49/19. Ubrogepant- (UBRELVY)- @-( Dec 2019) - Migraine with or without Aura
Drug Name:49/19. Ubrogepant- (UBRELVY)- @-( Dec 2019) - Migraine with or without Aura
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS- Details
1 CYP3A4 Inhibitors Co-administration of UBRELVY with ketoconazole, a strong CYP3A4 inhibitor, resulted in a significant increase in exposure of ubrogepant
UBRELVY should not be used with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin)
Co-administration of UBRELVY with verapamil, a moderate CYP3A4 inhibitor, resulted in an increase in ubrogepant exposure
Dose adjustment is recommended with concomitant use of UBRELVY and moderate CYP3A4 inhibitors (e.g., cyclosporine, ciprofloxacin, fluconazole, fluvoxamine, grapefruit juice)
No dedicated drug interaction study was conducted with ubrogepant and weak CYP3A4 inhibitors. Dose adjustment is recommended with concomitant use of UBRELVY with weak CYP3A4 nhibitors [see Dosage and Administration (2.2)].
2. CYP3A4 Inducers Co-administration of UBRELVY with rifampin, a strong CYP3A4 inducer, resulted in a significant reduction in ubrogepant exposure
In patients taking strong CYP3A4 inducers (e.g., phenytoin, barbiturates, rifampin, St. John’s Wort), loss of ubrogepant efficacy is expected, and concomitant use should be avoided.
Co-administration of UBRELVY with moderate or weak CYP3A4 inducers was not evaluated in a clinical study.
Dose adjustment is recommended with concomitant use of UBRELVY and moderate or weak CYP3A4 inducers
3 .BCRP and/or P-gp Only Inhibitors Ubrogepant is a substrate of BCRP and P-gp efflux transporters. Use of BCRP and/or P-gp only inhibitors (e.g., quinidine, carvedilol, eltrombopag, curcumin) may increase the exposure of ubrogepant
Clinical drug interaction studies with inhibitors of these transporters were not conducted. Dose adjustment is recommended with BCRP and/or P-gp only inhibitors
Indication:
Adverse Reaction:
ADVERSE REACTIONS
The most common adverse reactions (at least 2% and greater than placebo) were nausea and somnolence.
Contra-Indications:
Dosages/ Overdosage Etc:
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Drug Interactions
Inform patients that UBRELVY may interact with certain other drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription medications, over-the-counter medications, or herbal products
Advise patients to inform their healthcare provider of grapefruit juice intake because a dosage modification is recommended with coadministration.
Pregnancy
Advise patients to notify their healthcare provider if they become pregnant during treatment or plan to become pregnant
Lactation
Inform patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed
Distributed by: Allergan USA, Inc. Madison, NJ 07940 © 2019 Allergan. All rights reserved. UBRELVY™ is a trademark of Allergan Pharmaceuticals International Limited. Allergan® and its design are trademarks of Allergan, Inc. Patented. See www.allergan.com/pat
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action Ubrogepant is a calcitonin gene-related peptide receptor antagonist.
2. Pharmacodynamics-
Cardiac Electrophysiology- At a dose 2 times the maximum recommended daily dose, UBRELVY does not prolong the QT interval to any clinically relevant extent.
12.3 Pharmacokinetics Absorption Following oral administration of UBRELVY, ubrogepant is absorbed with peak plasma concentrations at approximately 1.5 hours. Ubrogepant displays dose-proportional pharmacokinetics within the recommended dose range [see Dosage and Administration (2.1)].
Effect of Food When UBRELVY was administered with a high-fat meal, the time to maximum ubrogepant plasma concentration was delayed by 2 hours and resulted in a 22% reduction in Cmax with no change in AUC. UBRELVY was administered without regard to food in clinical efficacy studies [see Dosage and Administration (2.1)]. Reference ID: 4538691
Distribution Plasma protein binding of ubrogepant is 87% in vitro. The mean apparent central volume of distribution of ubrogepant (V/F) after single dose oral administration is approximately 350 L.
Elimination Metabolism Ubrogepant is eliminated mainly through metabolism, primarily by CYP3A4. The parent compound (ubrogepant), and 2 glucuronide conjugate metabolites were the most prevalent circulating components in human plasma. The glucuronide metabolites are not expected to contribute to the pharmacological activity of ubrogepant since they were reported as about 6000-fold less potent in the CGRP receptor binding assay.
Excretion The elimination half-life of ubrogepant is approximately 5-7 hours. The mean apparent oral clearance (CL/F) of ubrogepant is approximately 87 L/hr. Ubrogepant is excreted mostly via the biliary/fecal route, while the renal route is a minor route of elimination.
Following single oral dose administration of [14C]-ubrogepant to healthy male subjects, 42% and 6% of the dose was recovered as unchanged ubrogepant in feces and urine, respectively.
Specific Populations Patients with Renal Impairment Population pharmacokinetic analysis based on pooled data from clinical studies was used to evaluate the effect of renal impairment characterized based on estimated creatinine clearance (CLcr) using the Cockcroft-Gault (CG) equation.
