ensifentrine inhaled (Rx)

1-10%

Back pain (1.8%)

Hypertension (1.7%)

Urinary tract infection (1.3%)

Diarrhea (1%)

<1%

Insomnia (0.6%)

Depression (0.4%)

Anxiety (0.2%)

Contraindications

Hypersensitivity to ensifentrine or any product component

Cautions

Acute bronchospasm

• Do not use for relief of acute symptoms (ie, as rescue treatment of acute episodes of bronchospasm)
• Safety and effectiveness have not been established for relief of acute symptoms and extra doses should not be used for that purpose
• Treat acute symptoms with an inhaled, short-acting bronchodilator

• Instruct patients to seek medical attention immediately if they experience any of the following

  • Decreasing effectiveness of inhaled, short-acting beta2-agonists
  • Need for more inhalations than usual of inhaled, short-acting beta2-agonists
  • Significant decrease in lung function as outlined by health care provider

Paradoxical bronchospasm

• May produce paradoxical bronchospasm, which may be life threatening
• If paradoxical bronchospasm occurs following dosing, immediately treat with an inhaled, short-acting bronchodilator
• Discontinued ensifentrine immediately and initiate alternant therapy

Psychiatric events including suicidality

• Associated with increased risk for psychiatric adverse reactions
• Psychiatric events, including suicide-related adverse reactions, were reported in clinical studies
• Before initiating treatment, healthcare providers should carefully weigh risk and benefits of treatment in patients with history of depression and/or suicidal thoughts or behavior
• Evaluate risks and benefits of continuing treatment if such events occur; advise patients, caregivers, and families to be alert for emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes
• Instruct patients/caregivers that it such changes occur to contact their healthcare provider so that risks and benefits of continuing treatment may be considered

Pregnancy

Data are not available regarding use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes

Animal studies

• Inhaled administration at exposures 30 times the exposure at the maximum recommended human daily inhalation dose (MRHDID) to male rats for 10 weeks before mating with untreated females produced increased pre- and post- implantation loss, and decreased live embryos in untreated female rats
• No adverse developmental effects were observed in pregnant rats and rabbits during organogenesis at maternal exposures up to 79 and 9 times the exposure at MRHDID, respectively
• No adverse developmental effects were to pregnant rats from organogenesis through lactation at exposures up to ~79 times the MRHDID

Lactation

Data are unavailable regarding presence in human milk, effects on breastfed children, or effects on milk production

There are no data from animal studies on presence in milk

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

Mechanism of Action

Dual inhibitor of phosphodiesterase-3 (PDE-3) and PDE-4 enzymes

PDE-3 primarily hydrolyzes second-messenger molecule cyclic adenosine monophosphate (cAMP), but is also capable of hydrolyzing cyclic guanosine monophosphate (cGMP)

PDE-4 hydrolyzes cAMP only

Inhibition results in accumulation of intracellular levels of cAMP and/or cGMP, resulting in various downstream signaling effects

Absorption

Peak plasma concentration: ~0.6-1.5 hr

Steady-state achieved by Day 3

Distribution

Protein bound: ~90%

Vd, central

• Patients with COPD: 8,150 L
• Healthy volunteers: 2,700 L

Vd, peripheral

• Patients with COPD: 5,490 L
• Healthy volunteers: 1,820 L

Metabolism

Primary metabolic routes are oxidative (hydroxylation, O-demethylation) followed by conjugation (eg, glucuronidation)

In vitro results indicate that, at physiologically relevant concentrations, ensifentrine was predominantly metabolized by CYP2C9 and to a lesser extent by CYP2D6

Elimination

Half-life: 10.6-12.6 hr

Excretion: Feces (majority); urine (<0.3%)

Compatibility

Compatibility of ensifentrine with other drugs has not been established

Do not physically mix with other drugs or solutions

Inhaled Administration

Remove unit-dose ampule from foil pouch immediately before use

Vigorously shake ampule

Squeeze and completely empty ampule contents into nebulizer cup

Discard ampule with any residual content

Administer by oral inhalation using a standard jet nebulizer equipped with a mouthpiece, connected to an air compressor

Storage

Store in protective foil pouch at 68-77ºF (20-25ºC), excursions permitted from 59-86ºF (15-30ºC), maintaining package orientation indicated on carton

Protect from direct sunlight and excessive heat

Do not freeze