UPTRAVI (Page 2 of 6)

2.3 Administration Instructions

Administer by intravenous infusion over 80 minutes using an infusion set made of DEHP-free polyvinyl chloride (PVC), natural latex rubber-free microbore tubing protected from light.

Do not use a filter for administration.

Once the solution for infusion glass container is empty, continue the infusion at the same rate with 0.9% saline to empty the remaining solution for infusion in the IV line, to ensure that the entire solution for infusion has been administered.

2.4 Interruptions and Discontinuations

If a dose of UPTRAVI is missed, patients should take a missed dose as soon as possible unless the next dose is within the next 6 hours.

If treatment is missed for 3 days or more, restart UPTRAVI at a lower dose and then retitrate.

2.5 Dosage Adjustment in Patients with Hepatic Impairment

No dose adjustment of UPTRAVI is necessary for patients with mild hepatic impairment (Child-Pugh class A).

For patients with moderate hepatic impairment (Child-Pugh class B), the starting dose of UPTRAVI tablets is 200 mcg once daily. Increase in increments of 200 mcg once daily at weekly intervals, as tolerated [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Avoid use of UPTRAVI in patients with severe hepatic impairment (Child-Pugh class C).

2.6 Dosage Adjustment with Co-administration of Moderate CYP2C8 Inhibitors

When co-administered with moderate CYP2C8 inhibitors (e.g., clopidogrel, deferasirox and teriflunomide), reduce the dosing of UPTRAVI to once daily [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

UPTRAVI is available in the following presentations:

Film-Coated Tablets

  • 200 mcg selexipag [Light yellow tablet debossed with 2]
  • 400 mcg selexipag [Red tablet debossed with 4]
  • 600 mcg selexipag [Light violet tablet debossed with 6]
  • 800 mcg selexipag [Green tablet debossed with 8]
  • 1000 mcg selexipag [Orange tablet debossed with 10]
  • 1200 mcg selexipag [Dark violet tablet debossed with 12]
  • 1400 mcg selexipag [Dark yellow tablet debossed with 14]
  • 1600 mcg selexipag [Brown tablet debossed with 16]

UPTRAVI for Injection

  • 1800 mcg selexipag [Lyophilized powder white to almost white broken cake or powdered material, supplied in a 10 mL single-dose glass vial]

4 CONTRAINDICATIONS

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

Concomitant use of strong inhibitors of CYP2C8 (e.g., gemfibrozil) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

5 WARNINGS AND PRECAUTIONS

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

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

The safety of UPTRAVI tablets has been evaluated in a long-term, placebo-controlled study enrolling 1,156 patients with symptomatic PAH (GRIPHON study) [see Clinical Studies (14)]. The exposure to UPTRAVI in this trial was up to 4.2 years with median duration of exposure of 1.4 years.

Table 2 presents adverse reactions more frequent on UPTRAVI tablets than on placebo by ≥3%.

Table 2: 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.

UPTRAVI for Injection

Infusion-site reactions (infusion site erythema/redness, pain and swelling) were reported with UPTRAVI for Injection.

Laboratory Test Abnormalities

Hemoglobin

In a Phase 3 placebo-controlled study in 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 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

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