced with the recreational use of CNS stimulants. Results from this clinical study demonstrated that ORZEYFUL produced Drug Liking scores greater than that of placebo and similar to or lower than phentermine.

In this crossover study, euphoria was not reported in placebo-treated patients, and was reported in 0 to 4.2% of ORZEYFUL-treated patients and 4.1% of phentermine treated patients. "Feeling jittery" was reported in 0% of placebo-treated patients, 0 to 2% of ORZEYFUL-treated patients and 0% of phentermine-treated patients.

Recommendations to Reduce the Risk of Abuse and Monitor for Abuse

Health care providers should carefully evaluate patients for a recent history of drug abuse, especially those with a history of CNS stimulant (e.g., methylphenidate, amphetamine, or cocaine) and follow such patients closely, observing them for signs of misuse or abuse of ORZEYFUL (e.g., incrementation of doses, drug-seeking behavior).

Physical dependence of ORZEYFUL was evaluated in clinical studies. The 277 patients that completed or discontinued treatment in repeat-dose studies were monitored for post-treatment adverse reactions and there was limited evidence of withdrawal-related adverse events upon ORZEYFUL discontinuation to indicate physical dependence.