c8 enzyme inhibitor, gemfibrozil, increases exposure (both c max 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.

edominately 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 controlled clinical experience with inhaled treprostinil has been on a background of bosentan (an endothelin receptor antagonist) or sildenafil (a phosphodiesterase type 5 inhibitor). the controlled clinical experience was limited to 12 weeks in duration [see clinical studies (14) ] . 1.2 pulmonary hypertension associated with ild tyvaso is indicated for the treatment of pulmonary hypertension associated with interstitial lung disease (ph-ild; who group 3) to improve exercise ability. the study 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) ] .

ncrease 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 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 inhalation solution.

atment sessions should be approximately 4 hours apart. initial dosage: therapy should begin with 3 breaths of tyvaso (18 mcg of treprostinil) per treatment session 4 times daily. if 3 breaths are not tolerated, reduce to 1 or 2 breaths and subsequently increase to 3 breaths, as tolerated. maintenance dosage: dosage should be increased by an additional 3 breaths per treatment session, 4 times daily at approximately 1- to 2-week intervals. studies establishing effectiveness in patients with pah and ph-ild have used target doses of 9 to 12 breaths per treatment session, 4 times daily. if adverse effects preclude titration to target dose, tyvaso should be continued at the highest tolerated dose. if a scheduled treatment session is missed or interrupted, therapy should be resumed as soon as possible at the usual dose. 2.2 administration tyvaso must be used only with the tyvaso inhalation system. patients should follow the instructions for use for operation of the tyvaso inhalation system and for daily cleaning of the device components after the last treatment session of the day. to avoid potential interruptions in drug delivery because of equipment malfunction, patients should have access to a back-up tyvaso inhalation system device. do not mix tyvaso with other medications in the tyvaso inhalation system. compatibility of tyvaso with other medications has not been studied. the tyvaso inhalation system should be prepared for use each day according to the instructions for use. one ampule of tyvaso contains a sufficient volume of medication for all 4 treatment sessions in a single day. prior to the first treatment session, the patient should twist the top off a single tyvaso ampule and squeeze the entire contents into the medicine cup. between each of the 4 daily treatment sessions, the device should be capped and stored upright with the remaining medication inside. at the end of each day, the medicine cup and any remaining medication must be discarded. the device must be cleaned each day according to the instructions for use. avoid skin or eye contact with tyvaso solution. do not orally ingest the tyvaso solution.

the most commonly reported adverse reactions on tyvaso included cough and throat irritation, headache, gastrointestinal effects, muscle, jaw or bone pain, dizziness, flushing, and syncope. table 1 lists the adverse reactions that occurred at a rate of at least 4% and were more frequent in patients treated with tyvaso than with placebo. table 1: adverse events in ≥4% of pah patients receiving tyvaso and more frequent more than 3% greater than placebo than placebo in triumph i adverse event treatment n (%) tyvaso n=115 placebo n=120 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) the safety of tyvaso was also studied in a long-term, open-label extension study in which 206 patients were dosed for a mean duration of 2.3 years, with a maximum exposure of 5.4 years. eighty-nine percent (89%) of patients achieved the target dose of 9 breaths, 4 times daily. forty-two percent (42%) achieved a dose of 12 breaths, 4 times daily. the adverse events during this chronic dosing study were qualitatively similar to those observed in the 12-week placebo-controlled trial. in a prospective, observational study comparing patients taking tyvaso (958 patient-years of exposure) and a control group (treatment with other approved therapies for pah; 1094 patient-years), tyvaso was associated with a higher rate of cough (16.2 vs. 10.9 per 100 patient-years), throat irritation (4.5 vs. 1.2 per 100 pt-years), nasal discomfort (2.6 vs. 1.3 per 100 pt-years), and hemoptysis (2.5 vs. 1.3 per 100 pt-years) compared to the control group. pulmonary hypertension associated with ild in a 16-week, placebo-controlled study (increase) of 326 patients with ph-ild (who group 3), adverse reactions were similar to the experience in studies of pah. 6.2 post-marketing experience the adverse reaction of angioedema has been identified during the post-approval use of tyvaso. because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

c8 enzyme inhibitor, gemfibrozil, increases exposure (both c max 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.

