8/20. Rimegepant-(NURTEC ODT)- (Feb -2020)- To treat Migraine
Drug Name:8/20. Rimegepant-(NURTEC ODT)- (Feb -2020)- To treat Migraine
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 INTERACTION-
Summary-
• Strong CYP3A4 Inhibitors: Avoid concomitant administration.
• Moderate CYP3A4 Inhibitors: Avoid another dose within 48 hours when administered with a moderate CYP3A4 inhibitor.
• Strong and Moderate CYP3A Inducers: Avoid concomitant administration.
• Inhibitors of P-gp or BCRP: Avoid concomitant administration.
Details
1 CYP3A4 Inhibitors- Concomitant administration of NURTEC ODT with strong inhibitors of CYP3A4 results in a significant increase in rimegepant exposure. Avoid concomitant administration of NURTEC ODT with strong inhibitors of CYP3A4
Concomitant administration of NURTEC ODT with moderate inhibitors of CYP3A4 may result in increased exposure of rimegepant.
Avoid another dose of NURTEC ODT within 48 hours when it is concomitantly administered with moderate inhibitors of CYP3A.
2. CYP3A Inducers- Concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A can result in a significant reduction in rimegepant exposure, which may lead to loss of efficacy of NURTEC ODT. Avoid concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A
3. Transporters- Rimegepant is a substrate of P-gp and BCRP efflux transporters. Concomitant administration of NURTEC ODT with inhibitors of P-gp or BCRP may result in a significant increase in rimegepant exposure Avoid NURTEC ODT with inhibitors of P-gp or BCRP.
Indication:
U.S. FDA APPROVED DRUGS DURING 2020
Sr.No- 8
Adverse Reaction:
ADVERSE REACTIONS
The adverse reaction reported in = 1% of patients treated with NURTEC ODT is nausea.
Contra-Indications:
WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions: If a serious hypersensitivity reaction occurs, discontinue NURTEC ODT and initiate appropriate therapy.
Severe hypersensitivity reactions have included dyspnea and rash, and can occur days after administration.
Dosages/ Overdosage Etc:
Patient Information:
PATIENT COUNSELING INFORMATION
Advise patients to read the FDA-approved patient labeling (Patient Information).
Handling of Orally Disintegrating Tablets- Packaging- Instruct patients not to remove the blister from the outer aluminum pouch until ready to use the orally disintegrating tablet inside
Hypersensitivity Reactions- Inform patients about the signs and symptoms of hypersensitivity reactions and that these reactions can occur days after administration of NURTEC ODT.
Advise patients to contact their healthcare provider immediately if signs or symptoms of hypersensitivity reactions occur.
Manufactured for: Biohaven Pharmaceuticals, Inc. New Haven, CT 06510 USA © 2020, Biohaven Pharmaceuticals Inc. NURTEC and Biohaven are trademarks of Biohaven Pharmaceutical Holding Company Ltd.
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action- Rimegepant is a calcitonin gene-related peptide receptor antagonist.
2. Pharmacodynamics- The relationship between pharmacodynamic activity and the mechanism(s) by which rimegepant exerts its clinical effects is unknown.
Cardiac Electrophysiology- At a single dose 4 times the recommended dose, rimegepant does not prolong the QT interval to any clinically relevant extent.
3. Pharmacokinetics- Absorption- Following oral administration of NURTEC ODT, rimegepant is absorbed with the maximum concentration at 1.5 hours.
The absolute oral bioavailability of rimegepant is approximately 64%.
Effects of Food- Following administration of NURTEC ODT under fed condition with a high-fat meal, Tmax was delayed by 1 hour and resulted in a 42 to 53% reduction in Cmax and a 32 to 38% reduction in AUC.
NURTEC ODT was administered without regard to food in clinical safety and efficacy studies. The impact of the reduction in rimegepant exposure because of administration with food on its efficacy is unknown.
Distribution- The steady state volume of distribution of rimegepant is 120 L. Plasma protein binding of rimegepant is approximately 96%.
Elimination- Metabolism- Rimegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9. Rimegepant is primarily eliminated in unchanged form (~77% of the dose) with no major metabolites (i.e., > 10%) detected in plasma.
Excretion- The elimination half-life of rimegepant is approximately 11 hours in healthy subjects. Following oral administration of [ 14C]-rimegepant to healthy male subjects, 78% of the total radioactivity was recovered in feces and 24% in urine.
Unchanged rimegepant is the major single component in excreted feces (42%) and urine (51%).
Specific Populations- Renal Impairment In a dedicated clinical study comparing the pharmacokinetics of rimegepant in subjects with mild (estimated creatinine clearance [CLcr] 60-89 mL/min), moderate (CLcr 30-59 mL/min), and severe (CLcr 15-29 mL/min) renal impairment to that with normal subjects (healthy matched control), the exposure of rimegepant following single 75 mg dose was approximately 40% higher in subjects with moderate renal impairment.
However, there was no clinically meaningful difference in the exposure of rimegepant in subjects with severe renal impairment compared to subjects with normal renal function (CLcr >=90mL/min).
NURTEC ODT has not been studied in patients with end-stage renal disease (CLcr < 15 mL/min)
Hepatic Impairment- In a dedicated clinical study comparing the pharmacokinetics of rimegepant in subjects with mild, moderate, and severe hepatic impairment to that with normal subjects (healthy matched control), the exposure of rimegepant (Cmax and AUC) following single 75 mg dose was approximately 2-fold higher in subjects with severe impairment (Child-Pugh class C).
