Tyvaso DPI: Package Insert and Label Information (Page 2 of 4)

8.7 Patients with Renal Impairment

No dose adjustments are required in patients with renal impairment. Treprostinil is not cleared by dialysis [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

In general, symptoms of overdose with inhaled treprostinil include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Provide general supportive care until the symptoms of overdose have resolved.

11 DESCRIPTION

11.1 Tyvaso DPI Cartridges

Tyvaso DPI consists of single-dose plastic cartridges filled with a white powder containing 1% of treprostinil, a prostacyclin mimetic, which is intended for administration by oral inhalation using the Tyvaso DPI Inhaler only. Treprostinil is adsorbed onto carrier particles consisting of fumaryl diketopiperazine (FDKP). Each cartridge contains 16, 32, 48, or 64 mcg of treprostinil with approximate fill weights of 1.6, 3.2, 4.8, or 6.4 mg of Tyvaso DPI, respectively.

Treprostinil is (1R ,2R ,3aS ,9aS)-[[2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1H -benz[f ]inden-5-yl]oxy]acetic acid. Treprostinil has a molecular weight of 390.52 and a molecular formula of C23 H34 O5 .

The structural formula of treprostinil is:

Chemical Structure
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12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Treprostinil is a prostacyclin analogue. The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation.

12.2 Pharmacodynamics

In a clinical trial of 240 healthy volunteers, single doses of Tyvaso Inhalation Solution 54 mcg (the target maintenance dose per session) and 84 mcg (supratherapeutic inhalation dose) prolonged the corrected QTc interval by approximately 10 ms. The QTc effect dissipated as the concentration of treprostinil decreased.

12.3 Pharmacokinetics

Absorption

Treprostinil plasma exposure data were obtained from a 6-treatment, 6-period, 6-sequence, crossover study of Tyvaso DPI and Tyvaso Inhalation Solution in healthy volunteers. The mean Cmax for the 16, 48, and 64 mcg doses of Tyvaso DPI were 0.39, 1.11, and 1.33 ng/mL, respectively, with corresponding median Tmax of 0.17 hr. The mean AUC0-5hr for the 16, 48, and 64 mcg doses of Tyvaso DPI were 0.275, 0.774, and 0.964 hr∙ng/mL, respectively.

Treprostinil systemic exposure (AUC0-5hr and Cmax ) of Tyvaso DPI post-inhalation was approximately proportional to the doses administered (16 to 64 mcg).

Distribution

Following parenteral infusion, the steady state volume of distribution (Vss ) of treprostinil is approximately 14 L/70 kg ideal body weight.

In vitro treprostinil is 91% bound to human plasma proteins over the 330 to 10,000 mcg/L concentration range.

Elimination

With a single dose of Tyvaso DPI, the mean terminal half-life of treprostinil ranged from 27 to 50 minutes.

Metabolism: Treprostinil is substantially metabolized by the liver, primarily by CYP2C8. Metabolites are excreted in urine (79%) and feces (13%) over 10 days. Five apparently inactive metabolites were detected in the urine, each accounting for 10 to 15% of the dose administered. Four of the metabolites are products of oxidation of the 3-hydroxyloctyl side chain and one is a glucuroconjugated derivative (treprostinil glucuronide).

Excretion: Of subcutaneously administered treprostinil, only 4% is excreted unchanged in urine.

Specific Populations

Hepatic Insufficiency

Plasma clearance of treprostinil, delivered subcutaneously, was reduced up to 80% in subjects presenting with mild-to-moderate hepatic insufficiency. Treprostinil has not been studied in patients with severe hepatic insufficiency [see Use in Specific Populations (8.6)].