Renal impairment did not reveal a significant difference in the pharmacokinetics of ubrogepant in patients with mild or moderate renal impairment (CLcr 30-89 mL/min) relative to those with normal renal function (CLcr >90 mL/min). Patients with severe renal impairment or ESRD (eGFR <30 mL/min) have not been studied.
Dose adjustment in patients with severe renal impairment (CLcr 15-29 mL/min) is recommended based on ADME information and a conservative assumption that severe renal impairment is unlikely to cause more than a two-fold increase in exposure of ubrogepant [see Dosage and Administration (2.6)]. No dosing recommendations can be made for patients with ESRD (CLcr<15 mL/min).
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), ubrogepant exposure was increased by 7%, 50%, and 115%, respectively.
Patients with severe hepatic impairment require dose adjustments [see Dosage and Administration (2.5)]. 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 ubrogepant. Therefore, no dose adjustments are warranted based on these factors.
Drug Interactions In Vitro Studies Enzymes Ubrogepant is not an inhibitor of CYP1A2, 2B6, or 3A4. Ubrogepant is a weak inhibitor of CYP2C8, 2C9, 2D6, 2C19, MAO-A, and UGT1A
The in vitro inhibition potential is not expected to be clinically significant. Ubrogepant is not an inducer of CYP1A2, 2B6, or 3A4 at clinically relevant concentrations. Transporters Ubrogepant is a substrate of BCRP and P-gp transporters in-vitro; therefore, use of inhibitors of BCRP and/or P-gp may increase the exposure of ubrogepant.
Dose adjustment for concomitant use of UBRELVY with inhibitors of BCRP and/or P-gp is recommended based on ADME and clinical interaction studies with Reference ID: 4538691 CYP3A4/P-gp inhibitors that show the highest predicted potential increase in exposure of ubrogepant is not expected to be more than two-fold [see Dosage and Administration (2.4) and Drug Interactions (7.3)]. Ubrogepant is a weak substrate of OATP1B1, OATP1B3, and OAT1, but not a substrate of OAT3. It is not an inhibitor of P-gp, BCRP, BSEP, MRP3, MRP4, OAT1, OAT3, or NTCP transporters, but is a weak inhibitor of OATP1B1, OATP1B3, and OCT2 transporters. Dose adjustments are needed only for P-gp, or BCRP inhibitors.
No clinical drug interactions are expected for UBRELVY with other transporters. In Vivo Studies CYP3A4 Inhibitors [see Dosage and Administration (2.2), Contraindications (4), and Drug Interactions (7.1)]: Co-administration of UBRELVY with ketoconazole, a strong CYP3A4 inhibitor, resulted in a 9.7-fold and 5.3-fold increase in AUCinf and Cmax of ubrogepant, respectively.
Co-administration of UBRELVY with verapamil, a moderate CYP3A4 inhibitor, resulted in about 3.5-fold and 2.8-fold increase in AUCinf and Cmax of ubrogepant, respectively. No dedicated drug interaction study was conducted to assess concomitant use with weak CYP3A4 inhibitors.
The conservative prediction of the maximal potential increase in ubrogepant exposure with weak CYP3A4 inhibitors is not expected to be more than 2-fold. CYP3A4 Inducers [see Dosage and Administration (2.3) and Drug Interactions (7.2)]: Co-administration of UBRELVY with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure.
No dedicated drug interaction studies were conducted to assess concomitant use with weak or moderate CYP3A4 inducers. Dose adjustment for concomitant use of UBRELVY with weak or moderate CYP3A4 inducers is recommended based on a conservative prediction of 50 % reduction in exposure of ubrogepant.
Other Drug-Drug Interaction Evaluations: No significant pharmacokinetic interactions were observed for either ubrogepant or co-administered drugs when UBRELVY was administered with oral contraceptives (containing norgestimate and ethinyl estradiol), acetaminophen, naproxen, sumatriptan, or esomeprazole (a proton pump inhibitor).
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Two-year oral carcinogenicity studies of ub
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy Risk Summary
There are no adequate data on the developmental risk associated with the use of UBRELVY in pregnant women.
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 ubrogepant in human milk, the effects of ubrogepant on the breastfed infant, or the effects of ubrogepant on milk production.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for UBRELVY and any potential adverse effects on the breastfed infant from UBRELVY or from the underlying maternal condition.
3.Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
4.Geriatric Use
In pharmacokinetic studies, no clinically significant pharmacokinetic differences were observed between elderly and younger subjects.
Clinical studies of UBRELVY 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.
5.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), ubrogepant exposure was increased by 7%, 50%, and 115%, respectively.
No dose adjustment is recommended for patients with mild or moderate hepatic impairment. Dose adjustment for UBRELVY is recommended for patients with severe hepatic impairment
6.Renal Impairment
The renal route of elimination plays a minor role in the clearance of ubrogepant.No dose adjustment is recommended for patients with mild or moderate renal impairment.
Dose adjustment is recommended for patients with severe renal impairment (CLcr 15-29 mL/min)
Avoid use of UBRELVY in patients with end-stage renal disease (ESRD) (CLcr <15 mL/min).
OVERDOSAGE
Reference ID: 4538691 The elimination half-life of ubrogepant is approximately 5 to 7 hours; therefore, monitoring of patients after overdose with UBRELVY should continue for at least 24 hours, or while symptoms or signs persist.
