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warnings and cautions
5 WARNINGS AND PRECAUTIONS Do not abruptly discontinue dosing. ( 2.5 , 5.1 ) Increased risk of bleeding, particularly in patients receiving anticoagulants. ( 5.2 ) In patients with diverticulosis Orenitram tablets can become lodged in a diverticulum. ( 5.3 ) 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 Risk of Bleeding Orenitram inhibits platelet aggregation and increases the risk of bleeding. 5.3 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 >5%) reported in clinical studies with Orenitram are headache, diarrhea, nausea, 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), the most commonly reported adverse reactions that occurred in patients receiving Orenitram included: headache, diarrhea, nausea, and flushing. Table 1 lists the most common adverse reactions that occurred at a rate on Orenitram at least 5% higher than on placebo. Orenitram patients in Table 1 for Study 1 (N = 151) had access to 0.25 mg tablets at randomization. Approximately 91% of such patients experienced an adverse reaction, but only 4% discontinued therapy for an adverse reaction (compared to 3% receiving placebo). The overall discontinuation rate for any reason was 17% for active and 14% for placebo. Table 1: Adverse Reactions with Rates at Least 5% Higher on Orenitram Monotherapy than on Placebo Reaction Orenitram N=151 Placebo N=77 Headache 63% 19% Diarrhea 30% 16% Nausea 30% 18% Flushing 15% 6% Pain in jaw 11% 4% Pain in extremity 14% 8% Hypokalemia 9% 3% Abdominal discomfort 6% 0% 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.