DRUG INTERACTIONS- (summary)

 Recommended dosage modifications: • Strong CYP3A4 Inhibitor: 10 mg once daily.

 • Strong and Moderate CYP3A4 Inducers: 30 mg or 60 mg once daily.

 • OATP Inhibitors: 10 mg or 30 mg once daily.

DRUG INTERACTIONS- Details)

1 CYP3A4 Inhibitors- Coadministration of QULIPTA with itraconazole, a strong CYP3A4 inhibitor, resulted in a significant increase in exposure of atogepant in healthy subjects 

The recommended dosage of QULIPTA with concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) is 10 mg once dail

. No dosage adjustment of QULIPTA is needed with concomitant use of moderate or weak CYP3A4 inhibitors.

2. CYP3A4 Inducers- Coadministration of QULIPTA with steady state rifampin, a strong CYP3A4 inducer, resulted in a significant decrease in exposure of atogepant in healthy subjects

 Concomitant administration of QULIPTA with moderate inducers of CYP3A4 can also result in decreased exposure of atogepant.

The recommended dosage of QULIPTA with concomitant use of strong or moderate CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort, efavirenz, etravirine) is 30 mg or 60 mg once daily .

No dosage adjustment of QULIPTA is needed with concomitant use of weak CYP3A4 inducers.

3. OATP Inhibitors- Coadministration of QULIPTA with single dose rifampin, an OATP inhibitor, resulted in a significant increase in exposure of atogepant in healthy subjects

 The recommended dosage of QULIPTA with concomitant use of OATP inhibitors (e.g., cyclosporine) is 10 mg or 30 mg once daily 

BRIEF SUMMARY

ATOGEPANT- (Sep 2021)

Indn-  To prevent Episode Migraine 

Comp.   Tablets: 10 mg, 30 mg, and 60 mg.  The recommended dosage is 10 mg, 30 mg, or 60 mg taken orally once daily with or without food.

ADR- The most common adverse reactions (at least 4% and greater than placebo) are nausea, constipation, a-                                                                                                     -

 CI- None.

Pat Inform-

Drug Interactions Inform patients that the drug may interact with certain other drugs, and that dosage modifications may be recommended when used with some other drugs.

Advise patients to report to their healthcare provider the use of any other prescription medications, overthe-counter medications, herbal products, or grapefruit juice 

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U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 40

Name of the Drug-    QULIPTA

Active Ingredient -   Atogepant

Pharmacological Classification- To prevent Episode Migraine                                                                                                                                                                                                                                                                                                                                      Date of Approval-          9/28/21    

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use                                    QULIPTA safely and effectively.                                                                                      See full prescribing information for QULIPTA. QULIPTA (atogepant) tablets, for oral use

Initial U.S. Approval: 2021

INDICATIONS AND USAGE-

 QULIPTA is a calcitonin gene-related peptide receptor antagonist indicated for the preventive treatment of episodic migraine in adults.

ADVERSE REACTIONS-

The most common adverse reactions (at least 4% and greater than placebo) are nausea, constipation, and fatigue.

CONTRAINDICATIONS-                                                                                                     - None.

DOSAGE AND ADMINISTRATION-

 • The recommended dosage is 10 mg, 30 mg, or 60 mg taken orally once daily with or without food.                                                                                                                         • Severe Renal Impairment or End-Stage Renal Disease: 10 mg once daily.

DOSAGE FORMS AND STRENGTHS-                                                                             Tablets: 10 mg, 30 mg, and 60 mg.

PATIENT COUNSELING INFORMATION-

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Drug Interactions Inform patients that QULIPTA may interact with certain other drugs, and that dosage modifications of QULIPTA may be recommended when used with some other drugs.

Advise patients to report to their healthcare provider the use of any other prescription medications, overthe-counter medications, herbal products, or grapefruit juice 

. Manufactured by: Forest Laboratories Ireland Ltd. Dublin, Ireland © 2021 AbbVie. All rights reserved. QULIPTA™ is a trademark of Allergan Pharmaceuticals International Limited, an AbbVie company

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                            Atogepant is a calcitonin gene-related peptide (CGRP) receptor antagonist.

2. Pharmacodynamics-                                                                                               Cardiac Electrophysiology -At a dose 5 times the maximum recommended daily dose, QULIPTA does not prolong the QT interval to any clinically relevant extent.

3. Pharmacokinetics-                                                                                                Absorption- Following oral administration of QULIPTA, atogepant is absorbed with peak plasma concentrations at approximately 1 to 2 hours. Following once daily dosing, atogepant displays dose-proportional pharmacokinetics up to 170 mg (approximately 3 times the highest recommended dosage), with no accumulation.

Effect of Food- When QULIPTA was administered with a high-fat meal, the food effect was not significant (AUC and Cmax were reduced by approximately 18% and 22%, respectively, with no effect on median time to maximum atogepant plasma concentration). QULIPTA was administered without regard to food in clinical efficacy studies.

Distribution- Plasma protein binding of atogepant was not concentration-dependent in the range of 0.1 to 10 µM; the unbound fraction of atogepant was approximately 4.7% in human plasma.

The mean apparent volume of distribution of atogepant (Vz/F) after oral administration is approximately 292 L

 Elimination-                                                                                                                Metabolism- Atogepant is eliminated mainly through metabolism, primarily by CYP3A4. The parent compound (atogepant), and a glucuronide conjugate metabolite (M23) were the most prevalent circulating components in human plasma. Reference ID: 4864125

Excretion -The elimination half-life of atogepant is approximately 11 hours. The mean apparent oral clearance (CL/F) of atogepant is approximately 19 L/hr. Following single oral dose of 50 mg 14C-atogepant to healthy male subjects, 42% and 5% of the dose was recovered as unchanged atogepant in feces and urine, respectively.

