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Selexipag

Generic name: selexipag systemic

Brand names: Uptravi

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Uptravi: 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1000 mcg, 1200 mcg, 1400 mcg, 1600 mcg

Tablet Therapy Pack, Oral:

Uptravi: 200 mcg (140s) and 800 mcg (60s) (200 ea)

Pharmacology

Mechanism of Action

Selexipag is a selective prostacyclin IP receptor agonist. Prostacyclin is produced in the endothelial cells and induces vasodilation; also inhibits platelet aggregation. Patients with pulmonary arterial hypertension appear to have a dysregulation in the prostacyclin metabolic pathways (Galie 2013).

Pharmacokinetics/Pharmacodynamics

Absorption

Rapid (Kaufmann 2015)

Distribution

Vdss: 11.7L

Metabolism

Metabolism: Hepatic via CYP3A4, CYP2C8, UGT1A3 and UGT2B7; hydrolyzed by carboxylesterase1 to the active metabolite, ACT-333679, which is a major contributor to the activity (Kaufmann 2015); the active metabolite is then glucuronidated.

Excretion

Feces (~93%); urine (12%; as inactive metabolites)

Time to Peak

Selexipag: 1 to 3 hours; Active metabolite: 3 to 4 hours; Delayed with food

Half-Life Elimination

Terminal: Selexipag: 0.8 to 2.5 hours; Active metabolite: 6.2 to 13.5 hours

Protein Binding

~99%; to albumin and alpha-1 acid glycoprotein

Use in Specific Populations

Special Populations: Renal Function Impairment

A 40% to 70% increase in exposure to selexipag and its active metabolite was observed in severe renal impairment (estimated glomerular filtration rate ≥15 to <30 mL/minute/1.73 m2).

Special Populations: Hepatic Function Impairment

In mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, exposure was 2- and 4-fold that seen in healthy subjects. Exposure to the active metabolite was doubled in moderate hepatic impairment.

Use: Labeled Indications

Pulmonary arterial hypertension: Treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH.

Contraindications

Concomitant use with strong CYP2C8 inhibitors (eg, gemfibrozil).

Canadian labeling: Additional contraindication (not in US labeling): Hypersensitivity to selexipag or any component of the formulation

Dosage and Administration

Dosing: Adult

Pulmonary arterial hypertension: Oral: Initial: 200 mcg twice daily; increase by 200 mcg twice daily, usually at weekly intervals, to the highest tolerated dose (maximum dose: 1,600 mcg twice daily). If a dose is not tolerated, reduce dose to previously tolerated dose.

Missed dose: If dose is missed, take dose as soon as possible unless the next dose is within the next 6 hours. If ≥3 days of treatment are missed, restart at a lower dose and then retitrate.

Dosage adjustment for concomitant moderate CYP2C8 inhibitors (eg, clopidogrel, deferasirox, teriflunomide): Reduce selexipag dose frequency to once daily (eg, if taking 200 mcg twice daily then reduce to 200 mcg once daily). Upon discontinuation of the moderate CYP2C8 inhibitor, increase selexipag frequency to twice daily.

Dosing: Geriatric

Refer to adult dosing.

Administration

Oral: Administer with or without food; tolerability may be improved when taken with food. Swallow tablets whole; do not split, crush, or chew.

Storage

Store at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted to 15°C and 30°C (59°F and 86°F).

Drug Interactions

CYP2C8 Inhibitors (Moderate): May increase serum concentrations of the active metabolite(s) of Selexipag. Management: Reduce the selexipag dose to once daily when combined with moderate CYP2C8 inhibitors. Revert back to twice daily selexipag dosing upon stopping the moderate CYP2C8 inhibitor. Consider therapy modification

CYP2C8 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of Selexipag. CYP2C8 Inhibitors (Strong) may increase the serum concentration of Selexipag. Avoid combination

Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Monitor therapy

RifAMPin: May decrease serum concentrations of the active metabolite(s) of Selexipag. Management: Increase the selexipag dose (up to 2-fold) when combined with rifampin. Monitor for decreased selexipag efficacy. Consider therapy modification

Adverse Reactions

>10%:

Cardiovascular: Flushing (12%)

Central nervous system: Headache (65%)

Dermatologic: Skin rash (11%)

Gastrointestinal: Diarrhea (42%), nausea (33%), vomiting (18%)

Neuromuscular & skeletal: Jaw pain (26%), limb pain (17%), myalgia (16%), arthralgia (11%)

1% to 10%:

Endocrine & metabolic: Hyperthyroidism (1%)

Gastrointestinal: Decreased appetite (6%)

Hematologic & oncologic: Decreased hemoglobin (below 10 g/dL: 9%), anemia (8%)

<1%, postmarketing, and/or case reports: Symptomatic hypotension

Warnings/Precautions

Concerns related to adverse effects:

  • Pulmonary edema: If signs/symptoms of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease (PVOD). If PVOD is confirmed, discontinue treatment.

Disease-related concerns

  • Hepatic impairment: Use with caution in patients with moderate hepatic impairment (dosage modification is recommended); avoid use in patients with severe hepatic impairment (has not been studied).

Concurrent drug therapy issues:

  • Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information

Monitoring Parameters

Liver function tests. Monitor for signs of pulmonary edema and for improvements in pulmonary function, exercise tolerance, and quality of life.

Pregnancy

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Women with pulmonary arterial hypertension (PAH) are encouraged to avoid pregnancy (McLaughlin 2009).

Patient Education

What is this drug used for?

  • It is used to treat high blood pressure in the lungs.

Frequently reported side effects of this drug

  • Headache
  • Diarrhea
  • Jaw pain
  • Nausea
  • Vomiting
  • Muscle pain
  • Joint pain
  • Painful extremities
  • Flushing
  • Lack of appetite

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

  • Trouble breathing
  • Wheezing
  • Cough
  • Severe loss of strength and energy
  • Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Source: Wolters Kluwer Health. Last updated February 1, 2020.