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Selexipag

Class: Vasodilating Agents
Chemical Name: 2-[4-[(5,6-diphenylpyrazin-2-yl)-propan-2-yl-amino]butoxy]-N-methylsulfonylacetamide
Molecular Formula: C26H32N4O4S
CAS Number: 475086-01-2
Brands: Uptravi

Introduction

Vasodilator; a selective nonprostanoid prostacyclin receptor (IP receptor) agonist.1 3 6 8 11

Uses for Selexipag

Pulmonary Arterial Hypertension

Management of pulmonary arterial hypertension (PAH; WHO group 1) to delay disease progression and reduce the risk of hospitalization.1 3 Efficacy established principally in patients with WHO functional class II–III PAH (idiopathic, heritable, or associated with connective tissue disease or congenital heart disease with repaired shunts).1 3

Treatment with selexipag alone or in combination with an endothelin receptor antagonist and/or a phosphodiesterase (PDE) type 5 inhibitor reduces risk of disease progression and hospitalization in patients with PAH, but has not been shown to reduce mortality.1 3 4

Considered one of several treatment options for management of PAH in patients who are not candidates for calcium-channel blocker therapy or in whom such therapy failed.4 6 27 38 40 Individualize choice of therapy; consider factors such as disease severity, route of administration, potential adverse effects and costs of treatment, clinician experience, and patient preference.27 38 40

Has been designated an orphan drug by FDA for treatment of PAH.5

Selexipag Dosage and Administration

General

Restricted Distribution

  • Available only through specialty pharmacies.8 17

  • For additional information, contact the manufacturer at 866-228-3546.17

Administration

Oral Administration

Administer orally twice daily without regard to meals; tolerability may be improved when taken with food.1

Do not split, chew, or crush tablets.1

Dosage

Adults

PAH
Oral

Individualize dosage based on tolerability.1

Initially, 200 mcg twice daily.1 Increase dosage in increments of 200 mcg twice daily (usually at weekly intervals) to the highest tolerated dose (maximum 1600 mcg twice daily).1

Adverse effects tend to occur more frequently during dose titration phase and may be managed with analgesics, antidiarrheals, and antiemetics.6 8 11

If a dose is missed, take as soon as it is remembered; if next dose is due within 6 hours, skip missed dose and take next dose at the regularly scheduled time.1

Prescribing Limits

Adults

PAH
Oral

Maximum 1600 mcg twice daily.1

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): No dosage adjustment necessary.1

Moderate hepatic impairment (Child-Pugh class B): Initially, 200 mcg once daily; increase dosage in increments of 200 mcg once daily at weekly intervals as tolerated.1

Severe hepatic impairment (Child-Pugh class C): Avoid use.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Patients with eGFR >15 mL/minute per 1.73 m2: No dosage adjustments necessary.1 (See Renal Impairment under Cautions.)

Patients with eGFR <15 mL/minute per 1.73 m2 or those undergoing dialysis: Not studied.1

Cautions for Selexipag

Contraindications

  • Concomitant use of potent inhibitors of CYPC28 (e.g., gemfibrozil).1

Warnings/Precautions

Pulmonary Effects

Consider possibility of associated pulmonary veno-occlusive disease (PVOD) and discontinue selexipag if manifestations of pulmonary edema occur.1

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnant women.1 Selexipag did not affect embryofetal development and survival in animal studies.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 8 Discontinue nursing or the drug.1 8

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No overall differences in safety and efficacy observed between geriatric and younger patients; however, increased sensitivity in some older individuals cannot be ruled out.1

Hepatic Impairment

Systemic exposure to selexipag is increased in patients with mild hepatic impairment (Child-Pugh class A); systemic exposure to both drug and active metabolite are increased in patients with moderate hepatic impairment (Child-Pugh class B).1 (See Hepatic Impairment under Dosage and Administration, and also see Special Populations under Pharmacokinetics.)

Not studied in patients with severe hepatic impairment (Child-Pugh class C); avoid use.1

Renal Impairment

Systemic exposure to selexipag is increased in patients with severe renal impairment (eGFR of 15–29 mL/minute per 1.73 m2).1 (See Renal Impairment under Dosage and Administration, and also see Special Populations under Pharmacokinetics.)

