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  • CLASSES

    Vasodilators

    DEA CLASS

    Rx

    DESCRIPTION

    Oral, selective prostacyclin receptor agonist
    For treatment of pulmonary arterial hypertension (WHO Group I)
    Delays disease progression and reduces risk of hospitalization

    COMMON BRAND NAMES

    UPTRAVI

    HOW SUPPLIED

    UPTRAVI Oral Tab: 200mcg, 400mcg, 600mcg, 800mcg, 1000mcg, 1200mcg, 1400mcg, 1600mcg, 200-800mcg

    DOSAGE & INDICATIONS

    For the treatment of pulmonary hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization.
    Oral dosage
    Adults

    200 mcg PO twice daily. Increase the dose by 200 mcg PO twice daily at weekly intervals to the highest tolerated dose up to 1600 mcg PO twice daily. If the patient reaches a dose that cannot be tolerated, reduce the dose to the previously tolerated dose. If a dose is missed, administer as soon as possible unless the next dose is within the next 6 hours. If treatment is missed for 3 days or more, reinitiate treatment at a lower dose and retitrate.

    MAXIMUM DOSAGE

    Adults

    3200 mcg/day PO.

    Geriatric

    3200 mcg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild hepatic impairment (Child-Pugh class A): No dosage adjustments needed.
    Moderate hepatic impairment (Child-Pugh class B): Initiate therapy with 200 mcg PO once daily and increase by weekly increments of 200 mcg once daily, as tolerated.
    Severe hepatic impairment (Child-Pugh class C): Avoid use.

    Renal Impairment

    CrCl more than 15 mL/min/1.73 m2: No dosage adjustments needed.
    CrCl less than 15 mL/min/1.73 m2: There are no data.
     
    Intermittent hemodialysis
    There are no data in patients undergoing dialysis.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Administer with or without food. Administration with food may improve tolerability. Do not split, crush, or chew the tablets.

    STORAGE

    UPTRAVI:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Pregnancy

    There are no adequate and well-controlled studies with the administration of selexipag in human pregnancy. Animal studies showed no clinically relevant effects on embryofetal development and survival at exposures approximately 47 to 50 times the maximum recommended human dose.

    Breast-feeding

    It is unknown whether selexipag is present in human milk. Selexipag or its metabolites were present in rat milk. Due to the potential for serious adverse reactions in a nursing infant, the decision should be made to discontinue breast-feeding or discontinue selexipag. Eproprostenol may be a reasonable alternative in nursing women.

    ADVERSE REACTIONS

    Severe

    veno-occlusive disease (VOD) / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known

    Moderate

    anemia / Delayed / 8.6-8.6
    hyperthyroidism / Delayed / 1.0-1.0

    Mild

    headache / Early / 65.0-65.0
    diarrhea / Early / 42.0-42.0
    nausea / Early / 33.0-33.0
    vomiting / Early / 18.0-18.0
    myalgia / Early / 16.0-16.0
    flushing / Rapid / 12.0-12.0
    arthralgia / Delayed / 11.0-11.0
    rash (unspecified) / Early / 11.0-11.0
    anorexia / Delayed / 6.0-6.0

