The following adverse reactions are discussed elsewhere in labeling: Infections associated with intravenous administration [see Warnings and Precautions (5.1) ] . Most common adverse reactions (incidence >3%) reported in clinical studies with Remodulin: subcutaneous infusion site pain and reaction, headache, diarrhea, nausea, jaw pain, vasodilatation, edema, and hypotension. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact United Therapeutics Corp. at 1-866-458-6479 or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical 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. Adverse Events with Subcutaneously Administered Remodulin Patients receiving Remodulin 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 Remodulin, infusion site pain and reaction were the most common adverse events among those treated with Remodulin. 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.
Table 3: Percentages of Subjects Reporting Subcutaneous Infusion Site Adverse Events Reaction Pain Placebo Remodulin Placebo Remodulin Severe 1 38 2 39 Requiring narcotics based on prescriptions for narcotics, not actual use NA medications used to treat infusion site pain were not distinguished from those used to treat site reactions NA 1 32 Leading to discontinuation 0 3 0 7 Other adverse events included diarrhea, jaw pain, edema, vasodilatation, and nausea, and these are generally considered to be related to the pharmacologic effects of Remodulin, 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 Remodulin than with placebo in controlled trials in PAH. Table 4: Adverse Reactions in Controlled 12-Week Studies of Subcutaneous Remodulin and at least 3% more frequent than on Placebo Adverse Reaction Remodulin (N=236) Percent of Patients Placebo (N=233) Percent of Patients Infusion Site Pain 85 27 Infusion Site Reaction 83 27 Headache 27 23 Diarrhea 25 16 Nausea 22 18 Rash 14 11 Jaw Pain 13 5 Vasodilatation 11 5 Edema 9 3 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 Remodulin group as compared to the placebo group (4% in Remodulin treatment group versus 2% in placebo-controlled group). As a potent vasodilator, hypotension is possible with the administration of Remodulin. The safety of Remodulin 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 Remodulin 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% Remodulin, 33% placebo); 173 (93%) were pump related and 14 (7%) related to the infusion set. Eight of these patients (4 Remodulin, 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 Remodulin (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 IV mode of infusion including arm swelling, paresthesia, hematoma, and pain [see Warnings and Precautions (5.1) ] .
6.2Post-Marketing Experience
In addition to adverse reactions reported from clinical trials, the following events have been identified during post-approval use of Remodulin. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The following events have been chosen for inclusion because of a combination of their seriousness, frequency of reporting, and potential connection to Remodulin. These events are thrombophlebitis associated with peripheral intravenous infusion, thrombocytopenia, bone pain, pruritus, dizziness, arthralgia, myalgia/muscle spasm, and pain in extremity.
In addition, generalized rashes, sometimes macular or papular in nature, and cellulitis have been infrequently reported.
