Selexipag
Brand name: Uptravi
Drug 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
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.
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. 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.
Has been designated an orphan drug by FDA for treatment of PAH.
Selexipag Dosage and Administration
General
Restricted Distribution
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Available only through specialty pharmacies.
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For additional information, contact the manufacturer at 866-228-3546.
Administration
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.
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.
Prescribing Limits
Adults
PAH
Oral
Maximum 1600 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 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. (See Hepatic Impairment under Cautions.)
Renal Impairment
Patients with eGFR >15 mL/minute per 1.73 m2: No dosage adjustments necessary. (See Renal Impairment under Cautions.)
Patients with eGFR <15 mL/minute per 1.73 m2 or those undergoing dialysis: Not studied.
Cautions for Selexipag
Contraindications
-
Concomitant use of potent inhibitors of CYPC28 (e.g., gemfibrozil).
Warnings/Precautions
Pulmonary Effects
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). (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.
Renal Impairment
Systemic exposure to selexipag is increased in patients with severe renal impairment (eGFR of 15–29 mL/minute per 1.73 m2). (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.
Common Adverse Effects
Headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, flushing, arthralgia, anemia, decreased appetite, rash.
Interactions for Selexipag
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
Drug |
Interaction |
Comments |
---|---|---|
Deferasirox |
May increase exposure to active metabolite of selexipag |
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 selexipag |
Endothelin-receptor antagonists |
No clinically relevant drug interaction observed |
No dosage adjustment necessary |
Gemfibrozil |
Increased exposure to selexipag by twofold and its active metabolite by 11-fold |
Concomitant use contraindicated |
Lopinavir and ritonavir |
Fixed combination of lopinavir and ritonavir (lopinavir/ritonavir): No clinically relevant pharmacokinetic interaction observed |
No dosage adjustment necessary |
PDE type 5 inhibitors |
No clinically relevant drug interaction observed |
No dosage adjustment necessary |
Rifampin |
May decrease exposure to active metabolite of selexipag |
Increase dosage of selexipag (up to twofold) when used concomitantly with rifampin; reduce selexipag dosage when rifampin is discontinued |
Teriflunomide |
May increase exposure to active metabolite of selexipag |
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 selexipag |
Warfarin |
No change in pharmacokinetics of warfarin or selexipag; no effect on INR |
No dosage adjustment necessary |
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.
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.
Stability
Storage
Oral
Tablets
20–25°C (may be exposed to 15–30°C).
Actions
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Selective nonprostanoid prostacyclin receptor (IP receptor) agonist; structurally distinct from prostacyclin and its analogs.
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Activation of the IP receptor increases production of cyclic adenosine monophosphate (cAMP), which leads to vascular smooth muscle relaxation.
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Has been shown to decrease pulmonary vascular resistance, increase cardiac index, and decrease systemic vascular resistance without causing systemic hypotension in patients with PAH.
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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 concomitant illnesses.
Importance of informing patients of other important precautionary information. (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. (See Restricted Distribution under Dosage and Administration.)
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 2023, Selected Revisions February 26, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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