    DRUG INTERACTIONS

    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Acetaminophen; Guaifenesin; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Acetaminophen; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Acrivastine; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Amphetamine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Amphetamine; Dextroamphetamine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Articaine; Epinephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Benzphetamine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Brompheniramine; Carbetapentane; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Brompheniramine; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Cabozantinib: (Moderate) Monitor for an increase in selexipag-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of selexipag may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and selexipag is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Carbetapentane; Guaifenesin; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Carbetapentane; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Carbetapentane; Phenylephrine; Pyrilamine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Carbetapentane; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Carbinoxamine; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Carbinoxamine; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Cetirizine; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Chlophedianol; Guaifenesin; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Chlorpheniramine; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Chlorpheniramine; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Clopidogrel: (Severe) Coadministration of selexipag and clopidogrel is contraindicated due to significantly increased exposure to selexipag and its active metabolite, which may cause side effects. Selexipag is a CYP2C8 substrate, and clopidogrel is a strong CYP2C8 inhibitor.
    Codeine; Phenylephrine; Promethazine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Deferasirox: (Major) Consider a less frequent dosing regimen (e.g., once daily) when initiating selexipag in patients receiving deferasirox. Reduce the selexipag dose when deferasirox is initiated in patients already taking selexipag. Coadministration can be expected to increase exposure to selexipag and its active metabolite. Selexipag is a substrate of CYP2C8; deferasirox is a moderate CYP2C8 inhibitor.
    Desloratadine; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Dexmethylphenidate: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Dextroamphetamine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Diethylpropion: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Diphenhydramine; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Dobutamine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Dopamine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Duloxetine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
    Elbasvir; Grazoprevir: (Major) Administering selexipag with elbasvir may result in elevated selexipag plasma concentrations. Selexipag is a substrate of CYP3A and the active metabolite is a substrate for breast cancer resistance protein (BCRP). Elbasvir is an inhibitor of BCRP. If these drugs are used together, closely monitor for signs of adverse events. (Major) Administering selexipag with grazoprevir may result in elevated selexipag plasma concentrations. Selexipag is a substrate of CYP3A and the active metabolite is a substrate for breast cancer resistance protein (BCRP). Grazoprevir is an inhibitor of BCRP, and also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Ephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Epinephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Fexofenadine; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Gemfibrozil: (Severe) Coadministration of selexipag and gemfibrozil is contraindicated due to doubled exposure to selexipag and approximately 11-fold increased exposure to the selexipag active metabolite, which may cause side effects. Selexipag is a CYP2C8 substrate, and gemfibrozil is a strong CYP2C8 inhibitor.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Guaifenesin; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Guaifenesin; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Hydrocodone; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Hydrocodone; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Ibuprofen; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Increase the dose of selexipag up to twice when coadministering with rifampin. Reduce the selexipag dose when rifampin is stopped. Coadministration of selexipag and rifampin resulted in halved exposure to the selexipag active metabolite. Selexipag is a substrate of CYP2C8, UGT1A3, and UGT2B7; rifampin is an inducer of CYP2C8, UGT1A3, and UGT2B7.
    Isoniazid, INH; Rifampin: (Major) Increase the dose of selexipag up to twice when coadministering with rifampin. Reduce the selexipag dose when rifampin is stopped. Coadministration of selexipag and rifampin resulted in halved exposure to the selexipag active metabolite. Selexipag is a substrate of CYP2C8, UGT1A3, and UGT2B7; rifampin is an inducer of CYP2C8, UGT1A3, and UGT2B7.
    Isoproterenol: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Lapatinib: (Major) Consider a less frequent dosing regimen (e.g., once daily) when initiating selexipag in patients receiving lapatinib. Reduce the selexipag dose when lapatinib is initiated in patients already taking selexipag. Coadministration can be expected to increase exposure to selexipag and its active metabolite. Selexipag is a substrate of CYP2C8; lapatinib is a moderate CYP2C8 inhibitor.
    Lisdexamfetamine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Lopinavir; Ritonavir: (Moderate) Concurrent use of lopinavir with selexipag may result in elevated selexipag serum concentrations. Selexipag is a substrate for the drug transporter organic anion transporting polypeptide (OATP1B1/1B3); lopinavir is an OATP1B1 inhibitor. Monitor for increased toxicities if these drugs are given together.
    Loratadine; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Mepivacaine; Levonordefrin: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Methamphetamine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Methylphenidate: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Midodrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Naproxen; Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Nilotinib: (Major) Consider a less frequent dosing regimen (e.g., once daily) when initiating selexipag in patients receiving nilotinib. Reduce the selexipag dose when nilotinib is initiated in patients already taking selexipag. Coadministration can be expected to increase exposure to selexipag and its active metabolite. Selexipag is a substrate of CYP2C8; nilotinib is a moderate CYP2C8 inhibitor.
    Norepinephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Osimertinib: (Moderate) Use caution if coadministration of osimertinib with selexipag is necessary, due to the risk of increased selexipag exposure. Osimertinib is a BCRP inhibitor in vitro, and selexipag is a BCRP substrate. Coadministration of osimertinib with rosuvastatin, a BCRP substrate, increased the rosuvastatin AUC and Cmax by 35% and 72%, respectively; exposure to selexipag may also be expected to increase.
    Pemoline: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Phendimetrazine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Phentermine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Phentermine; Topiramate: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Phenylephrine; Promethazine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Prilocaine; Epinephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Pseudoephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Racepinephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Regorafenib: (Minor) Use caution if coadministration of regorafenib with selexipag is necessary, and monitor for an increase in selexipag-related adverse reactions. Selexipag is a BCRP and UGT substrate. Regorafenib is BCRP inhibitor, while regorafenib, M-2, and M-5 all competitively inhibit UGT1A9 and 1A1 in vitro. Regorafenib-mediated BCRP and UGT1A1 inhibition may increase exposure to selexipag.
    Rifampin: (Major) Increase the dose of selexipag up to twice when coadministering with rifampin. Reduce the selexipag dose when rifampin is stopped. Coadministration of selexipag and rifampin resulted in halved exposure to the selexipag active metabolite. Selexipag is a substrate of CYP2C8, UGT1A3, and UGT2B7; rifampin is an inducer of CYP2C8, UGT1A3, and UGT2B7.
    Ritodrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and selexipag as coadministration may result in increased systemic exposure of selexipag. Selexipag is a substrate for the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); in vitro data show that sapropterin may inhibit these transporters. If these drugs are used together, closely monitor for increased side effects of selexipag.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concurrent administration of voxilaprevir with selexipag. Taking these medications together may increase selexipag plasma concentrations, potentially increasing the risk for adverse events. Selexipag is a substrate for the drug transporters P-glycoprotein (P-gp), Organic Anion Transporting Polypeptides 1B1/1B3 (OATP1B1/1B3), and Breast Cancer Resistance Protein (BCRP). Voxilaprevir is a P-gp, OATP1B1/1B3, and BCRP inhibitor.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Consider a less frequent dosing regimen (e.g., once daily) when initiating selexipag in patients receiving trimethoprim. Reduce the selexipag dose when trimethoprim is initiated in patients already taking selexipag. Coadministration can be expected to increase exposure to selexipag and its active metabolite. Selexipag is a substrate of CYP2C8; trimethoprim is a moderate CYP2C8 inhibitor.
    Sympathomimetics: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Tedizolid: (Moderate) If possible, stop use of selexipag temporarily during treatment with oral tedizolid. If coadministration cannot be avoided, closely monitor for selexipag-associated adverse events. Concentrations of the selexipag active metabolite may be increased when selexipag is administered concurrently with oral tedizolid. The active metabolite of selexipag is a substrate of the Breast Cancer Resistance Protein (BCRP); oral tedizolid inhibits BCRP in the intestine.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with selexipag is necessary, and monitor for an increase in selexipag-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) inhibitor in vitro, and selexipag is a P-gp substrate. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp substrates, but exposure to selexipag is likely to increase.
    Teriflunomide: (Major) Consider a less frequent dosing regimen (e.g., once daily) when initiating selexipag in patients receiving teriflunomide. Reduce the selexipag dose when teriflunomide is initiated in patients already taking selexipag. Coadministration can be expected to increase exposure to selexipag and its active metabolite. Selexipag is a substrate of CYP2C8; teriflunomide is a moderate CYP2C8 inhibitor.
    Trimethoprim: (Major) Consider a less frequent dosing regimen (e.g., once daily) when initiating selexipag in patients receiving trimethoprim. Reduce the selexipag dose when trimethoprim is initiated in patients already taking selexipag. Coadministration can be expected to increase exposure to selexipag and its active metabolite. Selexipag is a substrate of CYP2C8; trimethoprim is a moderate CYP2C8 inhibitor.
    Vandetanib: (Moderate) Use caution if coadministration of vandetanib with selexipag is necessary, due to a possible increase in selexipag-related adverse reactions. Selexipag is partially a substrate of P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of digoxin, another P-gp substrate, by 29% and 23%, respectively.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and selexipag is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies with the administration of selexipag in human pregnancy. Animal studies showed no clinically relevant effects on embryofetal development and survival at exposures approximately 47 to 50 times the maximum recommended human dose.

