Important Safety Information For

• UPTRAVI^®

  INDICATION

  UPTRAVI^® (selexipag) is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH.

  Effectiveness of UPTRAVI^® Tablets was established in a long-term study in PAH patients with WHO Functional Class II-III symptoms.

  Patients had idiopathic and heritable PAH (58%), PAH associated with connective tissue disease (29%), and PAH associated with congenital heart disease with repaired shunts (10%).

  IMPORTANT SAFETY INFORMATION

  CONTRAINDICATIONS

  Concomitant use of strong inhibitors of CYP2C8 (eg, gemfibrozil) with UPTRAVI^® is contraindicated.

  Hypersensitivity to the active substance or to any of the excipients is contraindicated.

  WARNINGS AND PRECAUTIONS

  Pulmonary Edema with Pulmonary Veno-Occlusive Disease (PVOD)

  Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue UPTRAVI^®.

  ADVERSE REACTIONS

  Adverse reactions more frequent compared to placebo (≥3%) seen with UPTRAVI^® Tablets are headache (65% vs 32%), diarrhea (42% vs 18%), jaw pain (26% vs 6%), nausea (33% vs 18%), myalgia (16% vs 6%), vomiting (18% vs 9%), pain in extremity (17% vs 8%), flushing (12% vs 5%), arthralgia (11% vs 8%), anemia (8% vs 5%), decreased appetite (6% vs 3%), and rash (11% vs 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.

  DRUG INTERACTIONS

  CYP2C8 Inhibitors

  Concomitant administration with gemfibrozil, a strong inhibitor of CYP2C8, doubled exposure to selexipag and increased exposure to the active metabolite by approximately 11-fold. Concomitant use of UPTRAVI^® with strong inhibitors of CYP2C8 is contraindicated.

  Concomitant administration of UPTRAVI^® with clopidogrel, a moderate inhibitor of CYP2C8, had no relevant effect on the exposure to selexipag and increased the exposure to the active metabolite by approximately 2.7-fold. Reduce the dosing of UPTRAVI^® to once daily in patients on a moderate CYP2C8 inhibitor.

  CYP2C8 Inducers

  Concomitant administration with an inducer of CYP2C8 and UGT 1A3 and 2B7 enzymes (rifampin) halved exposure to the active metabolite. Increase UPTRAVI^® dose, up to twice, when co-administered with rifampin. Reduce UPTRAVI^® when rifampin is stopped.

  DOSAGE AND ADMINISTRATION

  Recommended Dosage

  Recommended starting dose is 200 mcg twice daily for UPTRAVI^® Tablets. Tolerability may be improved when taken with food. Increase by 200 mcg twice daily, usually at weekly intervals, to the highest tolerated dose up to 1600 mcg twice daily. If dose is not tolerated, reduce to the previous tolerated dose.

  Patients With Hepatic Impairment

  For patients with moderate hepatic impairment (Child-Pugh class B), the starting dose of UPTRAVI^® Tablets is 200 mcg once daily. Increase by 200 mcg once daily at weekly intervals, as tolerated. Avoid use of UPTRAVI^® in patients with severe hepatic impairment (Child-Pugh class C).

  Co-administration With Moderate CYP2C8 Inhibitors

  When co-administered with moderate CYP2C8 inhibitors (eg, clopidogrel, deferasirox and teriflunomide), reduce the dosing of UPTRAVI^® to once daily.

  Dosage Strengths

  UPTRAVI^® tablet strengths:

  200, 400, 600, 800, 1000, 1200, 1400, and 1600 mcg.

  Additional Important Safety Information for UPTRAVI^® IV

  Use UPTRAVI^® for injection in patients who are temporarily unable to take oral therapy.

  Administer UPTRAVI^® for injection twice daily by intravenous infusion at a dose that corresponds to the patient’s current dose of UPTRAVI^® Tablets (see Table 1 in full Prescribing Information). Administer UPTRAVI^® for injection as an 80-minute intravenous infusion.

  Adverse Reactions: Infusion-site reactions (infusion-site erythema/redness, pain and swelling) were reported with UPTRAVI^® for injection.

  Please see full Prescribing Information.

  cp-126160v5

  INDICATION