Orenitram

5 WARNINGS AND PRECAUTIONS Do not abruptly discontinue dosing. ( 2.5 , 5.1 ) In patients with diverticulosis, Orenitram tablets can become lodged in a diverticulum. ( 5.2 ) 5.1 Worsening PAH Symptoms upon Abrupt Withdrawal Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in worsening of PAH symptoms. 5.2 Use in Patients with Blind-end Pouches The tablet shell does not dissolve. In patients with diverticulosis, Orenitram tablets can lodge in a diverticulum.

6 ADVERSE REACTIONS Most common adverse reactions (incidence >10%) reported in clinical studies in patients treated with Orenitram compared with placebo are headache, diarrhea, nausea, vomiting, jaw pain, and flushing. ( 6.1 ) 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 clinical practice. In a 12-week, placebo-controlled, monotherapy study (Study 1; WHO Group 1; functional class II-III), and an event-driven, placebo-controlled, combination therapy study (Study 4; WHO Group 1; functional class I-III), the most commonly reported adverse reactions that occurred in patients receiving Orenitram included: headache, diarrhea, nausea, and flushing. Orenitram patients in Study 1 (N=151) had access to 0.25 mg tablets at randomization. Approximately 91% of such patients in Study 1 experienced an adverse reaction, but only 4% discontinued therapy for an adverse reaction (compared to 3% receiving placebo). Study 4 enrolled a total of 690 patients, 346 received Orenitram and 344 received placebo. Overall, 19% of patients treated with Orenitram discontinued treatment in Study 4 due to an adverse event (compared to 4% of patients receiving placebo). The exposure to Orenitram in Study 4 was up to 5.1 years with a median duration of exposure of 1.2 years. Table 1 summarizes adverse events with rates at least 5% higher on Orenitram therapy than on placebo that were reported in either Study 1 or 4. Table 1: Adverse Events with Rates at Least 5% Higher on Orenitram Therapy than on Placebo in Either Study 1 or Study 4 Reaction Study 1 N=228 Includes all subjects in the Primary Analysis Population Study 4 N=690 Orenitram n=151 Placebo n=77 Orenitram n=346 Placebo n=344 Headache 63% 19% 75% 35% Diarrhea 30% 16% 69% 29% Nausea 30% 18% 40% 23% Vomiting 17% 16% 36% 10% Flushing 15% 6% 45% 8% Pain in jaw 11% 4% 18% 3% Pain in extremity 14% 8% 18% 9% Hypokalemia 9% 3% 4% 3% Abdominal discomfort 6% 0% 8% 4% Upper abdominal pain 5% 3% 12% 5% Orenitram was studied in a long-term, open-label, extension study in which 824 patients were dosed for a mean duration of approximately 2 years. About 70% of patients continued treatment with Orenitram for at least a year. The mean dose was 4.2 mg BID at one year. The adverse reactions were similar to those observed in the placebo-controlled trials. The safety of Orenitram was also evaluated in an open-label study transitioning patients from Remodulin. The safety profile during this study was similar to that observed in the three pivotal studies. 6.2 Post-Marketing Experience The following adverse reactions have been identified during postapproval use of Orenitram: dizziness, dyspepsia, vomiting, myalgia, and arthralgia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

<table width="75%" ID="table1"><caption>Table 1: Adverse Events with Rates at Least 5% Higher on Orenitram Therapy than on Placebo in Either Study 1 or Study 4</caption><col width="20%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2" valign="middle">Reaction</th><th styleCode="Rrule" colspan="2">Study 1 N=228<footnote>Includes all subjects in the Primary Analysis Population</footnote></th><th styleCode="Rrule" colspan="2">Study 4 N=690</th></tr><tr><th styleCode="Rrule" align="center">Orenitram n=151</th><th styleCode="Rrule">Placebo n=77</th><th styleCode="Rrule">Orenitram n=346</th><th styleCode="Rrule">Placebo n=344</th></tr></thead><tbody><tr><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">63%</td><td styleCode="Rrule">19%</td><td styleCode="Rrule">75%</td><td styleCode="Rrule">35%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule Toprule">Diarrhea</td><td styleCode="Rrule Toprule">30%</td><td styleCode="Rrule Toprule">16%</td><td styleCode="Rrule Toprule">69%</td><td styleCode="Rrule Toprule">29%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">30%</td><td styleCode="Rrule">18%</td><td styleCode="Rrule">40%</td><td styleCode="Rrule">23%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">17%</td><td styleCode="Rrule">16%</td><td styleCode="Rrule">36%</td><td styleCode="Rrule">10%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Flushing</td><td styleCode="Rrule">15%</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">45%</td><td styleCode="Rrule">8%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pain in jaw</td><td styleCode="Rrule">11%</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">18%</td><td styleCode="Rrule">3%</td></tr><tr><td styleCode="Lrule Rrule">Pain in extremity</td><td styleCode="Rrule">14%</td><td styleCode="Rrule">8%</td><td styleCode="Rrule">18%</td><td styleCode="Rrule">9%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule Toprule">Hypokalemia</td><td styleCode="Rrule Toprule">9%</td><td styleCode="Rrule Toprule">3%</td><td styleCode="Rrule Toprule">4%</td><td styleCode="Rrule Toprule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal discomfort</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">0%</td><td styleCode="Rrule">8%</td><td styleCode="Rrule">4%</td></tr><tr><td styleCode="Lrule Rrule">Upper abdominal pain</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">12%</td><td styleCode="Rrule">5%</td></tr></tbody></table>