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warnings and cautions
5 WARNINGS AND PRECAUTIONS Pulmonary edema in patients with pulmonary veno-occlusive disease. If confirmed, discontinue treatment. ( 5.1 ) 5.1 Pulmonary Edema with Pulmonary Veno-Occlusive Disease Should signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease. If confirmed, discontinue UPTRAVI.
6 ADVERSE REACTIONS Adverse reactions in adult and pediatric patients occurring more frequently (≥5%) on UPTRAVI compared to placebo are headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, and flushing. Additional adverse reaction occurring in pediatric patients more frequently (≥5%) on UPTRAVI compared to placebo is abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Actelion at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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. UPTRAVI Tablets Adult Patients The safety of UPTRAVI tablets has been evaluated in a long-term, placebo-controlled study enrolling 1,156 adult patients with symptomatic PAH (GRIPHON study) [see Clinical Studies (14.1) ] . The exposure to UPTRAVI in this trial was up to 4.2 years with median duration of exposure of 1.4 years. Table 3 presents adverse reactions more frequent on UPTRAVI tablets than on placebo by ≥3%. Table 3: Adverse Reactions UPTRAVI Placebo Adverse Reaction N=575 N=577 Headache 65% 32% Diarrhea 42% 18% Jaw pain 26% 6% Nausea 33% 18% Myalgia 16% 6% Vomiting 18% 9% Pain in extremity 17% 8% Flushing 12% 5% Arthralgia 11% 8% Anemia 8% 5% Decreased appetite 6% 3% Rash 11% 8% These adverse reactions are more frequent during the dose titration phase. Hyperthyroidism was observed in 1% (n=8) of patients on UPTRAVI tablets and in none of the patients on placebo. Pediatric Patients Two Years and Older The safety of UPTRAVI tablets has been evaluated in a long-term, Phase 3, double-blind, placebo-controlled study (SALTO), where a total of 138 pediatric patients with symptomatic PAH ≥2 to <18 years of age were randomized 1:1 to receive either UPTRAVI or placebo [see Clinical Studies (14.2) ] . The exposure to UPTRAVI in this study was up to 4.1 years with a median duration of exposure of 1.5 years. The safety profile in pediatric patients was consistent with that observed in adults with PAH. Compared to adults, a higher frequency of vomiting was observed (39% on UPTRAVI versus 19% on placebo). In addition, abdominal pain was observed in 15% of pediatric patients on UPTRAVI and in 6% on placebo. UPTRAVI-treated pediatric patients experienced a smaller mean increase in body weight and height compared to the placebo group. The mean change in weight Z-score from baseline at 48 weeks in UPTRAVI-treated pediatric patients (n=54) was –0.31 compared to –0.09 in the placebo group (n=61); and at 96 weeks in UPTRAVI-treated pediatric patients (n=32) was –0.46 compared to –0.12 in the placebo group (n=35). The mean change in height Z-score from baseline at 48 weeks in UPTRAVI-treated pediatric patients (n=54) was –0.16 compared to –0.04 in the placebo group (n=61); and at 96 weeks in the UPTRAVI-treated pediatric patients (n=32) was –0.30 compared to –0.05 in the placebo group (n=35). When treating pediatric patients with UPTRAVI, monitor growth. UPTRAVI for Injection Infusion-site reactions (infusion site erythema/redness, pain and swelling) were reported with UPTRAVI for Injection in adult patients. Laboratory Test Abnormalities Hemoglobin In a Phase 3 placebo-controlled study in adult patients with PAH, mean absolute changes in hemoglobin at regular visits compared to baseline ranged from −0.34 to −0.02 g/dL in the UPTRAVI group compared to −0.05 to 0.25 g/dL in the placebo group. A decrease in hemoglobin concentration to below 10 g/dL was reported in 8.6% of patients treated with UPTRAVI tablets and 5.0% of placebo-treated patients. Thyroid Function Tests In a Phase 3 placebo-controlled study in adult patients with PAH, a reduction (up to −0.3 MU/L from a baseline median of 2.5 MU/L) in median thyroid-stimulating hormone (TSH) was observed at most visits in the UPTRAVI group. In the placebo group, little change in median values was apparent. There were no mean changes in triiodothyronine or thyroxine in either group. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of UPTRAVI. 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. Vascular disorders: symptomatic hypotension