l 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 154 and 1479 times the human exposure, when based on c max and auc, respectively, following a single tyvaso dose of 54 mcg. 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 9 and 145 times the human exposure, when based on c max and auc, respectively, following a single tyvaso dose of 54 mcg. 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 tyvaso 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 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) ] . 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) ] .

ary 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 154 and 1479 times the human exposure, when based on c max and auc, respectively, following a single tyvaso dose of 54 mcg. 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 9 and 145 times the human exposure, when based on c max and auc, respectively, following a single tyvaso dose of 54 mcg. no treprostinil treatment-related effects on labor and delivery were seen in animal studies. animal reproduction studies are not always predictive of human response.

at of intravenous treprostinil in 18 healthy volunteers. mean estimates of the absolute systemic bioavailability of treprostinil after inhalation were approximately 64% (18 mcg) and 72% (36 mcg). treprostinil plasma exposure data were obtained from 2 studies at the target maintenance dose, 54 mcg. the mean c max at the target dose was 0.91 and 1.32 ng/ml with corresponding mean t max of 0.25 and 0.12 hr, respectively. the mean auc for the 54-mcg dose was 0.81 and 0.97 hr∙ng/ml, respectively. distribution following parenteral infusion, the apparent steady state volume of distribution (v ss ) 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. metabolism and excretion of subcutaneously administered treprostinil, only 4% is excreted unchanged in urine. 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 1 is a glucuroconjugated derivative (treprostinil glucuronide). the elimination of treprostinil (following subcutaneous administration of treprostinil) is biphasic, with a terminal elimination half-life of approximately 4 hours using a 2-compartment model. 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 auc 0-inf that was not significantly altered compared to healthy subjects [see use in specific populations (8.7) ] .

distribution (v ss ) 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. metabolism and excretion of subcutaneously administered treprostinil, only 4% is excreted unchanged in urine. 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 1 is a glucuroconjugated derivative (treprostinil glucuronide). the elimination of treprostinil (following subcutaneous administration of treprostinil) is biphasic, with a terminal elimination half-life of approximately 4 hours using a 2-compartment model. 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 auc 0-inf that was not significantly altered compared to healthy subjects [see use in specific populations (8.7) ] .

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 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 15 and 35 times, respectively, the clinical exposure at the target maintenance dose of 54 mcg.

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.

vious 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 6-minute walk distance (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 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 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 for various subgroups figure 1 figure 2 14.2 long-term treatment of pah in long-term follow-up of patients who were treated with tyvaso in the pivotal study and the open-label extension (n=206), 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 and cannot be used to determine the long-term effect of tyvaso 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. 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 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 titrated up to a dose of 9 breaths, 4 times daily or greater, with 48% of patients randomized to tyvaso 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 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 (ph-ild) 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) 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 in patients with ph-ild resulted in numerically fewer hospitalizations. the numbers of reported deaths were the same for both treatment groups (table 2). overall, treatment with tyvaso 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 2: clinical worsening events (ph-ild) tyvaso 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 3 figure 4 figure 5

-ampule carton of tyvaso (7 foil pouches each containing four 2.9 ml ampules; each ampule contains 1.74 mg treprostinil [0.6 mg per ml]) and the tyvaso inhalation system. (ndc 66302-206-01) tyvaso inhalation system refill kit containing a 28-ampule carton of tyvaso (7 foil pouches each containing four 2.9 ml ampules; each ampule contains 1.74 mg treprostinil [0.6 mg per ml]) and accessories. (ndc 66302-206-02) tyvaso 4 pack carton with 1 foil pouch containing four 2.9 ml ampules. each ampule contains 1.74 mg treprostinil (0.6 mg per ml). (ndc 66302-206-03) tyvaso inhalation system institutional starter kit containing a 4-ampule carton of tyvaso (1 foil pouch containing four 2.9 ml ampules; each ampule contains 1.74 mg treprostinil [0.6 mg per ml]) and the tyvaso inhalation system. (ndc 66302-206-04)