Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 05 December 2017

Indication(s)

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

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None (4)
Adverse reactions
6 ADVERSE REACTIONS The following potential adverse reactions are described in Warnings and Precautions (5): -Decrease in systemic blood pressure [see Warnings and Precautions (5.2)]. -Bleeding [see Warnings and Precautions (5.4)]. Most common adverse reactions (≥ 10%) are cough, headache, nausea, dizziness, flushing, throat irritation, pharyngolaryngeal pain and diarrhea. (6) To report SUSPECTED ADVERSE REACTIONS, contact United Therapeutics Corp. at 1-866-458-6479 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Adverse Reactions Identified in Clinical Trials 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. 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 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 FrequentMore than 3% greater than placebo than Placebo 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 nine breaths, four times daily. Forty-two percent (42%) achieved a dose of 12 breaths four 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. Adverse Events Associated with Route of Administration Adverse events in the treated group during the double-blind and open-label phase reflecting irritation to the respiratory tract included: cough, throat irritation, pharyngeal pain, epistaxis, hemoptysis and wheezing. Serious adverse events during the open-label portion of the study included pneumonia in fifteen subjects. There were three serious episodes of hemoptysis (one fatal) noted during the open-label experience. 6.2 Adverse Reactions Identified in Post-Marketing Experience The following adverse reaction 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: Angioedema.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Use only with the Tyvaso Inhalation System. (2.1) Administer undiluted, as supplied. A single breath of Tyvaso delivers approximately 6 mcg of treprostinil. (2.1) Administer in 4 separate treatment sessions each day approximately four hours apart, during waking hours. (2.1) Initial dosage: 3 breaths (18 mcg) per treatment session. If 3 breaths are not tolerated, reduce to 1 or 2 breaths. (2.1) Dosage should be increased by an additional 3 breaths per session at approximately 1-2 week intervals, if tolerated. (2.1) Titrate to target maintenance dosage of 9 breaths or 54 mcg per treatment session as tolerated. (2.1) 2.1 Usual Dosage in Adults Tyvaso is intended for oral inhalation using the Tyvaso Inhalation System, which consists of an ultrasonic, pulsed delivery device and its accessories. Tyvaso is dosed in 4 separate, equally spaced treatment sessions per day, during waking hours. Each treatment session will take 2 to 3 minutes. The treatment 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 at approximately 1- to 2- week intervals, if tolerated, until the target dose of 9 breaths (54 mcg of treprostinil) is reached, 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. The maximum recommended dosage is 9 breaths per treatment session, 4 times daily. 2.2 Patients with Hepatic Insufficiency Plasma clearance of treprostinil is reduced in patients with hepatic insufficiency. Patients with hepatic insufficiency may therefore be at increased risk of dose-dependent adverse reactions because of an increase in systemic exposure [see Warnings and Precautions (5.3), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 2.3 Patients with Renal Insufficiency Plasma clearance of treprostinil may be reduced in patients with renal insufficiency, since treprostinil and its metabolites are excreted mainly through the urinary route. Patients with renal insufficiency may therefore be at increased risk of dose-dependent adverse reactions [see Warnings and Precautions (5.3), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. 2.4 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.
Use in special populations
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 ≥9 and ≥145 times the human exposure when based on Cmax and AUC following a single treprostinil dose of 54 mcg, respectively. 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 pregnant rats, continuous subcutaneous infusions of treprostinil during organogenesis and late gestational development, at doses as high as 900 ng treprostinil/kg/min (about 117 times the starting human subcutaneous infusion rate, on a ng/m2 basis and about 16 times the average rate achieved in clinical trials), resulted in no evidence of harm to the fetus. In pregnant rabbits, effects of continuous subcutaneous infusions of treprostinil during organogenesis were limited to an increased incidence of fetal skeletal variations (bilateral full rib or right rudimentary rib on lumbar 1) associated with maternal toxicity (reduction in body weight and food consumption) at a dose of 150 ng treprostinil/kg/min (about 41 times the starting human subcutaneous infusion rate, on a ng/m2 basis, and 5 times the average rate used in clinical trials). In rats, continuous subcutaneous infusion of treprostinil from implantation to the end of lactation, at doses of up to 450 ng treprostinil/kg/min, did not affect the growth and development of offspring. 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 Cmax and AUC following a single Tyvaso dose of 54 mcg, respectively. 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 Cmax and AUC following a single Tyvaso dose of 54 mcg, respectively. 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 Clinical studies of Tyvaso did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from 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), Dosage and Administration (2.2) and Warnings and Precautions (5.3)]. 8.7 Patients with Renal Insufficiency No studies have been performed in patients with renal insufficiency. Since treprostinil and its metabolites are excreted mainly through the urinary route, patients with renal insufficiency may have decreased clearance of the drug and its metabolites and consequently, dose-related adverse outcomes may be more frequent [see Clinical Pharmacology (12.3), Dosage and Administration (2.3) and Warnings and Precautions (5.3)].

Interactions

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 (5.5)]. 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 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.

More information

Category Value
Authorisation number NDA022387
Agency product number RUM6K67ESG
Orphan designation No
Product NDC 66302-206
Date Last Revised 26-10-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 857799
Marketing authorisation holder United Therapeutics Corp.