Ensifentrine (Monograph)

Brand name: Ohtuvayre™
Drug class: Dual Phosphodiesterase Inhibitors

Medically reviewed by Drugs.com on Jan 10, 2025. Written by ASHP.

Introduction

Selective dual phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) inhibitor.

Uses for Ensifentrine

COPD

Maintenance treatment of COPD in adults. Not indicated for treatment of acute bronchospasm.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) publishes an annual guideline on COPD. Several drug classes are available for treatment of COPD including short-acting β-adrenergic agonists (SABA), long-acting β-adrenergic agonists (LABA), short-acting muscarinic antagonists (SAMA), long-acting muscarinic agonists (LAMA), methylxanthines, roflumilast, and mucolytic agents. Individualize choice of therapy based on patient- and drug-related factors.

Ensifentrine provides another alternative maintenance treatment for patients with COPD, but the drug has not yet been incorporated into clinical guidelines.

Ensifentrine Dosage and Administration

General

Pretreatment Screening

Prior to initiating treatment, carefully weigh risks and benefits of treatment in patients with a history of depression and/or suicidal thoughts/behavior.

Patient Monitoring

Monitor for paradoxical bronchospasm; treat immediately with short-acting bronchodilator and discontinue ensifentrine if paradoxical bronchospasm occurs.
Monitor for new onset or worsening depression and/or suicidal thoughts/behavior. Carefully evaluate the risks and benefits of continuing treatment with ensifentrine if such events occur.

Administration

Administer by oral inhalation via standard jet nebulizer. Do not inject or swallow.

Administer twice daily, once in the morning and once in the evening.

Remove unit-dose ampule from foil pouch immediately before use and shake vigorously to ensure complete resuspension of the active ingredient.

Squeeze and completely empty contents of ampule into nebulizer cap for administration by oral inhalation; discard ampule with any remaining content.

Do not mix with other drugs or add to solutions containing other drugs.

Dosage

Adults

COPD

Oral Inhalation

3 mg (one ampule) twice daily.

Special Populations

Hepatic Impairment

Use with caution. Manufacturer makes no dosage adjustment recommendations.

Renal Impairment

Dosage adjustment in patents with mild or moderate renal impairment not necessary; not studied in patients with severe renal impairment.

Geriatric Patients

Manufacturer makes no dosage adjustment recommendations.

Cautions for Ensifentrine

Contraindications

Known hypersensitivity to ensifentrine or any component of the product.

Warnings/Precautions

Acute Episodes of Bronchospasm

Do not use for relief of acute symptoms (i.e., as rescue therapy for the treatment of acute episodes of bronchospasm).

Treat acute symptoms with an inhaled, short-acting bronchodilator.

Paradoxical Bronchospasm

May produce paradoxical bronchospasm, which may be life threatening.

If paradoxical bronchospasm occurs, treat immediately with inhaled, short-acting bronchodilator. Discontinue ensifentrine.

Psychiatric Events Including Suicidality

Psychiatric adverse events, including suicide, have occurred.

Monitor patients for new onset or worsening depression and/or suicidal thoughts/behavior.

Specific Populations

Pregnancy

No available data on ensifentrine use in pregnant women.

Lactation

Not known whether ensifentrine is distributed into human milk. Effects of the drug on breast-fed infants or milk production also not known.

Females and Males of Reproductive Potential

In animal studies, decreased sperm counts, testicular atrophy/degeneration, and intraluminal germ cell debris in the epididymis observed. Effects were reversible after a 4-week ensifentrine-free period. No effects on female fertility observed.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No differences in safety or efficacy observed between geriatric patients ≥65 years of age and younger patients.

Hepatic Impairment

Use with caution in patients with hepatic impairment. Systemic exposure increased by 2.3-fold in this population compared with healthy patients.

Renal Impairment

No differences in safety or efficacy observed between patients with mild-moderate renal impairment and patients with normal renal function. Not evaluated in patients with severe renal impairment.

Common Adverse Effects

Most common adverse reactions (≥1%): back pain, hypertension, urinary tract infection, diarrhea.

Drug Interactions

Metabolized predominantly by CYP2C9, and to a lesser extent by CYP2D6.

Does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.

Does not inhibit breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), organic anion transporting polypeptides 1B1 (OATP1B1), OATP1B3, organic anion transporter 1 (OAT1), OAT3, organic cation transporter 2 (OCT2), multidrug and toxin extrusion protein (MATE1), or MATE2-K.

Substrate of BCRP but not substrate of P-gp, OATP1B1, or OATP1B3.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP2C9 inhibitors: Ensifentrine peak plasma concentrations and AUC were 1.4- and 1.6-fold higher following concomitant administration with fluconazole (a CYP2C9 inhibitor).

Ensifentrine Pharmacokinetics

Absorption

Bioavailability

Median time to achieve peak plasma concentrations is 0.6 to 1.5 hours after dosing.

Distribution

Extent

Approximately 90% of ensifentrine is delivered to the lung.

Plasma Protein Binding

90%.

Elimination

Metabolism

Present in plasma largely as unchanged drug (96 to 99%). Metabolized primarily by hydroxylation, O-demethylation, and conjugation. Also metabolized by CYP2C9 and CYP2D6.

Elimination Route

Excreted in feces. Urinary elimination negligible (<0.3% of the dose).

Half-life

Ranges from 10.6 to 12.6 hours.

Stability

Storage

Oral Inhalation

Inhalation Suspension

Store unit-dose ampules in the protective foil pouch at controlled room temperature (20-25°C). Protect from light and excessive heat; do not freeze.

Actions

Selective dual inhibitor of PDE3 and PDE4.
PDE3 hydrolyzes cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) present in airway smooth muscle, which mediates bronchial tone.
PDE4 hydrolyzes cAMP and is involved in inflammatory cell activation and migration and cystic fibrosis transmembrane conductance regulator stimulation in bronchial epithelial cells.
Dual inhibition of PDE3 and PDE4 has demonstrated more synergistic effects when compared to inhibition of PDE3 or PDE4 alone on contraction of airway smooth muscle and suppression of the inflammatory response.

Advice to Patients

Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Inform patients that ensifentrine is not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose. Advise patients to treat acute symptoms with an inhaled, short-acting β₂-agonist such as albuterol. Provide patients with such medicine and instruct them in how it should be used.
Instruct patients to seek medical attention immediately if they experience any of the following: decreasing effectiveness of inhaled, short-acting β₂-agonists; need for more inhalations than usual of inhaled, short-acting β₂-agonists; or significant decrease in lung function as outlined by the health care provider.
As with other inhaled medicines, ensifentrine can cause paradoxical bronchospasm. If paradoxical bronchospasm occurs, instruct patients to discontinue ensifentrine.
Advise patients, caregivers, and families to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider so that the risks and benefits of continuing treatment with ensifentrine may be considered.
Instruct patients that ensifentrine should only be administered via a standard jet nebulizer. Patients should be instructed not to inject or swallow ensifentrine. Patients should be instructed not to mix other medications with ensifentrine in a nebulizer.
Inform patients to use the contents of one ampule of ensifentrine orally inhaled twice daily, once in the morning and once in the evening. Instruct patients to vigorously shake the drug to ensure complete resuspension of the active ingredient immediately prior to use.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ensifentrine is available through specialty pharmacy distributors. Contact Verona Pathway Plus^TM at 833-372-8492 or consult the Verona Pathway Plus^TMAccess and Support website for specific ordering and availability information ([Web]).