Relpax (eletriptan hydrobromide)

Available as eletriptan hydrobromide; dosage is expressed in terms of eletriptan.

Eletriptan is available in a tablet formulation for oral administration. Eletriptan may be administered without regard to meals.

Tablets should be stored at 20-25degreesC with excursions permitted between 15-30degreesC.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

5-Ht1d Agonists/Ergot Alkaloids

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The 5-HT1D agonists and ergot alkaloids can produce vasospastic reactions.

CLINICAL EFFECTS: Concurrent therapy may produce additive vasospastic effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that sumatriptan should not be used within 24 hours of an ergotamine-containing or ergotamine-like medication (such as dihydroergotamine or methysergide).(1,2) The Australian(3) and UK(4,5) manufacturers state that 24 hours should elapse before sumatriptan is administered following an ergotamine-containing preparation and 6 hours should elapse before an ergotamine-containing preparation is administered following sumatriptan. The US manufacturer states that zolmitriptan should not be used within 24 hours of an ergotamine-containing or ergotamine-like medication.(6) The UK manufacturer states that zolmitriptan should not be used within 6 hours of an ergotamine-containing or ergotamine-like medication.(7) The The Australian manufacturer states that 24 hours should elapse before zolmitriptan is administered following an ergotamine-containing preparation and 6 hours should elapse before an ergotamine-containing medication is administered following zolmitriptan.(8) The US manufacturer states that the use of rizatriptan within 24 hours of an ergotamine-containing or ergot-type medication is contraindicated.(9) The US manufacturer states that the use of naratriptan within 24 hours of an ergotamine-containing or ergot-type medication is contraindicated.(10) The Australian manufacturer states that concurrent use of naratriptan and ergotamine or ergotamine derivatives is not recommended.(11) The US manufacturer states that the use of eletriptan within 24 hours of an ergotamine-containing or ergot-type medication is contraindicated.(12) The UK manufacturer states that the use of eletriptan within 24 hours of an ergotamine-containing or ergot-type medication is not recommended.(13)

DISCUSSION: Because of the theoretical risk of additive vasospastic effects, the US manufacturer states that the use of sumatriptan within 24 hours of an ergotamine-containing or ergotamine-like medication is contraindicated.(1,2) The Australian(3) and UK(4,5) manufacturer states that 24 hours should elapse before sumatriptan is administered following an ergotamine-containing preparation and 6 hours should elapse before an ergotamine-containing medication is administered following sumatriptan. Although the pharmacokinetics of zolmitriptan were not affected by ergotamine, the UK manufacturer of zolmitriptan recommends that 6 hours should elapse between the administration of zolmitriptan and an ergotamine preparation.(7) The US manufacturer of zolmitriptan states under contraindications that zolmitriptan should not be used within 24 hours of an ergotamine-containing or ergot-type medication.(6) The Australian manufacturer states that 24 hours should elapse before zolmitriptan is administered following an ergotamine-containing preparation and 6 hours should elapse before an ergotamine-containing medication is administered following zolmitriptan.(8) Because of the additive risk of prolonged vasospastic reactions, the manufacturers of rizatriptan(9) and naratriptan(10) in the US state that the use of ergotamine-containing or ergot-type medications and these agents is contraindicated. The Australian manufacturer states that concurrent use of naratriptan and ergotamine or ergotamine derivatives is not recommended.(11) Administration of oral ergotamine one and two hours after eletriptan resulted in additive increases in blood pressure.(13)

Eletriptan/Levoketoconazole

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Levoketoconazole is a strong inhibitor of CYP3A4 and may inhibit the metabolism of eletriptan via this pathway.(1-3)

CLINICAL EFFECTS: Concurrent use may result in elevated levels of and adverse effects from eletriptan.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of eletriptan states that eletriptan should not be used within at least 72 hours of administration of a strong CYP3A4 inhibitor.(2)

