Tyvaso DPI: Package Insert and Label Information

TYVASO DPI- treprostinil inhalant
TYVASO DPI- treprostinil
United Therapeutics Corporation

1 INDICATIONS AND USAGE

1.1 Pulmonary Arterial Hypertension

Tyvaso DPI is indicated for the treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to improve exercise ability. Studies with Tyvaso establishing effectiveness predominately included patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%).

The effects diminish over the minimum recommended dosing interval of 4 hours; treatment timing can be adjusted for planned activities.

While there are long-term data on use of treprostinil by other routes of administration, nearly all clinical experience with inhaled treprostinil has been on a background of an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5) inhibitor. The controlled clinical experience with Tyvaso was limited to 12 weeks in duration [see Clinical Studies (14)].

1.2 Pulmonary Hypertension Associated with ILD

Tyvaso DPI is indicated for the treatment of pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO Group 3) to improve exercise ability. The study with Tyvaso establishing effectiveness predominately included patients with etiologies of idiopathic interstitial pneumonia (IIP) (45%) inclusive of idiopathic pulmonary fibrosis (IPF), combined pulmonary fibrosis and emphysema (CPFE) (25%), and WHO Group 3 connective tissue disease (22%) [see Clinical Studies (14.3)].

2 DOSAGE AND ADMINISTRATION

2.1 Administration

Use Tyvaso DPI only with the Tyvaso DPI Inhaler. Tyvaso DPI is administered using a single inhalation per cartridge. Administer Tyvaso DPI in 4 separate, equally spaced treatment sessions per day, during waking hours. The treatment sessions should be approximately 4 hours apart.

If the prescribed dose is higher than 64 mcg per treatment session, more than 1 cartridge will be needed per session. Patients should follow the instructions for use for operation and care of the Tyvaso DPI Inhaler.

Do not use the Tyvaso DPI Inhaler with other medications.

Between each of the 4 daily treatment sessions, store the Tyvaso DPI Inhaler with the mouthpiece attached and empty. Wipe the outside of the inhaler with a clean, dry cloth only, if needed. Do not rinse or wash the Tyvaso DPI Inhaler; always keep the inhaler dry. After 7 days of use, throw away the used Tyvaso DPI Inhaler into regular household trash.

2.2 Usual Dosage in Adults

Initial Dosage:

Tyvaso DPI therapy should begin with one 16 mcg cartridge per treatment session, 4 times daily.

Maintenance Dosage:

Increase dosage by an additional 16 mcg per treatment session at approximately 1- to 2-week intervals. The target maintenance dosage is usually 48 mcg to 64 mcg per session.

If adverse effects preclude titration, continue Tyvaso DPI at the highest tolerated dose.

If a scheduled treatment session is missed, resume therapy as soon as possible at the usual dose.

Dosage for Transition from Tyvaso® (treprostinil) Inhalation Solution:

The following regimens of Tyvaso DPI and Tyvaso give similar exposure:

Tyvaso DPI Cartridge Strength Tyvaso Number of Breaths
16 mcg ≤5 (≤30 mcg)
32 mcg 6 to 7 (36 to 42 mcg)
48 mcg 8 to 10 (48 to 60 mcg)
64 mcg 11 to 12 (66 to 72 mcg)

3 DOSAGE FORMS AND STRENGTHS

Inhalation powder: Single-dose plastic cartridges containing 16, 32, 48, or 64 mcg of treprostinil as a dry powder formulation.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Risk of Symptomatic Hypotension

Treprostinil is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure, treatment with Tyvaso DPI may produce symptomatic hypotension.

5.2 Risk of Bleeding

Tyvaso DPI inhibits platelet aggregation and increases the risk of bleeding.