Renal Impairment

In patients with severe renal impairment requiring dialysis (n=8), administration of a single 1 mg dose of orally administered treprostinil pre- and post-dialysis resulted in AUC0-inf that was not significantly altered compared to healthy subjects [see Use in Specific Populations (8.7)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A 2-year rat carcinogenicity study was performed with treprostinil inhalation at target doses of 5.26, 10.6, and 34.1 mcg/kg/day. There was no evidence for carcinogenic potential associated with treprostinil inhalation in rats at systemic exposure levels up to 36 times the clinical exposure at the 64 mcg dose of treprostinil inhalation powder. In vitro and in vivo genetic toxicology studies did not demonstrate any mutagenic or clastogenic effects of treprostinil. Treprostinil sodium did not affect fertility or mating performance of male or female rats given continuous subcutaneous infusions at rates of up to 450 ng treprostinil/kg/min. In this study, males were dosed from 10 weeks prior to mating and through the 2-week mating period. Females were dosed from 2 weeks prior to mating until gestational day 6.

Oral administration of treprostinil diolamine to Tg.rasH2 mice at 0, 5, 10, and 20 mg/kg/day in males and 0, 3, 7.5, and 15 mg/kg/day in females daily for 26 weeks did not significantly increase the incidence of tumors.

Treprostinil diolamine was tested in vivo in a rat micronucleus assay and did not induce an increased incidence of micronucleated polychromatic erythrocytes.

13.2 Animal Toxicology and/or Pharmacology

In a 2-year rat study with treprostinil inhalation solution at target doses of 5.26, 10.6, and 34.1 mcg/kg/day, there were more deaths (11) in the mid- and high-dose treprostinil groups during the first 9 weeks of the study, compared to 1 in control groups. At the high-dose level, males showed a higher incidence of inflammation in teeth and preputial gland, and females showed higher incidences of inflammation and urothelial hyperplasia in the urinary bladder. The exposures in rats at mid- and high-dose levels were about 14 and 36 times, respectively, the clinical exposure at the 64 mcg dose of treprostinil inhalation powder.

14 CLINICAL STUDIES

14.1 Pulmonary Arterial Hypertension (WHO Group 1) (TRIUMPH I)

TRIUMPH I, was a 12-week, randomized, double-blind, placebo-controlled, multicenter study of patients with PAH (NCT00147199). The study population included 235 clinically stable subjects with PAH (WHO Group 1), nearly all with NYHA Class III (98%) symptoms who were receiving either bosentan (an endothelin receptor antagonist) or sildenafil (a phosphodiesterase-5 inhibitor) for at least 3 months prior to study initiation. Concomitant therapy also could have included anticoagulants, other vasodilators (e.g., calcium channel blockers), diuretics, oxygen, and digitalis, but not a prostacyclin. These patients were administered either placebo or Tyvaso Inhalation Solution in 4 daily treatment sessions with a target dose of 9 breaths (54 mcg) per session over the course of the 12-week study. Patients were predominately female (82%), had the origin of PAH as idiopathic/heritable (56%), secondary to connective tissue diseases (33%) or secondary to HIV or previous use of anorexigens (12%); bosentan was the concomitant oral medication in 70% of those enrolled, sildenafil in 30%.

The primary efficacy endpoint of the trial was the change in 6MWD relative to baseline at 12 weeks. 6MWD was measured at peak exposure (between 10 and 60 minutes after dosing), and 3 to 5 hours after bosentan or 0.5 to 2 hours after sildenafil. Patients receiving Tyvaso Inhalation Solution had a placebo-corrected median change from baseline in peak 6MWD of 20 meters at Week 12 (p<0.001). The distribution of these 6MWD changes from baseline at Week 12 were plotted across the range of observed values (Figure 1). 6MWD measured at trough exposure (defined as measurement of 6MWD at least 4 hours after dosing) improved by 14 meters. There were no placebo-controlled 6MWD assessments made after 12 weeks.

Figure 1: Distributions of 6MWD Changes from Baseline at Week 12 During Peak Plasma Concentration of Tyvaso Inhalation Solution

Figure 1
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The placebo-corrected median treatment effect on 6MWD was estimated (using the Hodges-Lehmann estimator) within various subpopulations defined by age quartile, gender, geographic region of the study site, disease etiology, baseline 6MWD quartile, and type of background therapy (Figure 2).