There were no clinically meaningful differences in the exposure of rimegepant in subjects with mild (Child-Pugh class A) and moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function.
Other Specific Populations- No clinically significant differences in the pharmacokinetics of rimegepant were observed based on age, sex, race/ethnicity, body weight, or CYP2C9 genotype.
Drug Interaction Studies- In Vitro Studies • Enzymes Rimegepant is a substrate of CYP3A4 and CYP2C9 (see In Vivo Studies). Rimegepant is not an inhibitor of CYP1A2, 2B6, 2C9, 2C19, 2D6, or UGT1A1 at clinically relevant concentrations. However, rimegepant is a weak inhibitor of CYP3A4 with time-dependent inhibition.
Rimegepant is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.
• Transporters- Rimegepant is a substrate of P-gp and BCRP. Concomitant administration of inhibitors of P-gp or BCRP may increase the exposure of rimegepant.
No dedicated drug interaction study was conducted to assess their effects on the pharmacokinetics of rimegepant.
Rimegepant is not a substrate of OATP1B1 or OATP1B3. Considering its low renal clearance, rimegepant was not evaluated as a substrate of the OAT1, OAT3, OCT2, MATE1, or MATE2-K.
Rimegepant is not an inhibitor of P-gp, BCRP, OAT1, or MATE2-K at clinically relevant concentrations. It is a weak inhibitor of OATP1B1 and OAT3.
Rimegepant is an inhibitor of OATP1B3, OCT2, and MATE1. No clinical drug interactions are expected for NURTEC ODT with these transporters at clinically relevant concentrations.
In Vivo Studies CYP3A4 Inhibitors In a dedicated drug interaction study, concomitant administration of 75 mg rimegepant (single dose) with itraconazole, a strong CYP3A4 inhibitor, at steady state resulted in increased exposures of rimegepant (AUC by 4-fold and Cmax by ~1.5-fold)
No dedicated drug interaction study was conducted to assess the effect of concomitant administration of a weak inhibitor of CYP3A4 on the pharmacokinetics of rimegepant.
The concomitant administration of rimegepant with a moderate inhibitor of CYP3A4 may increase rimegepant exposures (AUC) by less than 2-fold
Concomitant administration of rimegepant with a weak inhibitor of CYP3A4 is not expected to have a clinically significant impact on rimegepant exposures.
CYP3A Inducers- In a dedicated drug interaction study, concomitant administration of 75 mg rimegepant (single dose) with rifampin, a strong CYP3A4 inducer, at steady state resulted in decreased exposures of rimegepant (AUC by 80% and Cmax by 64%), which may lead to loss of efficacy
No dedicated drug interaction study was conducted to assess the effect of concomitant administration of a moderate or weak inducer of CYP3A4 on the pharmacokinetics of rimegepant.
Since rimegepant is a moderately sensitive substrate for CYP3A4, drugs that are moderate inducers of CYP3A4 can also cause significant reduction in rimegepant exposure resulting in loss of efficacy
Clinically significant interaction is not expected with concomitant administration of weak inducers of CYP3A4 and rimegepant. CYP2C9 Inhibitors In a dedicated drug interaction study, concomitant administration of 75 mg rimegepant (single dose) with fluconazole, a combined moderate CYP3A4 and CYP2C9 inhibitor, resulted in increased exposures of rimegepant (AUC by 1.8-fold) with no relevant effect on Cmax.
Rimegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9. Increase in the exposure of rimegepant can be attributed to combined inhibition of CYP2C9 and CYP3A4 with fluconazole administration suggesting a minor contribution from CYP2C9.
Thus, CYP2C9 inhibition alone is not expected to significantly affect rimegepant exposures.
Other Drugs: No significant pharmacokinetic interactions were observed when rimegepant was concomitantly administered with oral contraceptives (norelgestromin, ethinyl estradiol), midazolam (a sensitive CY3A4 substrate), or sumatriptan
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 NURTEC ODT in pregnant women.
In animal studies, oral administration of rimegepant during organogenesis resulted in adverse effects on development in rats (decreased fetal body weight and increased incidence of fetal variations) at exposures greater than those used clinically and which were associated with maternal toxicity.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
The estimated rate of major birth defects (2.2 to 2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.
2. Lactation- There are no data on the presence of rimegepant or its metabolites in human milk, the effects of rimegepant on the breastfed infant, or the effects of rimegepant on milk production.
There are no animal data on the excretion of rimegepant in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NURTEC ODT and any potential adverse effects on the breastfed infant from NURTEC ODT 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 NURTEC ODT did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
5.Hepatic Impairment- No dosage adjustment of NURTEC ODT is required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Plasma concentrations of rimegepant were significantly higher in subjects with severe (Child-Pugh C) hepatic impairment.
Avoid use of NURTEC ODT in patients with severe hepatic impairment
6.Renal Impairment No dosage adjustment of NURTEC ODT is required in patients with mild, moderate, or severe renal impairment. NURTEC ODT has not been studied in patients with end-stage renal disease and in patients on dialysis.
Avoid use of NURTEC ODT in patients with end-stage renal disease (CLcr < 15 mL/min)
OVERDOSAGE
There is limited clinical experience with NURTEC ODT overdosage.
Treatment of an overdose of NURTEC ODT should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.
No specific antidote for the treatment of rimegepant overdose is available. Rimegepant is unlikely to be significantly removed by dialysis because of high serum protein binding