DISCUSSION: In clinical studies, ketoconazole (400 mg), a strong CYP3A4 inhibitor, increased the eletriptan maximum concentration (Cmax) and area-under-curve (AUC) by 2.7-fold and 5.9-fold, respectively. The half-life of eletriptan increased from 4.8 hours to 8.3 hours.(1) The time to Cmax (Tmax) increased from 2.8 hours to 5.4 hours.(2)

Eletriptan/Nefazodone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Nefazodone may inhibit the metabolism of eletriptan by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use may result in elevated levels of and adverse effects from eletriptan.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of eletriptan states that eletriptan should not be used within at least 72 hours of nefazodone.(1)

DISCUSSION: Concurrent use with ketoconazole, another potent inhibitor of CYP3A4, resulted in about a 3-fold increase in the maximum concentration (Cmax) and about a 6-fold increase in the area-under-curve (AUC) of eletriptan. Eletriptan half-life increased from 5 hours to 8 hours and the time to Cmax (Tmax) increased from 2.8 hours to 5.4 hours.(1) Concurrent use with erythromycin, also an inhibitor of CYP3A4, increased the Cmax and AUC of eletriptan by about 2-fold and about 4-fold, respectively.(1)

Eletriptan/Ribociclib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Ribociclib is a strong inhibitor of CYP3A4 and may inhibit the metabolism of eletriptan via this pathway.(1)

CLINICAL EFFECTS: Concurrent use may result in elevated levels of and adverse effects from eletriptan.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of eletriptan states that eletriptan should not be used within at least 72 hours of administration of a strong CYP3A4 inhibitor.(2) If migraine treatment is needed during ribociclib therapy use triptans not metabolized by CYP3A4 such as frovatriptan, sumatriptan, or zolmitriptan.(2-4)

DISCUSSION: In a study in healthy subjects, concomitant administration of ribociclib (400 mg once daily for 8 days) with midazolam increased the midazolam maximum concentration (Cmax) and area under the curve (AUC) by 2.1-fold and 3.8-fold, respectively. Administration of ribociclib 600 mg once daily is predicted to increase the midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.(5)

Eletriptan/Selected Azole Antifungals

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Itraconazole, ketoconazole, posaconazole and voriconazole are strong inhibitors of CYP3A4 and may inhibit the metabolism of eletriptan via this pathway.(1-3)

CLINICAL EFFECTS: Concurrent use may result in elevated levels of and adverse effects from eletriptan.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of eletriptan states that eletriptan should not be used within at least 72 hours of administration of a strong CYP3A4 inhibitor.(2) The UK manufacturer of eletriptan states that eletriptan should not be used together with itraconazole or ketoconazole.(1) If migraine treatment is needed during azole antifungal therapy use triptans not metabolized by CYP3A4 such as frovatriptan, sumatriptan, or zolmitriptan.(4-7) The AU manufacturer of eletriptan states that eletriptan should not be used within 48 hours of treatment with a strong CYP3A4 inhibitor such as ketoconazole and itraconazole.(8)

DISCUSSION: In clinical studies, ketoconazole (400 mg) increased the eletriptan maximum concentration (Cmax) and area-under-curve (AUC) by 2.7-fold and 5.9-fold, respectively. The half-life of eletriptan increased from 4.8 hours to 8.3 hours.(1) The time to Cmax (Tmax) increased from 2.8 hours to 5.4 hours.(2)

Eletriptan/Selected Protease Inhibitors; Cobicistat

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Cobicistat or protease inhibitors which are strong inhibitors of CYP3A4 may reduce the CYP3A4 mediated metabolism of eletriptan.(1-6)

CLINICAL EFFECTS: Concurrent use of eletriptan with strong inhibitors of CYP3A4(1-7) may result in elevated levels of and adverse effects from eletriptan.(1-6) Agents linked to this monograph are: atazanavir, boceprevir, cobicistat, ensitrelvir, indinavir, lopinavir, nelfinavir, nirmatrelvir, paritaprevir, saquinavir, telaprevir, and tipranavir.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of eletriptan states that eletriptan should not be used within at least 72 hours of potent inhibitors of CYP3A4.(2) The UK manufacturer of eletriptan states that eletriptan should not be used together with indinavir, nelfinavir, or ritonavir.(1) If migraine treatment is needed during protease inhibitor therapy, use triptans not metabolized by CYP3A4 such as frovatriptan, sumatriptan, or zolmitriptan.(8-11)