Figure 2: Placebo-Corrected Median Treatment Effect (Hodges-Lehmann Estimate with 95% CI) on 6MWD Change from Baseline at Week 12 During Peak Plasma Concentration of Tyvaso Inhalation Solution for Various Subgroups

Figure 2
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14.2 Long-term Treatment of PAH

In long-term follow-up of patients who were treated with Tyvaso Inhalation Solution in the pivotal study and the open-label extension (N=206) (NCT00147199), Kaplan-Meier estimates of survival at 1, 2, and 3 years were 97%, 91%, and 82%, respectively. These uncontrolled observations do not allow comparison with a control group not given Tyvaso Inhalation Solution and cannot be used to determine the long-term effect of Tyvaso Inhalation Solution on mortality.

14.3 Pulmonary Hypertension Associated with ILD (WHO Group 3)

INCREASE was a 16-week, randomized, double-blind, placebo-controlled, multicenter study that enrolled 326 patients with PH-ILD (NCT02630316). Enrolled study patients predominately had etiologies of idiopathic interstitial pneumonia (45%) inclusive of idiopathic pulmonary fibrosis, combined pulmonary fibrosis and emphysema (25%), and WHO Group 3 connective tissue disease (22%). The mean baseline 6MWD was 260 meters.

Patients in the INCREASE study were randomized (1:1) to either placebo or Tyvaso Inhalation Solution in 4 daily treatment sessions with a target dose of 9 breaths (54 mcg) per session and a maximum dose of 12 breaths (72 mcg) per session over the course of the 16-week study. Approximately 75% of patients randomized to Tyvaso Inhalation Solution titrated up to a dose of 9 breaths, 4 times daily or greater, with 48% of patients randomized to Tyvaso Inhalation Solution reaching a dose of 12 breaths, 4 times daily during the study.

The primary efficacy endpoint was the change in 6MWD measured at peak exposure (between 10 and 60 minutes after dosing) from baseline to Week 16. Patients receiving Tyvaso Inhalation Solution had a placebo-corrected median change from baseline in peak 6MWD of 21 meters at Week 16 (p=0.004) using Hodges-Lehmann estimate (Figure 3).

Figure 3: Hodges-Lehmann Estimate of Treatment Effect by Visit for 6MWD at Peak Exposure of Tyvaso Inhalation Solution (PH-ILD)

Figure 3
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The treatment effect on 6MWD at Week 16 was consistent for various subgroups, including etiology of PH-ILD, disease severity, age, sex, baseline hemodynamics, and dose (Figure 4).

Figure 4: Forest Plot on Subgroup Analyses of Peak 6MWD (Meter) at Week 16 (PH-ILD)

Figure 4
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Time to clinical worsening in the INCREASE study was defined as the time of randomization until 1 of the following criteria were met: hospitalization due to a cardiopulmonary indication, decrease in 6MWD >15% from baseline directly related to PH-ILD at 2 consecutive visits and at least 24 hours apart, death (all causes), or lung transplantation. Treatment with Tyvaso Inhalation Solution in patients with PH-ILD resulted in numerically fewer hospitalizations. The numbers of reported deaths were the same for both treatment groups (Table 3). Overall, treatment with Tyvaso Inhalation Solution demonstrated a statistically significant increase in the time to first clinical worsening event (log-rank test p=0.041; Figure 5), and a 39% overall reduction in the risk of a clinical worsening event (HR=0.61 [95% CI; 0.40, 0.92]; Figure 5).

Table 3: Clinical Worsening Events (PH-ILD)
Tyvaso Inhalation Solution n=163 n (%)Placebo n=163 n (%)HR (95% CI)
Clinical worsening 37 (22.7%)54 (33.1%)0.61 (0.40, 0.92)
First contributing event Hospitalization due to a cardiopulmonary indication 18 (11.0%)24 (14.7%)
Decrease in 6MWD >15% from baseline directly related to PH-ILD 13 (8.0%)26 (16.0%)
Death (all causes) 4 (2.5%)4 (2.5%)
Lung transplantation 2 (1.2%)0
First of each event Hospitalization due to a cardiopulmonary indication 21 (12.9%)30 (18.4%)
Decrease in 6MWD >15% from baseline directly related to PH-ILD 16 (9.8%)31 (19.0%)
Death (all causes) 8 (4.9%)10 (6.1%)
Lung transplantation 2 (1.2%)1 (0.6%)

