Qulipta (atogepant)

Avoidance of use or dosage modification of atogepant is necessary if the drug is used concomitantly with a strong CYP3A4 inhibitor, a CYP3A4 inducer (strong, moderate, or weak), or an OATP inhibitor.

If concomitant use with a strong CYP3A4 inhibitor is necessary, the manufacturer recommends an atogepant dosage of 10 mg once daily.

Concomitant use with a moderate or strong CYP3A4 inducer is not recommended.

If concomitant use with a weak CYP3A4 inducer is necessary, the manufacturer recommends an atogepant dosage of 60 mg once daily. Concurrent administration reduces atogepant exposure; therefore, clinicians should monitor for reduced efficacy with concurrent use.

If concomitant use with an OATP inhibitor is necessary, the manufacturer recommends an atogepant dosage of 30 mg once daily.

Dosage adjustment of atogepant is necessary if the drug is used concomitantly with a strong cytochrome P-450 (CYP) 3A4 inhibitor, a CYP3A4 inducer (strong, moderate, or weak), or an organic anion transport protein (OATP) inhibitor.

If concomitant use with a strong CYP3A4 inducer is necessary, the manufacturer recommends an atogepant dosage of 60 mg once daily. Concurrent administration reduces atogepant exposure; therefore, clinicians should monitor for reduced efficacy with concurrent use.

If concomitant use with a moderate CYP3A4 inducer is necessary, the manufacturer recommends an atogepant dosage of 60 mg once daily.

If concomitant use with a weak CYP3A4 inducer is necessary, the manufacturer recommends an atogepant dosage of 30 or 60 mg once daily.

If concomitant use with an OATP inhibitor is necessary, the manufacturer recommends an atogepant dosage of 10 or 30 mg once daily.

Atogepant tablets are administered orally without regard to food.

Store atogepant tablets at 20-25degreesC (excursions permitted between 15-30degreesC).

No dosing information is available for this tab.

Atogepant is metabolized principally by cytochrome P-450 (CYP) 3A4. In vitro, the drug does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4; monoamine oxidase-A (MAO-A); or uridine diphosphate-glucuronosyltransferase (UGT) 1A1 at clinically relevant concentrations. The drug also does not induce CYP isoenzymes 1A2, 2B6, or 3A4 at clinically relevant concentrations.

In vitro studies indicate that atogepant is a substrate of breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), organic anion transporting polypeptide (OATP) 1B1 and 1B3, and organic anion transporter (OAT) 1, but is not a substrate of OAT3, organic cation transporter (OCT) 2, or multidrug and toxic compound extrusion (MATE) 1. The drug is a weak inhibitor of OATP1B1, OATP1B3, OCT2, and MATE1; however, this inhibition potential is not expected to be clinically important. Atogepant does not inhibit P-gp, BCRP, bile salt export pump (BSEP), multidrug resistance protein (MRP) 3, MRP4, OAT1, OAT3, or sodium taurocholate cotransporting polypeptide (NTCP).

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Atogepant/Encorafenib; Rifampin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Atogepant is a substrate of CYP3A4 and OATP1B1/1B3.(1) Encorafenib and rifampin are inhibitors of the OATP transporters may decrease the hepatic uptake of atogepant. Encorafenib and rifampin are also strong CYP3A4 inducers and may increase the metabolism of atogepant.(2,3)

CLINICAL EFFECTS: The exact course of this interaction is unknown. When encorafenib or rifampin is first started and before CYP enzyme induction occurs, atogepant levels may increase and result in side effects from atogepant, including nausea, constipation and fatigue. After CYP3A4 enzymes are induced, atogepant levels and effectiveness may decrease.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When used concurrently with an OATP inhibitor, the recommended atogepant dose for episodic migraine is 10 mg or 30 mg once daily, and the recommended atogepant dose for chronic migraine is 30 mg once daily. When used concurrently with a strong CYP3A4 inducer, the recommended atogepant dose for episodic migraine is 30 mg or 60 mg daily. When atogepant is used for chronic migraine, concurrent CYP3A4 inducers should be avoided.(1) Atogepant dose may need to be adjusted in the first weeks of concurrent therapy with encorafenib or rifampin. Monitor the patient for side effects and efficacy.

DISCUSSION: In a clinical trial of healthy subjects, single-dose rifampin increased the atogepant area-under-curve (AUC) and maximum concentration (Cmax) by 2.85-fold and 2.23-fold, respectively.(1) In a study of healthy subjects, steady state rifampin decreased the AUC and Cmax of atogepant by 60% and 30%, respectively.(1)

Atogepant/Moderate Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Moderate CYP3A4 inducers may increase the metabolism of atogepant by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of moderate CYP3A4 inducers with atogepant may result in decreased levels and clinical effectiveness of atogepant.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of atogepant recommends that patients on concomitant moderate CYP3A4 inducers receive atogepant 60 mg once daily for prevention of episodic migraines and use of atogepant is not recommended for prevention of chronic migraines.(1) Patients receiving concurrent therapy with CYP3A4 inducers and atogepant should be observed for decreased clinical effectiveness.

DISCUSSION: In a study of healthy subjects, rifampin, a strong CYP3A4 inducer, decreased the area-under-curve (AUC) and maximum concentration (Cmax) of atogepant by 60% and 30%, respectively. Topiramate, a weak CYP3A4 inducer, decreased atogepant AUC and Cmax by 25% and 24%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine and tovorafenib.(1,2)

Atogepant/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inducers may increase the metabolism of atogepant by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of strong CYP3A4 inducers with atogepant may result in decreased levels and clinical effectiveness of atogepant.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of atogepant recommends that patients on concomitant strong CYP3A4 inducers receive atogepant 60 mg once daily for prevention of episodic migraines and use of atogepant is not recommended for prevention of chronic migraines.(1) Patients receiving concurrent therapy with CYP3A4 inducers and atogepant should be observed for decreased clinical effectiveness.

