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The following potential adverse reactions are described in WARNINGS AND PRECAUTIONS:
- Decrease in systemic blood pressure [see WARNINGS AND PRECAUTIONS].
- Bleeding [see WARNINGS AND PRECAUTIONS].
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, 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 than Placebo
|Adverse Event||Treatment n (%)|
n = 115
n = 120
|Cough||62 (54)||35 (29)|
|Headache||47 (41)||27 (23)|
|Throat Irritation /
|29 (25)||17 (14)|
|Nausea||22 (19)||13 (11)|
|Flushing||17 (15)||1 (<1)|
|Syncope||7 (6)||1 (<1)|
|*More than 3% greater than placebo|
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 (89%) percent of patients achieved the target dose of nine breaths, four times daily. Forty-two (42%) percent 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 per 100 patient-years vs. 10.9 per 100 pt-years), throat irritation (4.5 per 100 pt-years vs. 1.2 per 100 pt-years), nasal discomfort (2.6 per 100 pt-years vs. 1.3 per 100 pt-years), and haemoptysis (2.5 per 100 pt-years 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 openlabel experience.
Adverse Reactions Identified In Post-Marketing Experience
The following adverse reaction has been identified during the postapproval 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:
Read the Tyvaso (treprostinil inhalation solution) Side Effects Center for a complete guide to possible side effects
Pharmacokinetic/pharmacodynamic interaction studies have not been conducted with inhaled treprostinil (Tyvaso); however, some of such studies have been conducted with orally (treprostinil diolamine) and subcutaneously administered treprostinil (Remodulin®).
Antihypertensive Agents Or Other Vasodilators
Since treprostinil inhibits platelet aggregation, there may be an increased risk of bleeding, particularly among patients receiving anticoagulants.
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.
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.
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].
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.
Read the Tyvaso Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 7/21/2016
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