Not studied in patients on dialysis or in those with eGFR <15 mL/minute per 1.73 m2.1

Common Adverse Effects

Headache,1 3 diarrhea,1 3 jaw pain,1 3 nausea,1 3 myalgia,1 3 vomiting,1 3 pain in extremity,1 3 flushing,1 3 arthralgia,1 3 anemia,1 3 decreased appetite,1 rash.1

Interactions for Selexipag

Selexipag and its active metabolite are metabolized by CYP2C8 (principally) and CYP3A4.1 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.1

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

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP2C8: Possible increased exposure to selexipag and its active metabolite; concomitant use contraindicated.1 4

Moderate inhibitors of CYP2C8: Although not specifically evaluated, increased exposure to selexipag and its active metabolite is possible.1 Consider a less frequent dosing regimen (e.g., once daily) when initiating selexipag in patients receiving a moderate CYP2C8 inhibitor.1 Reduce dosage of selexipag when initiating a moderate CYP2C8 inhibitor.1 18

Inducers of CYP2C8: Possible decreased exposure to active metabolite of selexipag.1

Inhibitors of CYP3A4: Not expected to alter pharmacokinetics of selexipag and its active metabolite to a clinically important extent; dosage adjustment of selexipag does not appear to be necessary.9

Drugs Affecting Transport Proteins

Inhibitors of OATP1B1, OATP1B3, and P-gp: Not expected to alter pharmacokinetics of selexipag and its active metabolite to a clinically important extent; dosage adjustment of selexipag does not appear to be necessary.9

Specific Drugs

Drug

Interaction

Comments

Deferasirox

May increase exposure to active metabolite of selexipag1

Consider a less frequent dosing regimen of selexipag (e.g., once daily) when initiating the drug in patients already receiving deferasirox; reduce selexipag dosage when deferasirox is initiated in patients already receiving selexipag1 18

Endothelin-receptor antagonists

No clinically relevant drug interaction observed1 6

No dosage adjustment necessary1

Gemfibrozil

Increased exposure to selexipag by twofold and its active metabolite by 11-fold1 4

Concomitant use contraindicated1

Lopinavir and ritonavir

Fixed combination of lopinavir and ritonavir (lopinavir/ritonavir): No clinically relevant pharmacokinetic interaction observed1 9

No dosage adjustment necessary1

PDE type 5 inhibitors

No clinically relevant drug interaction observed1 6

No dosage adjustment necessary1

Rifampin

May decrease exposure to active metabolite of selexipag1

Increase dosage of selexipag (up to twofold) when used concomitantly with rifampin;1 reduce selexipag dosage when rifampin is discontinued1

Teriflunomide

May increase exposure to active metabolite of selexipag1

Consider a less frequent dosing regimen of selexipag (e.g., once daily) when initiating the drug in patients already receiving teriflunomide; reduce selexipag dosage when teriflunomide is initiated in patients already receiving selexipag1 18

Warfarin

No change in pharmacokinetics of warfarin or selexipag; no effect on INR1 10

No dosage adjustment necessary1

Selexipag Pharmacokinetics

Absorption

Bioavailability

Following oral administration, absolute bioavailability is approximately 49%, most likely due to first-pass metabolism.1 6

Peak plasma concentrations of selexipag and its active metabolite are obtained within 1–3 and 3–4 hours, respectively.1

Food

Administration with food delays time to peak concentrations and decreases peak plasma concentrations, but does not substantially alter exposure to selexipag or its active metabolite.1 6

Special Populations

Mild hepatic impairment (Child-Pugh class A): Selexipag exposure increased twofold; exposure to active metabolite unchanged.1

Moderate hepatic impairment (Child-Pugh class B): Selexipag exposure increased fourfold; exposure to active metabolite doubled.1

Severe renal impairment (eGFR of 15–29 mL/minute per 1.73 m2): Exposure to selexipag and its active metabolite increased by 40–70%.1

Distribution

Plasma Protein Binding

Approximately 99% (albumin and α-1-acid glycoprotein).1

Elimination

Metabolism

Hydrolyzed by hepatic and intestinal carboxylesterases to active metabolite.1 8

Both parent drug and active metabolite undergo oxidative metabolism (principally by CYP2C8 and to a lesser extent by CYP3A4) to less active hydroxylated and dealkylated metabolites.1 8

Active metabolite is further metabolized by uridine diphosphate-glucuronosyltransferases (UGT) 1A3 and 2B7.1 8

Elimination Route

Predominantly in feces (93%).1

Half-life

Selexipag: Approximately 0.8–2.5 hours.1 8

Active metabolite: Approximately 6.2–13.5 hours.1 8 Effective half-life approximately 3–4 hours.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Selective nonprostanoid prostacyclin receptor (IP receptor) agonist; structurally distinct from prostacyclin and its analogs.1 3 6 8 11

  • Activation of the IP receptor increases production of cyclic adenosine monophosphate (cAMP), which leads to vascular smooth muscle relaxation.6 12 14 16

  • Has been shown to decrease pulmonary vascular resistance, increase cardiac index, and decrease systemic vascular resistance without causing systemic hypotension in patients with PAH.1 14

  • Exhibits high selectivity for the IP receptor versus other prostanoid receptors.1 4 6 15

Advice to Patients

Importance of advising patients not to split, chew, or crush tablets.1

Importance of taking a missed dose as soon as it is remembered but not within 6 hours of the next regularly scheduled dose.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Available only through specialty pharmacies.8 17 (See Restricted Distribution under Dosage and Administration.)