Specific Populations-                                                                                             Patients with Renal Impairment The renal route of elimination plays a minor role in the clearance of atogepant. Based on a population pharmacokinetic analysis, there is no significant difference in the pharmacokinetics of atogepant in patients with mild or moderate renal impairment (CLcr 30-89 mL/min) relative to those with normal renal function (CLcr >90 mL/min).

As patients with severe renal impairment or end-stage renal disease (ESRD; CLcr <30 mL/min) have not been studied, use of the lowest effective dosage of atogepant (10 mg) is recommended in those patients.

 Patients with Hepatic Impairment- In patients with pre-existing mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe hepatic impairment (Child-Pugh Class C), the total atogepant exposure was increased by 24%, 15%, and 38%, respectively.

Due to a potential for liver injury in patients with severe hepatic impairment, avoid use of QULIPTA in patients with severe hepatic impairment

Other Specific Populations-                                                                                             Based on a population pharmacokinetic analysis, age, sex, race, and body weight did not have a significant effect on the pharmacokinetics (Cmax and AUC) of atogepant. Therefore, no dose adjustments are warranted based on these factors.

Drug Interactions In Vitro Studies-                                                                             Enzymes In vitro, atogepant is not an inhibitor for CYPs 3A4, 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 at clinically relevant concentrations.

Atogepant does not inhibit MAO-A or UGT1A1 at clinically relevant concentrations. Atogepant is not anticipated to be a clinically significant perpetrator of drug-drug interactions through CYP450s, MAO-A, or UGT1A1 inhibition. Atogepant is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.

Transporters -Atogepant is a substrate of P-gp, BCRP, OATP1B1, OATP1B3, and OAT1. Dose adjustment for concomitant use of QULIPTA with inhibitors of OATP is recommended based on a clinical interaction study with a OATP inhibitor.

Coadministration of atogepant with BCRP and/or P-gp inhibitors is not expected to increase the exposure of atogepant. Atogepant is not a substrate of OAT3, OCT2, or MATE1.

Atogepant is not an inhibitor of P-gp, BCRP, OAT1, OAT3, NTCP, BSEP, MRP3, or MRP4 at clinically relevant concentrations. Atogepant is a weak inhibitor of OATP1B1, OATP1B3, OCT1, and MATE1. No clinical drug interactions are expected for atogepant as a perpetrator with these transporters.

In Vivo Studies CYP3A4 Inhibitors -                                                                                 Co-administration of QULIPTA with itraconazole, a strong CYP3A4 inhibitor, resulted in a clinically significant increase (Cmax by 2.15-fold and AUC by 5.5-fold) in the exposure of atogepant in healthy subjects 

Population pharmacokinetic modeling suggested co-administration of QULIPTA with moderate (e.g., cyclosporine, ciprofloxacin, fluconazole, fluvoxamine, grapefruit juice) or weak (e.g., cimetidine, esomeprazole) CYP3A4 inhibitors increase atogepant AUC by 1.7- and 1.1-fold, respectively.

The changes in atogepant exposure when coadministered with weak or moderate CYP3A4 inhibitors are not expected to be clinically significant. CYP3A4 Inducers Co-administration of QULIPTA with rifampin, a strong CYP3A4 inducer, decreased atogepant AUC by 60% and Cmax by 30% in healthy subjects 

No dedicated drug interaction studies were conducted to assess concomitant use with moderate or weak CYP3A4 inducers. Moderate inducers of CYP3A4 can decrease atogepant exposure [see Drug Interactions (7.2)].

Other  Drug Interaction evaluationtions- Co-administration of QULIPTA with oral contraceptive components ethinyl estradiol and levonorgestrel, famotidine, esomeprazole, acetaminophen, naproxen, or sumatriptan did not result in significant pharmacokinetic interactions for either atogepant or co-administered drugs.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                           There are no adequate data on the developmental risk associated with the use of QULIPTA in pregnant women.

In animal studies, oral administration of atogepant during the period of organogenesis (rats and rabbits) or throughout pregnancy and lactation (rats) resulted in adverse developmental effects (decreased fetal and offspring body weight in rats; increased incidence of fetal structural variations in rabbits) at exposures greater than those used clinically [see Data].

In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The estimated rate of major birth defects (2.2%-2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy.

2. Lactation-                                                                                                                There are no data on the presence of atogepant in human milk, the effects of atogepant on the breastfed infant, or the effects of atogepant on milk production. In lactating rats, oral dosing with atogepant resulted in levels of atogepant in milk approximately 2-fold higher than that in maternal plasma.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for QULIPTA and any potential adverse effects on the breastfed infant from QULIPTA or from the underlying maternal condition.

3.Pediatric Use-                                                                                                         Safety and effectiveness in pediatric patients have not been established.

4. Geriatric Use-                                                                                                          Population pharmacokinetic modeling suggests no clinically significant pharmacokinetic differences between elderly and younger subjects.

Clinical studies of QULIPTA did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients

. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

5. Renal Impairment -                                                                                                      The renal route of elimination plays a minor role in the clearance of atogepant                In patients with severe renal impairment (CLcr 15-29 mL/min), and in patients with end-stage renal disease (ESRD) (CLcr <15 mL/min), the recommended dosage of QULIPTA is 10 mg once daily. For patients with ESRD undergoing intermittent dialysis, QULIPTA should preferably be taken after dialysis 

No dose adjustment is recommended for patients with mild or moderate renal impairment.

6. Hepatic Impairment-                                                                                                   No dose adjustment of QULIPTA is recommended for patients with mild or moderate hepatic impairment. Avoid use of QULIPTA in patients with severe hepatic impairment