Ohtuvayre
(Ensifentrine)Dosage & Administration
The recommended dosage of OHTUVAYRE is 3 mg (one unit-dose ampule) twice daily, once in the morning and once in the evening, administered by oral inhalation using a standard jet nebulizer with a mouthpiece.
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Ohtuvayre Prescribing Information
OHTUVAYRE is indicated for the maintenance treatment of chronic obstructive pulmonary disease (COPD) in adult patients.
The recommended dosage of OHTUVAYRE is 3 mg (one unit-dose ampule) twice daily, once in the morning and once in the evening, administered by oral inhalation using a standard jet nebulizer with a mouthpiece.
Inhalation suspension: 3 mg/2.5 mL (1.2 mg/mL) of sterile, yellow to pale yellow, aqueous suspension in low-density polyethylene unit-dose ampules.
Hepatic impairment: Ensifentrine exposure increases in patients with hepatic impairment. Use with caution. (
Ensifentrine systemic exposure increased by 2.3-fold in subjects with moderate or severe hepatic impairment compared with healthy subjects
Exposure to ensifentrine increased approximately 1.4-fold greater than dose proportional following a dose 3 times the recommended dosage. Steady-state was attained by Day 3 following twice-daily dosing. Population pharmacokinetic analysis predicts accumulation of ensifentrine of 1.3 and 1.4-fold for Cmaxand AUC in healthy subjects and 1.4 and 1.5-fold for Cmaxand AUC in subjects with COPD. Population pharmacokinetic analysis indicates that relative bioavailability in subjects with COPD is approximately 35% lower when compared to healthy subjects. Exposure to ensifentrine was associated with high inter-subject variability.
Following inhaled administration of OHTUVAYRE in healthy subjects and subjects with COPD, ensifentrine Cmaxwas attained around 0.6 to 1.5 hours after dosing.
A randomized, 2-period, cross-over study assessing systemic exposure following inhalation of 2 times the recommended dose of ensifentrine with and without charcoal block demonstrated that the majority of an inhaled dose (approximately 90%) is delivered to the lung from which it is absorbed.
Apparent central and peripheral volume of distribution for ensifentrine in healthy subjects were 2700 L and 1820 L, respectively, as estimated in population PK analysis. In patients with COPD, apparent central and peripheral volumes were estimated as 8150 L and 5490 L, respectively.
In vitro plasma protein binding of ensifentrine is approximately 90%.
Following twice-daily administration for 6 days, terminal elimination half-life ranged from 10.6 to 12.6 hours in healthy subjects and subjects with COPD (1.5 mg to 12 mg twice daily).
Following administration of a single nebulized dose, 8 times the recommended dose of ensifentrine, unchanged ensifentrine was identified as the major drug-related component in human plasma, accounting for 96 and 99% of the drug-related material identified in Tmaxand time-normalized (0-24 h) plasma samples, respectively.
The primary metabolic routes for ensifentrine are oxidative (hydroxylation, O-demethylation) followed by conjugation (e.g., glucuronidation).
In vitro results indicate that, at physiologically relevant concentrations, ensifentrine was predominantly metabolized by CYP2C9 and to a lesser extent by CYP2D6.
The majority of ensifentrine is excreted in feces. After a 3 mg nebulized dose, urinary elimination of unchanged ensifentrine was negligible (<0.3% of the dose).
Population pharmacokinetic analysis showed no evidence of a clinically significant effect of demographic covariates such as age (18 to 80 years), sex (56% male), ethnicity (Hispanic, Non-Hispanic), race (white, black) and weight (42 to 180 kg) on ensifentrine pharmacokinetics.
A dedicated study with OHTUVAYRE evaluating the effect of renal impairment on the pharmacokinetics of ensifentrine was not conducted.
The effect of renal impairment on the exposure to ensifentrine for up to 24 weeks was evaluated in a population pharmacokinetic analysis. Estimated glomerular filtration rate (eGFR) varied from 25.5 to 191 mL/min representing a range of moderate to no renal impairment. While continuous covariates of renal function did not show a significant correlation with ensifentrine exposure, categorical characterization of renal function indicated a 25% mean reduction in the apparent clearance in subjects with moderate renal impairment. The pharmacokinetics of ensifentrine in severe renal impairment (creatine clearance <30 mL/min) or subjects with end-stage renal disease have not been evaluated.
The pharmacokinetics of ensifentrine were evaluated in subjects with moderate (Child-Pugh Class B) (N=10) to severe (Child-Pugh Class C) (N=2) hepatic impairment. Ensifentrine Cmaxand AUCinfwere approximately 2.3-fold and 2.2-fold higher in subjects with moderate hepatic impairment compared with healthy controls. Ensifentrine Cmaxand AUCinfwere approximately 1.2-fold and 2.3-fold higher in subjects with severe hepatic impairment compared with healthy controls (N=7).
Population PK analysis did not identify markers of liver function (ALT, AST, bilirubin, and ALP) as a significant covariate for exposure of ensifentrine.
OHTUVAYRE is contraindicated in patients with hypersensitivity to ensifentrine or any component of this product.
- Should not use OHTUVAYRE to treat acute symptoms of bronchospasm. ()
5.1 Acute Episodes of BronchospasmOHTUVAYRE should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. OHTUVAYRE has not been studied in the relief of acute symptoms and extra doses of OHTUVAYRE should not be used for that purpose. The safety and effectiveness of OHTUVAYRE for relief of acute symptoms have not been established. Acute symptoms should be treated with an inhaled, short-acting bronchodilator.
- If paradoxical bronchospasm occurs, discontinue OHTUVAYRE and institute alternative therapy. ()
5.2 Paradoxical BronchospasmAs with other inhaled medicines, OHTUVAYRE may produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with OHTUVAYRE, it should be treated immediately with an inhaled, short-acting bronchodilator. OHTUVAYRE should be discontinued immediately and alternative therapy should be instituted.
- An increase in psychiatric adverse reactions, including suicidality, were reported with use of OHTUVAYRE. Carefully weigh the risks and benefits of treatment with OHTUVAYRE in patients with a history of depression and/or suicidal thoughts or behavior. ()
5.3 Psychiatric Events Including SuicidalityTreatment with OHTUVAYRE is associated with an increase in psychiatric adverse reactions. Psychiatric events including suicide-related adverse reactions were reported in clinical studies in patients who received OHTUVAYRE. One patient who received OHTUVAYRE in the pooled 24-week safety population
[see Adverse Reactions (6.1)]experienced a suicide-related adverse reaction (suicide attempt), and in another controlled study, one patient who received ensifentrine experienced a suicide-related adverse reaction (suicide). Additionally, the most commonly reported psychiatric adverse reactions in the pooled 24-week safety population were insomnia (6 patients [0.6%] OHTUVAYRE 3 mg; 2 patients [0.3%] placebo), and anxiety (2 patients [0.2%] OHTUVAYRE 3 mg; 1 patient [0.2%] placebo). Depression-related reactions including depression, major depression, and adjustment disorder with depressed mood occurred in 4 patients [0.4%] receiving OHTUVAYRE and no patients receiving placebo.Before initiating treatment with OHTUVAYRE, healthcare providers should carefully weigh the risk and benefits of treatment with OHTUVAYRE in patients with a history of depression and/or suicidal thoughts or behavior. Healthcare providers should carefully evaluate the risks and benefits of continuing treatment with OHTUVAYRE if such events occur.