Uptravi (selexipag)

Dosage of selexipag should be individualized based on patient tolerability. The recommended initial dosage of selexipag for the treatment of pulmonary arterial hypertension (PAH) in adults is 200 mcg twice daily. Subsequent dosage should be increased in increments of 200 mcg twice daily (usually at weekly intervals) to the highest tolerated dosage up to 1600 mcg twice daily. Adverse effects tend to occur more frequently during the dose titration phase and may be managed with analgesics, antidiarrheals, and antiemetics.

Reduce the dosing interval of selexipag to once daily when co-administered with moderate CYP2C8 inhibitors (e.g., clopidogrel, deferasirox, teriflunomide).

Selexipag is administered as oral tablets or as an IV infusion following reconstitution and dilution of the lyophilized powder. The parenteral preparation is intended for use in patients who are temporarily unable to take oral therapy.

No dosing information is available for this tab.

Selexipag and its active metabolite are metabolized principally by cytochrome P-450 (CYP) isoenzyme 2C8 (CYP2C8) and to a lesser extent by CYP3A4. In vitro studies indicate that selexipag and its active metabolite do not inhibit or induce CYP enzymes at clinically relevant concentrations nor do they inhibit hepatic or renal transport proteins.

In vitro studies indicate that selexipag and its active metabolite are substrates of organic anion transport protein (OATP) 1B1 and 1B3. Selexipag is a substrate of P-glycoprotein (P-gp), and the active metabolite is a substrate of breast cancer resistance protein (BCRP).

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Selexipag/Strong Cyp2c8 Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP2C8 inhibitors may inhibit the metabolism of selexipag.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong CYP2C8 inhibitor may increase levels and effects of selexipag, including headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, flushing, decreased hemoglobin, and hyperthyroidism.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of strong CYP2C8 inhibitors and selexipag is contraindicated.(1,2) If concurrent use is warranted, monitor patients closely for increased effects of selexipag, including headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, flushing, decreased hemoglobin, and hyperthyroidism.

DISCUSSION: Gemfibrozil doubled the area-under-curve (AUC) of selexipag and increased the AUC of its active metabolite 11-fold.(1,2) Strong inhibitors of CYP2C8 include gemfibrozil.(3,4)

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Selexipag/Moderate Cyp2c8 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate CYP2C8 inhibitors may inhibit the metabolism of selexipag.(1)

CLINICAL EFFECTS: Concurrent use of a moderate CYP2C8 inhibitor may increase levels and effects of selexipag, including headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, flushing, decreased hemoglobin, and hyperthyroidism.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When co-administered with a moderate inhibitor of CYP2C8, reduce the dose of selexipag to once daily. If the moderate CYP2C8 inhibitor is discontinued, increase the dose of selexipag to twice daily.(1) If concurrent use is warranted, monitor patients closely for increased effects of selexipag, including headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, flushing, decreased hemoglobin, and hyperthyroidism.

DISCUSSION: Clopidogrel (300 mg for 1 day then 75 mg daily, a moderate CYP2C8 inhibitor) had no effect on exposure to selexipag but increased the area-under-curve (AUC) of selexipag's active metabolite by 2.7-fold.(1) A study in healthy subjects evaluated concurrent therapy with selexipag 200 mcg twice daily with clopidogrel 300 mg single does or 75 mg daily. The AUC and the maximum concentration (Cmax) of ACT-333679, the major contributor to the drug effect, increased 2.25-fold (90% confidence interval (CI) 2.06, 2.46) and 1.69-fold (90% CI 1.55, 1.84), respectively with clopidogrel 300 mg and 2.70-fold (90% CI 2.45, 2.96) and 1.90-fold (90% CI 1.72, 2.11), respectively with clopidogrel 75 mg.(2) Moderate CYP2C8 inhibitors linked include: clopidogrel, deferasirox, leflunomide, letermovir, selpercatinib, and teriflunomide.(3-4)

Selexipag/Rifampin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Rifampin may induce the metabolism of selexipag by CYP2C8 and UGT 1A3 and 2B7 enzymes.(1)

CLINICAL EFFECTS: Concurrent use of rifampin may decrease levels and effectiveness of selexipag.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When used with rifampin, increase the dose of selexipag up to two-fold. Reduce the dose of selexipag when rifampin is discontinued.(1)

DISCUSSION: Rifampin decreased the area-under-curve (AUC) of the active metabolite of selexipag by 50%.

*Concomitant use of potent inhibitors of CYPC28 (e.g., gemfibrozil).

*Hypersensitivity to selexipag or any excipients.

• Pulmonary veno-occlusive disease

• Child-pugh class B hepatic impairment
• Disease of liver

There are no moderate contraindications for this drug.

Adverse effects that occurred more frequently (>=5%) with selexipag compared to placebo in clinical studies include headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, and flushing.

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

Less Frequent

• Anemia
• Hyperthyroidism

More Frequent

• Acute abdominal pain
• Diarrhea
• Flushing
• Headache disorder
• Jaw pain
• Myalgia
• Nausea
• Pain in extremities
• Vomiting

Less Frequent

• Anorexia
• Arthralgia
• Skin rash

Rare or Very Rare

• Hypotension
• Injection site sequelae

No enhanced messaging available.

Safety and efficacy of selexipag have not been established in pediatric patients.

There are no adequate and well-controlled studies of selexipag in pregnant women. Selexipag did not affect embryofetal development and survival in animal studies.

It is not known whether selexipag is distributed into human milk. The drug and its metabolites are distributed into milk in rats. Because of the potential for serious adverse reactions to selexipag in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

The manufacturer makes no specific dosage recommendations for geriatric patients.

Of the 1368 patients in clinical studies of selexipag, 18% were 65 years of age or older. No overall differences in safety and efficacy were observed between geriatric and younger patients; however, increased sensitivity in some older individuals cannot be ruled out.