5.3 Effect of Other Drugs on Treprostinil

Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g., gemfibrozil) may increase exposure (both Cmax and AUC) to treprostinil. Co-administration of a CYP2C8 enzyme inducer (e.g., rifampin) may decrease exposure to treprostinil. Increased exposure is likely to increase adverse events associated with treprostinil administration, whereas decreased exposure is likely to reduce clinical effectiveness [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

5.4 Bronchospasm

Like other inhaled prostaglandins, Tyvaso DPI 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 with Tyvaso DPI.

6 ADVERSE REACTIONS

The following potential adverse reactions are described in Warnings and Precautions (5):

Decrease in systemic blood pressure [see Warnings and Precautions (5.1)].
Bleeding [see Warnings and Precautions (5.2)].

6.1 Clinical Trials Experience

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.

Pulmonary Arterial Hypertension

Tyvaso DPI

In a 3-week, open-label, single-sequence, safety and tolerability study (BREEZE) conducted in 51 patients on stable doses of Tyvaso Inhalation Solution who switched to a corresponding dose of Tyvaso DPI, the most commonly reported adverse events on Tyvaso DPI during the 3-week treatment phase included cough, headache, dyspnea, and nausea. Patient tolerability, as assessed by incidence of new adverse events following transition to Tyvaso DPI, was consistent with the expected known safety profile of Tyvaso Inhalation Solution. Table 1 lists the adverse events that occurred at a rate of at least 4%.

Table 1: Adverse Events in ≥4% of PAH Patients Receiving Tyvaso DPI in BREEZE (Treatment Phase)
Adverse Event Tyvaso DPI (n=51) n (%)
Cough 18 (35.3)
Headache 8 (15.7)
Dyspnea 4 (7.8)
Nausea 3 (5.9)

The safety of Tyvaso DPI was also studied in an extension phase of the study in which 49 patients were dosed for a duration of 43 patient-years. Fifty-nine percent (59%) of patients achieved a dose of 64 mcg, 4 times daily or higher. The adverse events during this long-term, extension phase were similar to those observed in the 3-week treatment phase.

Tyvaso Inhalation Solution

In a 12-week, placebo-controlled study (TRIUMPH I) of 235 patients with PAH (WHO Group 1 and nearly all NYHA Functional Class III), the most commonly reported adverse reactions on Tyvaso Inhalation Solution included cough and throat irritation, headache, gastrointestinal effects, muscle, jaw or bone pain, dizziness, flushing, and syncope. Table 2 lists the adverse reactions that occurred at a rate of at least 4% and were more frequent in patients treated with Tyvaso Inhalation Solution than with placebo.

Table 2: Adverse Events in ≥4% of PAH Patients Receiving Tyvaso Inhalation Solution and More Frequent * than Placebo in TRIUMPH I
Adverse Event Treatment n (%)
Tyvaso Inhalation Solution n=115 Placebo n=120
*
More than 3% greater than placebo
Cough 62 (54) 35 (29)
Headache 47 (41) 27 (23)
Throat Irritation / Pharyngolaryngeal Pain 29 (25) 17 (14)
Nausea 22 (19) 13 (11)
Flushing 17 (15) 1 (<1)
Syncope 7 (6) 1 (<1)

Pulmonary Hypertension Associated with ILD

In a 16-week, placebo-controlled study (INCREASE) of 326 patients with PH-ILD (WHO Group 3), adverse reactions on Tyvaso Inhalation Solution were similar to the experience in studies of PAH.

7 DRUG INTERACTIONS

7.1 Bosentan

In a human pharmacokinetic study conducted with bosentan (250 mg/day) and an oral formulation of treprostinil (treprostinil diolamine), no pharmacokinetic interactions between treprostinil and bosentan were observed.

7.2 Sildenafil

In a human pharmacokinetic study conducted with sildenafil (60 mg/day) and an oral formulation of treprostinil (treprostinil diolamine), no pharmacokinetic interactions between treprostinil and sildenafil were observed.

7.3 Effect of Cytochrome P450 Inhibitors and Inducers

In vitro studies of human hepatic microsomes showed that treprostinil does not inhibit cytochrome P450 (CYP) isoenzymes CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A. Additionally, treprostinil does not induce cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A.

Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil diolamine) indicated that co-administration of the cytochrome P450 (CYP) 2C8 enzyme inhibitor, gemfibrozil, increases exposure (both Cmax and AUC) to treprostinil. Co-administration of the CYP2C8 enzyme inducer, rifampin, decreases exposure to treprostinil. It is unclear if the safety and efficacy of treprostinil by the inhalation route are altered by inhibitors or inducers of CYP2C8 [see Warnings and Precautions (5.3)].

7.4 Effect of Other Drugs on Treprostinil

Drug interaction studies have been carried out with treprostinil (oral or subcutaneous) co-administered with acetaminophen (4 g/day), warfarin (25 mg/day), and fluconazole (200 mg/day), respectively, in healthy volunteers. These studies did not show a clinically significant effect on the pharmacokinetics of treprostinil. Treprostinil does not affect the pharmacokinetics or pharmacodynamics of warfarin. The pharmacokinetics of R- and S- warfarin and the international normalized ratio (INR) in healthy subjects given a single 25 mg dose of warfarin were unaffected by continuous subcutaneous infusion of treprostinil at an infusion rate of 10 ng/kg/min.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Limited case reports of treprostinil use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. However, there are risks to the mother and the fetus associated with pulmonary arterial hypertension (see Clinical Considerations). In animal studies, no adverse reproductive and developmental effects were seen for treprostinil at ≥8 and ≥134 times the human exposure when based on Cmax and AUC, respectively, following a single, inhaled 64 mcg dose of treprostinil inhalation powder.

The estimated background risk of major birth defects and miscarriage for the indicated populations 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.

Clinical Considerations

Disease-associated maternal and embryo-fetal risk

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

Data

Animal reproduction studies have been conducted with treprostinil via continuous subcutaneous administration and with treprostinil diolamine administered orally. In studies with orally administered treprostinil diolamine, no adverse effect doses for fetal viability/growth, fetal development (teratogenicity), and postnatal development were determined in rats. In pregnant rats, no evidence of harm to the fetus was observed following oral administration of treprostinil diolamine at the highest dose tested (20 mg/kg/day), which represents about 129 and 1366 times the human exposure, when based on Cmax and AUC, respectively, following a single, inhaled 64 mcg dose of treprostinil inhalation powder. In pregnant rabbits, external fetal and soft tissue malformations and fetal skeletal malformation occurred. The dose at which no adverse effects were seen (0.5 mg/kg/day) represents about 8 and 134 times the human exposure, when based on Cmax and AUC, respectively, following a single, inhaled 64 mcg dose of treprostinil inhalation powder. No treprostinil treatment-related effects on labor and delivery were seen in animal studies. Animal reproduction studies are not always predictive of human response.

8.2 Lactation

Risk Summary

There are no data on the presence of treprostinil in human milk, the effects on the breastfed infant, or the effects on milk production.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Clinical studies of inhaled treprostinil did not include patients younger than 18 years to determine whether they respond differently from older patients.

8.5 Geriatric Use

Across clinical studies used to establish the effectiveness of Tyvaso Inhalation Solution in patients with PAH and PH-ILD, 268 (47.8%) patients aged 65 years and over were enrolled. The treatment effects and safety profile observed in geriatric patients were similar to younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of hepatic, renal, or cardiac dysfunction, and of concomitant diseases or other drug therapy.

8.6 Patients with Hepatic Insufficiency

Plasma clearance of treprostinil, delivered subcutaneously, was reduced up to 80% in subjects with mild-to-moderate hepatic insufficiency. Uptitrate slowly when treating patients with hepatic insufficiency because of the risk of an increase in systemic exposure which may lead to an increase in dose-dependent adverse effects. Treprostinil has not been studied in patients with severe hepatic insufficiency [see Clinical Pharmacology (12.3)].

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