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warnings and cautions
5 WARNINGS AND PRECAUTIONS Tyvaso may cause symptomatic hypotension. ( 5.1 ) Tyvaso inhibits platelet aggregation and increases the risk of bleeding. ( 5.2 ) Tyvaso dosage adjustments may be necessary if inhibitors or inducers of CYP2C8 are added or withdrawn. ( 5.3 , 7.3 ) May cause bronchospasm: Patients with a history of hyperreactive airway disease may be more sensitive. ( 5.4 ) 5.1 Risk of Symptomatic Hypotension Treprostinil is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure, treatment with Tyvaso may produce symptomatic hypotension. 5.2 Risk of Bleeding Tyvaso 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 C max 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 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.
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) ] . Most common adverse reactions (≥4%) are cough, headache, nausea, dizziness, flushing, throat irritation, pharyngolaryngeal pain, diarrhea, and syncope. ( 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 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 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 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.