Yutrepia Drug Information

• 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 )] . Most common adverse reactions with YUTREPIA (³10%) are cough, headache, throat irritation, and dizziness. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Liquidia Technologies, Inc. at 1-888-393-LQDA (5732) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. The safety and tolerability of YUTREPIA was evaluated in an open label study (INSPIRE) of 121 patients with PAH (WHO Group 1 and NYHA Functional Class II [80 patients] and Class III [41 patients]) followed for up to 2 months. The most commonly reported adverse reactions included cough, headache, throat irritation, dizziness, which are known side effects of treprostinil inhalation solution. Table 2 lists the adverse reactions that occurred at a rate of at least 4% of the overall INSPIRE safety population. The adverse reactions in the INSPIRE study were consistent with those observed in previous studies of inhaled treprostinil. Table 2: Adverse Reactions Occurring in ≥ 4% of Patients in the INSPIRE Study *Transition: Patients were on stable doses of treprostinil inhalation solution for at least 3 months prior to enrollment in the study and transitioned to treatment with YUTREPIA. †Add-on: Patients were prostacyclin-naïve and were taking no more than 2 approved oral PAH therapies for at least 3 months at time of enrollment and addition of treatment with YUTREPIA. Adverse Reaction Transition* N=55 Add-On† N=66 n (%) n (%) Cough 15 (27) 36 (55) Headache 14 (25) 18 (27) Throat Irritation 5 (9) 14 (21) Dizziness 6 (11) 7 (11) Diarrhea 3 (6) 8 (12) Chest Discomfort 5 (9) 5 (8) Nausea 4 (7) 5 (8) Dyspnea 3 (6) 3 (5) Flushing 1 (2) 5 (8) Oropharyngeal Pain 1 (2) 4 (6) 6.2 Adverse Reactions Identified in Post-Marketing Experience The following adverse reaction has been identified during the post-approval use of treprostinil inhalation solution. 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:
• Angioedema

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 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 .

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 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.

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 3 9 and 3 145 times the human exposure when based on C max and AUC, respectively, following a single YUTREPIA dose of 79.5 mcg . 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 154 and 1479 times the human exposure, when based on C max and AUC, respectively, following a single YUTREPIA dose of 79.5 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 YUTREPIA dose of 79.5 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.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

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