Qulipta

2.1        Recommended Dosage

QULIPTA is taken orally with or without food.

Episodic Migraine

The recommended dosage of QULIPTA for episodic migraine is 10 mg, 30 mg, or 60 mg taken once daily.

Chronic Migraine

The recommended dosage of QULIPTA for chronic migraine is 60 mg taken once daily.

2.2        Dosage Modifications 

Dosing modifications for concomitant use of specific drugs and for patients with renal impairment are provided in Table 1.

8.1        Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors outcomes in women who become pregnant while taking QULIPTA. Patients should be encouraged to enroll by calling 1-833-277-0206 or visiting http://empresspregnancyregistry.com.

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.

Data

Animal Data

Oral administration of atogepant (0, 5, 15, 125, or 750 mg/kg/day) to pregnant rats during the period of organogenesis resulted in decreases in fetal body weight and in skeletal ossification at the two highest doses tested (125 and 750 mg/kg), which were not associated with maternal toxicity.  At the no-effect dose (15 mg/kg/day) for adverse effects on embryofetal development, plasma exposure (AUC) was approximately 4 times that in humans at the maximum recommended human dose (MRHD) of 60 mg/day.

Oral administration of atogepant (0, 30, 90, or 130 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in an increase in fetal visceral and skeletal variations at the highest dose tested (130 mg/kg/day), which was associated with minimal maternal toxicity. At the no-effect dose (90 mg/kg/day) for adverse effects on embryofetal development, plasma exposure (AUC) was approximately 3 times that in humans at the MRHD.

Oral administration of atogepant (0, 15, 45, or 125 mg/kg/day) to rats throughout gestation and lactation resulted in decreased pup body weight at the highest dose tested (125 mg/kg/day), which persisted into adulthood. At the no-effect dose (45 mg/kg/day) for adverse effects on pre- and postnatal development, plasma exposure (AUC) was approximately 5 times that in humans at the MRHD.

8.2        Lactation

Risk Summary

Data from a lactation study in twelve healthy adult females indicate that atogepant is excreted in breast milk in low amounts. The estimated relative infant dose is approximately 0.19% of the maternal weight-adjusted dose, and the milk-to-plasma ratio is 0.08 (see Data). There are no data on the effects of atogepant on the breastfed infant or the effects on milk production. 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.

Data

A study was conducted in twelve healthy adult lactating females who were between 23 and 34 years of age and between 1 month and 6 months postpartum. Each subject was administered a single oral dose of atogepant 60 mg. Maternal plasma and breast milk were collected for 24 hours after dosing. Using a 150 mL/kg/day estimated infant milk intake, the mean estimated relative infant dose was approximately 0.19% of the maternal weight-adjusted dose. The mean milk-to-plasma ratio was 0.08. All subjects had detectable levels of atogepant in breast milk during the study; by 16 to 24 hours after dosing, 25% of females in the study had detectable levels of atogepant in breast milk. The mean cumulative amount of atogepant excreted in breast milk over 24 hours was less than 0.01 mg of a 60 mg dose.

8.4        Pediatric Use

Safety and effectiveness in pediatric patients have not been established. 

8.5        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.

8.6        Renal Impairment

The renal route of elimination plays a minor role in the clearance of atogepant [see Clinical Pharmacology ( 12.3)]. For episodic migraine, 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; in patients with ESRD undergoing intermittent dialysis, QULIPTA should preferably be taken after dialysis [see Dosage and Administration ( 2.2)]. For chronic migraine, avoid use of QULIPTA in patients with severe renal impairment and in patients with ESRD. No dose adjustment is recommended for patients with mild or moderate renal impairment.

8.7        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 [see Adverse Reactions ( 6.1) and Clinical Pharmacology ( 12.3)].

5.1        Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, dyspnea, rash, pruritus, urticaria, and facial edema, have been reported with use of QULIPTA [see Adverse Reactions ( 6.2)]. Hypersensitivity reactions can occur days after administration. If a hypersensitivity reaction occurs, discontinue QULIPTA and institute appropriate therapy [see Contraindications ( 4)].

5.2        Hypertension

Development of hypertension and worsening of pre-existing hypertension have been reported following the use of CGRP antagonists, including QULIPTA, in the postmarketing setting. Some of the patients who developed new-onset hypertension had risk factors for hypertension. There were cases requiring initiation of pharmacological treatment for hypertension and, in some cases, hospitalization. Hypertension may occur at any time during treatment, but was most frequently reported within 7 days of therapy initiation. QULIPTA was discontinued in many of the reported cases.

Monitor patients treated with QULIPTA for new-onset hypertension, or worsening of pre-existing hypertension, and consider whether discontinuation of QULIPTA is warranted if evaluation fails to establish an alternative etiology or blood pressure is inadequately controlled.

5.3        Raynaud’s Phenomenon

Development of Raynaud’s phenomenon and recurrence or worsening of pre-existing Raynaud’s phenomenon have been reported in the postmarketing setting following the use of CGRP antagonists, including QULIPTA. In reported cases with small molecule CGRP antagonists, symptom onset occurred a median of 1.5 days following dosing. Many of the cases reported serious outcomes, including hospitalizations and disability, generally related to debilitating pain. In most reported cases, discontinuation of the CGRP antagonist resulted in resolution of symptoms.

QULIPTA should be discontinued if signs or symptoms of Raynaud’s phenomenon develop, and patients should be evaluated by a healthcare provider if symptoms do not resolve. Patients with a history of Raynaud’s phenomenon should be monitored for, and informed about the possibility of, worsening or recurrence of signs and symptoms.