    It is unknown whether selexipag is present in human milk. Selexipag or its metabolites were present in rat milk. Due to the potential for serious adverse reactions in a nursing infant, the decision should be made to discontinue breast-feeding or discontinue selexipag. Eproprostenol may be a reasonable alternative in nursing women.

    MECHANISM OF ACTION

    Prostacyclin synthase is reduced in patients with pulmonary arterial hypertension, resulting in reduced production of prostacyclin, a potent vasodilator with antiproliferative effects. Selexipag is an oral selective prostacyclin receptor (IP receptor) agonist that is structurally distinct from prostacyclin. Activation of the prostacyclin receptor produces cyclic adenosine monophosphate, which induces vascular smooth muscle relaxation and produces decreases in vascular pressure and pulmonary vascular resistance and an increase in cardiac index.

    PHARMACOKINETICS

    Selexipag is administered orally. Selexipag and its active metabolite are highly bound (approximately 99%) to plasma protein. Selexipag is hydrolyzed by carboxylesterase 1 to yield its active metabolite. The exposure at steady-state to the active metabolite is approximately 3- to 4-fold that of selexipag. The volume of distribution of selexipag at steady state is 11.7 L. Elimination of selexipag is predominantly via metabolism. The terminal half-life of selexipag is 0.8 to 2.5 hours, and the terminal half-life of the active metabolite is 6.2 to 13.5 hours. Minimal accumulation of the active metabolite was noted upon twice daily administration, suggesting that the effective half-life is in the range of 3 to 4 hours. In a study of radiolabeled selexipag, neither selexipag nor its active metabolite was found in urine.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP2C8, CYP3A4, UGT1A3, UGT2B7, OATP1B1, OATP1B3, P-gp, BCRP.
    Selexipag and its metabolite both undergo oxidative metabolism mainly by CYP2C8 and to a smaller extent by CYP3A4. Glucuronidation of the active metabolite is catalyzed by UGT1A3 and UGT2B7. Selexipag and its metabolite are substrates of OATP1B1 and OATP1B3. Selexipag is a substrate of P-glycoprotein (P-gp), and the active metabolite is a substrate of the the breast cancer resistance protein (BCRP). At clinically relevant concentrations, selexipag and its active metabolite do not inhibit or induce cytochrome P450 isoenzymes or hepatic or renal transport proteins.

    Oral Route

    After oral administration, the maximum plasma concentration of selexipag and its active metabolite are reached in approximately 1 to 3 hours and 3 to 4 hours, respectively. The absorption of selexipag is prolonged in the presence of food, resulting in a delayed time to peak plasma concentration and a lower (approximately 30%) peak plasma concentration. The exposure to selexipag and the active metabolite did not change significantly in the presence of food.