Selexipag

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

200 mcg

Uptravi

Actelion

400 mcg

Uptravi

Actelion

600 mcg

Uptravi

Actelion

800 mcg

Uptravi

Actelion

1000 mcg

Uptravi

Actelion

1200 mcg

Uptravi

Actelion

1400 mcg

Uptravi

Actelion

1600 mcg

Uptravi

Actelion

Titration Pack

140 Tablets, Selexipag 200 mcg (Uptravi)

60 Tablets, Selexipag 800 mcg (Uptravi)

Uptravi Titration Pack

Actelion

AHFS DI Essentials. © Copyright 2018, Selected Revisions February 26, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Actelion Pharmaceuticals US. Uptravi (selexipag) tablets prescribing information. South San Francisco, CA; 2017 Jul.

3. Sitbon O, Channick R, Chin KM et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2015; 373:2522-33. [PubMed 26699168]

4. . Selexipag (Uptravi) for pulmonary arterial hypertension. Med Lett Drugs Ther. 2016; 58:21-3. [PubMed 26859660]

5. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2017 Apr 12.

6. Duggan ST, Keam SJ, Burness CB. Selexipag: A Review in Pulmonary Arterial Hypertension. Am J Cardiovasc Drugs. 2017; 17:73-80. [PubMed 27988834]

7. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 207947Orig1s000: summary review. From FDA website.

8. Baker WL, Darsaklis K, Singhvi A et al. Selexipag, an oral prostacyclin-receptor agonist for pulmonary arterial hypertension. Ann Pharmacother. 2017;

9. Kaufmann P, Niglis S, Bruderer S et al. Effect of lopinavir/ritonavir on the pharmacokinetics of selexipag an oral prostacyclin receptor agonist and its active metabolite in healthy subjects. Br J Clin Pharmacol. 2015; 80:670-7. [PubMed 25851691]

10. Bruderer S, Okubo K, Mukai H et al. Investigation of Potential Pharmacodynamic and Pharmacokinetic Interactions Between Selexipag and Warfarin in Healthy Male Subjects. Clin Ther. 2016; 38:1228-1236.e1. [PubMed 27063071]

11. Hardin EA, Chin KM. Selexipag in the treatment of pulmonary arterial hypertension: design, development, and therapy. Drug Des Devel Ther. 2016; 10:3747-3754. [PubMed 27895464]

12. Ataya A, Cope J, Alnuaimat H. A Review of Targeted Pulmonary Arterial Hypertension-Specific Pharmacotherapy. J Clin Med. 2016; 5 [PubMed 27929408]

14. Simonneau G, Torbicki A, Hoeper MM et al. Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J. 2012; 40:874-80. [PubMed 22362844]

15. Morrison K, Ernst R, Hess P et al. Selexipag: a selective prostacyclin receptor agonist that does not affect rat gastric function. J Pharmacol Exp Ther. 2010; 335:249-55. [PubMed 20660124]

16. Humbert M, Lau EM, Montani D et al. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation. 2014; 130:2189-208. [PubMed 25602947]

17. Actelion Pharmaceuticals US. Uptravi (selexipag) tablets help to get you started. South San Francisco, CA; 2016. Available online.

18. Actelion Pharmaceuticals US. South San Francisco, CA; Personal communication.

25. Zhu B, Wang L, Sun L et al. Combination therapy improves exercise capacity and reduces risk of clinical worsening in patients with pulmonary arterial hypertension: a meta-analysis. J Cardiovasc Pharmacol. 2012; 60:342-6. [PubMed 22691882]

27. Barst RJ, Gibbs JS, Ghofrani HA et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009; 54(1 Suppl):S78-84.

29. Gokhman R, Smithburger PL, Kane-Gill SL et al. Pharmacologic and Pharmacokinetic Rationale for Combination Therapy in Pulmonary Arterial Hypertension. J Cardiovasc Pharmacol. 2010; 56:686-95. [PubMed 20838230]

38. McLaughlin VV, Archer SL, Badesch DB et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009; 53:1573-619. [PubMed 19389575]

40. Galiè N, Corris PA, Frost A et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013; 62(25 Suppl):D60-72. [PubMed 24355643]

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