Selexipag (Monograph)

Brand name: Uptravi
Drug class: Vasodilating Agents, Miscellaneous
Chemical name: 2-[4-[(5,6-diphenylpyrazin-2-yl)-propan-2-yl-amino]butoxy]-N-methylsulfonylacetamide
Molecular formula: C₂₆H₃₂N₄O₄S
CAS number: 475086-01-2

Medically reviewed by Drugs.com on Mar 27, 2023. Written by ASHP.

Introduction

Vasodilator; a selective nonprostanoid prostacyclin receptor (IP receptor) agonist.

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. 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).

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.

Expert consensus guidelines from the American College of Chest Physicians (ACCP) recommend that all adult patients with symptomatic PAH be treated with established PAH-specific medications. Selection of drug therapy should be based on disease severity (WHO/NYHA class) in addition to comorbid conditions, concomitant medications, adverse effects, route of administration, costs, and patient preferences.

The ACCP guideline panel determined that there was insufficient evidence to make a recommendation either for or against the use of selexipag because of limitations in the clinical trial data.

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

Selexipag Dosage and Administration

General

Patient Monitoring

Monitor patients for signs and symptoms of pulmonary edema.

Administration

Administer orally or by IV infusion. Parenteral preparation intended for use in patients who are temporarily unable to take oral therapy.

Oral Administration

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

Do not split, chew, or crush tablets.

IV Administration

Administer by IV infusion twice daily. Use an infusion set made of DEHP-free polyvinyl chloride, natural latex rubber-free microbore tubing protected from light. Do not use a filter for administration.

Reconstitute and further dilute prior to administration.

Reconstitution

Remove carton from refrigerator and allow to stand for approximately 30–60 minutes to reach room temperature (20–25°C). Protect vial from light.

Reconstitute using a polypropylene syringe with 8.6 mL of 0.9% sodium chloride injection; slowly inject diluent into vial to obtain a concentration of 225 mcg/mL. Document date and time of first vial puncture.

Dilution

Dilute in glass containers only. Transfer 100 mL of 0.9% sodium chloride injection into empty sterile glass container. Withdraw required volume of reconstituted selexipag solution using a single polypropylene syringe and add to glass container containing 100 mL 0.9% sodium chloride injection to obtain desired final dose. Assign a 4-hour expiry from time of first vial puncture; wrap glass container completely with light protective cover.

Complete infusion within 4 hours from first vial puncture (including infusion time).

Rate of Administration

Administer diluted selexipag for injection by IV infusion over 80 minutes using an infusion set made of DEHP-free polyvinyl chloride, natural latex rubber-free microbore tubing protected from light. Do not use a filter for administration.

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

Dosage

Adults

PAH

Oral

Individualize dosage based on tolerability.

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

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

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.

IV

Administer at a dose that corresponds to the patient’s current oral dose (see Table 1).

Dosage Modification for Co-administration of Moderate CYP2C8 Inhibitors

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

Prescribing Limits

Adults

PAH

Oral

Maximum 1600 mcg twice daily.

IV

Maximum 1800 mcg twice daily.

Special Populations

Hepatic Impairment

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

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

Severe hepatic impairment (Child-Pugh class C): Avoid use.

Renal Impairment

Patients with eGFR >15 mL/minute per 1.73 m²: No dosage adjustments necessary.

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

Geriatric Use

No specific dosage recommendations at this time.

Cautions for Selexipag

Contraindications

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

• Hypersensitivity to selexipag or any excipients.

Warnings/Precautions

Pulmonary Edema with Pulmonary Veno-Occlusive Disease

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

Specific Populations

Pregnancy

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

Lactation

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

Pediatric Use

Safety and efficacy not established.

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.

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).

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

Renal Impairment

Systemic exposure to selexipag is increased in patients with severe renal impairment (eGFR of 15–29 mL/minute per 1.73 m²).

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

Common Adverse Effects

Adverse effects (≥5% and more frequently than placebo): 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.

Drug Interactions

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

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).

Drugs Affecting Hepatic Microsomal Enzymes

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

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

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

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.

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.

Specific Drugs

Selexipag Pharmacokinetics

Absorption

Bioavailability

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

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

Corresponding oral and IV doses provide similar exposure to the active metabolite in PAH patients at steady-state, whereas exposure to selexipag is approximately twice as high after IV administration compared to oral administration.

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.

Special Populations

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

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

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

Distribution

Plasma Protein Binding

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

Elimination

Metabolism

Hydrolyzed by hepatic and intestinal carboxylesterases to active metabolite.

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.

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

Elimination Route

Predominantly in feces (93%).

Half-life

Selexipag: Approximately 0.8–2.5 hours.

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

Special Populations

No clinically relevant effects of sex, race, age, or body weight.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted to 15–30°C).

Parenteral

Injection, for IV infusion

2–8°C in original carton; protect from light.

Actions

• Selective nonprostanoid prostacyclin receptor (IP receptor) agonist; structurally distinct from prostacyclin and its analogs.

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

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

• Exhibits high selectivity for the IP receptor versus other prostanoid receptors.

Advice to Patients

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

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

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

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

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

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

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Frequently asked questions

• What is the drug Uptravi used for?

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