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.

Adverse Events with Subcutaneously Administered Treprostinil

Patients receiving treprostinil as a subcutaneous infusion reported a wide range of adverse events, many potentially related to the underlying disease (dyspnea, fatigue, chest pain, right ventricular heart failure, and pallor). During clinical trials with subcutaneous infusion of treprostinil, infusion site pain and reaction were the most common adverse events among those treated with treprostinil. Infusion site reaction was defined as any local adverse event other than pain or bleeding/bruising at the infusion site and included symptoms such as erythema, induration or rash. Infusion site reactions were sometimes severe and could lead to discontinuation of treatment.

Other adverse events included diarrhea, jaw pain, edema, vasodilatation and nausea, and these are generally considered to be related to the pharmacologic effects of treprostinil, whether administered subcutaneously or intravenously.

Adverse Reactions during Chronic Dosing

Table 4 lists adverse reactions that occurred at a rate of at least 3% more frequent in patients treated with subcutaneous treprostinil than with placebo in controlled trials in PAH.

Reported adverse reactions (at least 3% more frequent on drug than on placebo) are included with the exception of those too general to be informative, and those not plausibly attributable to the use of the drug, because they were associated with the condition being treated or are very common in the treated population.

While hypotension occurred in both groups, the event was experienced twice as frequently in the treprostinil group as compared to the placebo group (4% in treprostinil treatment group versus 2% in placebo-controlled group). As a potent vasodilator, hypotension is possible with the administration of treprostinil.

The safety of treprostinil was also studied in a long-term, open-label extension study in which 860 patients were dosed for a mean duration of 1.6 years, with a maximum exposure of 4.6 years. Twenty-nine (29%) percent achieved a dose of at least 40 ng/kg/min (max: 290 ng/kg/min). The safety profile during this chronic dosing study was similar to that observed in the 12-week placebo-controlled study except for the following suspected adverse drug reactions (occurring in at least 3% of patients): anorexia, vomiting, infusion site infection, asthenia, and abdominal pain.

Adverse Events Attributable to the Drug Delivery System

In controlled studies of treprostinil administered subcutaneously, there were no reports of infection related to the drug delivery system. There were 187 infusion system complications reported in 28% of patients (23% treprostinil, 33% placebo); 173 (93%) were pump related and 14 (7%) related to the infusion set. Eight of these patients (4 treprostinil, 4 placebo) reported non- serious adverse events resulting from infusion system complications. Adverse events resulting from problems with the delivery systems were typically related to either symptoms of excess treprostinil (e.g., nausea) or return of PAH symptoms (e.g., dyspnea). These events were generally resolved by correcting the delivery system pump or infusion set problem, such as replacing the syringe or battery, reprogramming the pump, or straightening a crimped infusion line. Adverse events resulting from problems with the delivery system did not lead to clinical instability or rapid deterioration. In addition to these adverse events due to the drug delivery system during subcutaneous administration, the following adverse events may be attributable to the intravenous mode of infusion including arm swelling, paresthesias, hematoma and pain [see Warnings and Precautions (5.1)].