treprostinil inhaled (Rx)

>10%

Cough (54%)

Headache (41%)

Throat irritation/pharyngolaryngeal pain (25%)

Nausea (19%)

Flushing (15%)

1-10%

Syncope (6%)

Postmarketing Reports

Angioedema

Contraindications

None

Cautions

Efficacy of treprostinil inhaled has not been established in patients with significant underlying lung disease (eg, asthma or chronic obstructive pulmonary disease); monitor patients with acute pulmonary infections to detect any worsening of lung disease and loss of drug effect

May produce symptomatic hypotension in patients with low systemic arterial pressure

Titrate slowly in patients with hepatic or renal insufficiency

Inhibits platelet aggregation and increases the risk of bleeding

Bronchospasm

• As with other inhaled prostaglandins, therapy may cause acute bronchospasm
• Patients with asthma or chronic obstructive pulmonary disease (COPD), or other bronchial hyperreactivity, are at increased risk for bronchospasm
• Ensure that such patients are treated optimally for reactive airway disease prior to and during treatment

Drug interaction overview

• Oral treprostinil is a CYP2C8 substrate
• It is unclear if systemic exposure of treprostinil by the inhalation route are altered by inhibitors or inducers of CYP2C8

Pregnancy

Limited case reports of treprostinil insufficient to inform a drug-associated risk of adverse developmental outcomes; however, there are risks to mother and fetus associated with pulmonary arterial hypertension associated with an increased risk of maternal and fetal mortality; in animal studies, no adverse reproductive and developmental effects observed

Animal data

• Animal reproductive studies have shown an adverse effect on fetus; in rats, administration to pregnant rats during period of organogenesis at doses greater than or equal to 10 mg/kg/day (approximately 15 times the human exposure at the dose of 3.5 mg BID on an AUC basis) resulted in decreased pregnancy rate, increased post-implantation loss, and decreased fetal viability and growth
• In rabbits, teratogenicity and decreased fetal viability and growth were observed at doses greater than or equal to 1.5 mg/kg/day (approximately 7 times the human exposure at dose of 3.5 mg BID on an AUC basis)

Clinical considerations

• Pulmonary arterial hypertension is associated with an increased risk of maternal and fetal mortality

Lactation

Data are not available regarding presence in human milk, effects on breastfed infants, or effects on milk production

Pregnancy Categories

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

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Prostacyclin analog; elicits direct vasodilation of both pulmonary and systemic arterial vascular beds; decreases ventricular afterload; also inhibits platelet aggregation

Absorption

Bioavailability: ~64% (18 mcg inhalation); ~72% (36 mcg inhalation)

Peak plasma concentration: 0.91-1.3 ng/mL (54 mcg inhalation)

Peak plasma time: 0.12-0.25 hr (54 mcg inhalation)

AUC: 0.81-0.97 ng·hr/mL (54 mcg inhalation)

Distribution

Protein bound: 91%

Vd: 14 L/70 kg IBW (parenteral infusion)

Metabolism

Substantially metabolized by the liver, primarily by CYP2C8

Elimination

Half-life (SC): 4 hr

Excretion (SC): Urine 79%; feces 13%

Incompatibilities

Solution or dry powder for inhalation

• Do not mix with other medications in the inhalation system
• Compatibility with other medications has not been studied

Oral Inhalation Preparation

Solution for inhalation

• Only use with Tyvaso Inhalation System, which consists of an ultrasonic, pulsed delivery device and its accessories
• Follow instructions for operating inhalation system and for device cleaning after last daily treatment session
• Avoid potential interruptions in drug delivery because of equipment malfunction, by having a back-up inhalation system device
• Prepare inhalation system for use each day according to instructions for use
• One ampule of treprostinil contains a sufficient volume of medication for all 4 treatment sessions/day
• Before first treatment session, twist the top off a single ampule and squeeze entire contents into medicine cup
• Between each treatment session, cap device and store upright with remaining medication inside
• At end of each day, discard medicine cup and any remaining medication

Oral Inhalation Administration

Solution for inhalation

• Avoid skin or eye contact; rinse with water if contact occurs
• Do not orally ingest
• Inhale orally via Tyvaso Inhalation System in 4 daily treatment session ~4 hr apart during waking hours
• Each session will take 2-3 minutes
• Missed dose: Take as soon as possible and adjust remainder of daily scheduled doses to be 4 hr apart

Dry powder for inhalation

• Administered using a single inhalation per cartridge
• Administer in 4 separate, equally spaced treatment sessions/day, during waking hours (~4 hr apart)
• Missed dose: Resume therapy as soon as possible at the usual dose
• Between each treatment session, store with mouthpiece attached and empty
• Wipe outside of inhaler with clean, dry cloth only, if needed
• Do not rinse or wash; always keep inhaler dry
• After 7 days of use, throw away used inhaler into regular household trash

Storage

Solution for inhalation

• Store ampules in foil packs at 25ºC (77ºF); excursions are permitted between 15-30ºC (59-86ºF); protect from light
• Once foil pack is opened, ampules should be used within 7 days
• Following transfer of solution to inhalation device, solution should remain in device for ≤24 hr; discard unused portion

Dry powder for inhalation

• If refrigerated, cartridges and inhaler should be at room temperature for 10 minutes before use

• Inhaler

  • Store at 2-25ºC (36-77ºF); excursions permitted
  • Can be used for up to 7 days from the date of first use
  • After 7 days of use, discard inhaler and replaced with a new inhaler

• Unopened blister strip cartridges

  • Refrigerate at 2-8ºC (36-46ºF) until expiration date, OR
  • Use within 5 weeks at 20-25ºC (68-77ºF), excursions permitted to 15-30ºC (59-86ºF)

• Opened blister strip cartridges

  • Do not put blister strip back into refrigerator after being opened or stored at room temperature
  • Use within 3 days at 20-25ºC (68-77ºF), excursions permitted to 15-30ºC (59-86ºF)