DISCUSSION: In a study of healthy subjects, rifampin, a strong CYP3A4 inducer, decreased the area-under-curve (AUC) and maximum concentration (Cmax) of atogepant by 60% and 30%, respectively. Topiramate, a weak CYP3A4 inducer, decreased atogepant AUC and Cmax by 25% and 24%, respectively.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifapentine, and St. John's wort.(1,2)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Atogepant/Oatp1b1-3 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Atogepant is a substrate of OATP1B1 and 1B3. Inhibitors of these transporters may increase the GI absorption and/or decrease the hepatic uptake of atogepant.(1)

CLINICAL EFFECTS: Concurrent use of OATP1B1 or 1B3 inhibitors may result in elevated levels of and side effects from atogepant, including nausea, constipation and fatigue.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of atogepant states that, when used concurrently with an OATP inhibitor for prevention of episodic migraine, the atogepant dose should be limited to 10 mg or 30 mg once daily. When used concurrently with an OATP inhibitor for prevention of chronic migraines, the atogepant dose should be limited to 30 mg once daily.(1)

DISCUSSION: In a clinical trial of healthy subjects, single-dose rifampin, an OATP inhibitor, increased the atogepant area-under-curve (AUC) and maximum concentration (Cmax) by 2.85-fold and 2.23-fold, respectively.(1) OATP1B1 and 1B3 inhibitors include: atazanavir, belumosudil, cyclosporine, darunavir, eltrombopag, erythromycin, gemfibrozil, glecaprevir-pibrentasvir, ledipasvir, leflunomide, leniolisib, letermovir, paritaprevir, resmetirom, ritonavir, roxadustat, simeprevir, sofosbuvir, teriflunomide, vadadustat, velpatasvir, and voclosporin.(1,2)

Atogepant/Strong Cyp3a4 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of atogepant.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from atogepant, including nausea, constipation, and fatigue.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of atogepant recommends that patients on concomitant strong CYP3A4 inhibitors receive atogepant 10 mg once daily for prevention of episodic migraines and for prevention of chronic migraines.(1)

DISCUSSION: In a study of healthy subjects, itraconazole, a strong CYP3A4 inhibitor, increased the atogepant area-under-curve (AUC) by 5.5-fold and maximum concentration (Cmax) by 2.15-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(2,3)

Atogepant/Weak Cyp3a4 Inducers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Weak CYP3A4 inducers may increase the metabolism of atogepant by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of weak CYP3A4 inducers with atogepant may result in decreased levels and clinical effectiveness of atogepant.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of atogepant recommends that patients on concomitant weak CYP3A4 inducers receive atogepant 30 mg or 60 mg once daily for prevention of episodic migraines and receive atogepant 60 mg once daily for prevention of chronic migraines.(1) Patients receiving concurrent therapy with CYP3A4 inducers and atogepant should be observed for decreased clinical effectiveness.

DISCUSSION: In a study of healthy subjects, rifampin, a strong CYP3A4 inducer, decreased the area-under-curve (AUC) and maximum concentration (Cmax) of atogepant by 60% and 30%, respectively. Topiramate, a weak CYP3A4 inducer, decreased atogepant AUC and Cmax by 25% and 24%, respectively.(1) Weak CYP3A4 inducers linked to this monograph include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(1,2)

*Hypersensitivity to atogepant or any of the inactive ingredients in the formulation.

• Child-pugh class C hepatic impairment

• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Disease of liver

• Hypertension
• Raynaud's phenomenon

Common adverse reactions reported in >=4% of patients receiving atogepant in clinical studies include nausea, constipation, and fatigue/somnolence.

Less Frequent

• Anaphylaxis
• Dyspnea

Rare or Very Rare

• Abnormal hepatic function tests

More Frequent

• Constipation
• Fatigue
• Nausea

Less Frequent

• Anorexia
• Facial edema
• Pruritus of skin
• Skin rash
• Urticaria

Rare or Very Rare

• Dizziness
• Hypersensitivity drug reaction
• Hypertension
• Raynaud's phenomenon

No enhanced messaging available.

Safety and efficacy of atogepant have not been established in pediatric patients.

There are no adequate data on the developmental risk associated with the use of atogepant in pregnant women. Based on animal studies, the drug may cause fetal harm. In animal studies, adverse effects on embryofetal development (e.g., decreased fetal and offspring body weight in rats, increased fetal structural variations in rabbits) were observed following administration of the drug during pregnancy and lactation at dosages higher than those used clinically.

Published data suggest that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy. A pregnancy exposure registry exists that monitors outcomes in pregnant women administered atogepant. Patients can enroll by calling 1-833-277-0206 or by visiting https://empresspregnancyregistry.com.

Atogepant is distributed into human milk at low amounts. The effects of atogepant on the breast-fed infant and on milk production are not known.

Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for atogepant and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

Select dosage with caution, usually starting at the low end of the dosage range.

Clinical studies of atogepant did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently than younger adults. In pharmacokinetic studies, no clinically important differences in the pharmacokinetics of atogepant were observed between geriatric individuals and younger adults. The manufacturer states that, in general, dosage selection for geriatric patients should be cautious and start at the low end of the dosage range.