Figure 5: Kaplan-Meier Plot of Time to Clinical Worsening Events (PH-ILD)

Figure 5
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16 HOW SUPPLIED/STORAGE AND HANDLING

Tyvaso DPI (treprostinil) inhalation powder is available as 16 mcg, 32 mcg, 48 mcg, or 64 mcg of treprostinil in single-dose plastic cartridges with approximate fill weights of 1.6 mg, 3.2 mg, 4.8 mg, or 6.4 mg of Tyvaso DPI, respectively. Four cartridges are contained in a single cavity of a blister strip. A card contains 7 blister strips separated by perforations for a total of 28 cartridges of each labeled strength in Titration and Maintenance Kits. For convenience, the perforation allows users to remove a single blister strip containing 4 cartridges. The Institutional Kits contain 4 blister strips for a total of 16 cartridges of each labeled strength.

The cartridges are color-coded, purple for 16 mcg, dark blue for 32 mcg, light blue for 48 mcg, and light green for 64 mcg. Each cartridge is marked with “Tyvaso DPI” and the corresponding dosage strength of “16 mcg”, “32 mcg”, “48 mcg”, or “64 mcg”.

The Tyvaso DPI Inhaler is individually packaged in a clear overwrap. The inhaler is fully assembled with a removable mouthpiece cover. The Tyvaso DPI Inhaler can be used for up to 7 days from the date of first use. After 7 days of use, the inhaler must be discarded and replaced with a new inhaler.

Tyvaso DPI is available in the following configurations:

Kit Contents
Description NDC Number of Cartridges and Strength Number of Inhalers
Tyvaso DPI (treprostinil) Inhalation Powder Titration Kit 66302-600-02 112 cartridges, each containing 16 mcg per cartridge 5
84 cartridges, each containing 32 mcg per cartridge
66302-610-02 112 cartridges, each containing 16 mcg per cartridge 5
112 cartridges, each containing 32 mcg per cartridge
28 cartridges, each containing 48 mcg per cartridge
Tyvaso DPI (treprostinil) Inhalation Powder Maintenance Kit 66302-616-03 112 cartridges, each containing 16 mcg per cartridge 5
66302-632-03 112 cartridges, each containing 32 mcg per cartridge 5
66302-648-03 112 cartridges, each containing 48 mcg per cartridge 5
66302-664-03 112 cartridges, each containing 64 mcg per cartridge 5
66302-620-03 112 cartridges, each containing 32 mcg per cartridge 5
112 cartridges, each containing 48 mcg per cartridge
Tyvaso DPI (treprostinil) Inhalation Powder Institutional Kit 66302-716-04 16 cartridges, each containing 16 mcg per cartridge 2
66302-732-04 16 cartridges, each containing 32 mcg per cartridge 2
66302-748-04 16 cartridges, each containing 48 mcg per cartridge 2
66302-764-04 16 cartridges, each containing 64 mcg per cartridge 2
66302-720-04 16 cartridges, each containing 32 mcg per cartridge 2
16 cartridges, each containing 48 mcg per cartridge

Blister Storage:

Storage
Tyvaso DPI Presentation Refrigerated storage 2°C to 8°C (36°F to 46°F) Room temperature storage 20°C to 25°C (68°F to 77°F), excursions permitted 15°C to 30°C (59°F to 86°F)
Sealed (Unopened) Blister Cards or Strips May be stored until the expiration date printed on the blisters. Must be used within 5 weeks.
Opened Blister Strips Do not put a blister card or strip back into the refrigerator after being opened or stored at room temperature. Must be used within 3 days.

Inhaler Storage:

Store at 2°C to 25°C (36°F to 77°F); excursions permitted. The Tyvaso DPI Inhaler may be stored refrigerated but should be at room temperature for 10 minutes before use. The inhaler can be used for up to 7 days from the date of first use. After 7 days of use, the inhaler must be discarded and replaced with a new inhaler.

Handling:

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

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