UPTRAVI

UPTRAVI- selexipag tablet, coated
UPTRAVI TITRATION PACK- selexipag
Actelion Pharmaceuticals US, Inc.

1 INDICATIONS AND USAGE

1.1 Pulmonary Arterial Hypertension

UPTRAVI 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 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%), PAH associated with congenital heart disease with repaired shunts (10%) [see Clinical Studies (14.1)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended starting dose of UPTRAVI is 200 micrograms (mcg) given twice daily. Tolerability may be improved when taken with food [see Clinical Pharmacology (12.3)].

Increase the dose in increments of 200 mcg twice daily, usually at weekly intervals, to the highest tolerated dose up to 1600 mcg twice daily. If a patient reaches a dose that cannot be tolerated, the dose should be reduced to the previous tolerated dose.

Do not split, crush, or chew tablets.

2.2 Interruptions and Discontinuations

If a dose of medication 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.

2.3 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 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).

2.4 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. Revert back to twice daily dosing frequency of UPTRAVI when co-administration of moderate CYP2C8 inhibitor is stopped [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

UPTRAVI is available in the following strengths:

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

4 CONTRAINDICATIONS

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 Veno-Occlusive Disease (PVOD)

Should signs of pulmonary edema occur, consider the possibility of associated PVOD. 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.

The safety of UPTRAVI has been evaluated in a long-term, placebo-controlled study enrolling 1156 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 1 presents adverse reactions more frequent on UPTRAVI than on placebo by ≥3%.

Table 1 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 and in none of the patients on placebo.

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 selexipag 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 selexipag 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 selexipag 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 postapproval 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.

Symptomatic hypotension

7 DRUG INTERACTIONS

7.1 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 administration of UPTRAVI with strong inhibitors of CYP2C8 (e.g., gemfibrozil) is contraindicated [see Contraindications (4) and Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)]. Reduce the dosing of UPTRAVI to once daily in patients on a moderate CYP2C8 inhibitor [see Dosage and Administration (2.4)].

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