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.

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.

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.

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