DISCUSSION: In a clinical trial, another strong CYP3A4 inhibitor ketoconazole 400 mg, increased the eletriptan maximum concentration (Cmax) and exposure (area-under-curve, AUC) by 2.7-fold and 5.9-fold, respectively. The half-life of eletriptan increased from 4.8 hours to 8.3 hours.(1) In another trial, a high dose of a moderate to strong CYP3A4 inhibitor, erythromycin (1000 mg), increased the eletriptan Cmax and AUC by 2-fold and 3.6-fold, respectively. The half-life of eletriptan increased from 4.6 hours to 7.1 hours.(2)

Eletriptan/Slt Macro;Ketolide Antibiotics

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Macrolide or ketolide antibiotics which are moderately-strong to strong inhibitors of CYP3A4 may inhibit the metabolism of eletriptan.(1-3)

CLINICAL EFFECTS: Concurrent use may result in elevated levels of and adverse effects from eletriptan.(1,2) Antibiotic agents linked to this monograph are clarithromycin, erythromycin, josamycin, telithromycin and troleandomycin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of eletriptan states that eletriptan should not be used within at least 72 hours of treatment with strong CYP3A4 inhibitors such as clarithromycin or troleandomycin.(2) The UK manufacturer of eletriptan states that eletriptan should not be used together with clarithromycin, erythromycin, or josamycin.(1) If migraine treatment is needed during macrolide or ketolide antibiotic therapy use triptans not metabolized by CYP3A4 such as frovatriptan, sumatriptan, or zolmitriptan.(4-7)

DISCUSSION: In a clinical study with a moderate to strong CYP3A4 inhibitor, erythromycin 1000 mg increased the eletriptan maximum concentration (Cmax) and area-under-curve (AUC) by 2-fold and 3.6-fold, respectively. The half-life of eletriptan increased from 4.6 hours to 7.1 hours.(1) In a clinical study with a strong CYP3A4 inhibitor, ketoconazole (400 mg) increased the eletriptan maximum concentration (Cmax) and area-under-curve (AUC) by 2.7-fold and 5.9-fold, respectively. The half-life of eletriptan increased from 4.8 hours to 8.3 hours.(1) The time to Cmax (Tmax) increased from 2.8 hours to 5.4 hours.(2)

Selected Sensitive Cyp3a4 Substrates/Adagrasib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Adagrasib is a strong inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme.(1)

CLINICAL EFFECTS: Concurrent use of adagrasib may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of adagrasib states that coadministration of CYP3A4 substrates should be avoided.(1)

DISCUSSION: In a study, adagrasib (400 mg twice daily) increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of a single dose of midazolam by 21-fold and 4.8-fold, respectively. In a study, adagrasib (600 mg twice daily) increased the AUC and Cmax of a single dose of midazolam by 31-fold and 3.1-fold, respectively.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: atazanavir, atorvastatin, brotizolam, darunavir, ebastine, eletriptan, indinavir, nisoldipine, paritaprevir, and tipranavir.(1-3)

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

Selected Sensitive Cyp3a4 Substrates/Oral Lefamulin

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

MECHANISM OF ACTION: Lefamulin is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,3)

CLINICAL EFFECTS: Concurrent use of oral lefamulin may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: If oral lefamulin must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor for adverse effects of the CYP3A4 substrate.(1) Drug-specific recommendations: The manufacturer of abemaciclib recommends monitoring for adverse reactions and considering a dose reduction of abemaciclib in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(2)

DISCUSSION: In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) Sensitive CYP3A4 substrates linked to this monograph include: abemaciclib, acalabrutinib, alprazolam, atorvastatin, brotizolam, budesonide, buspirone, cobimetinib, darifenacin, ebastine, eletriptan, elvitegravir, everolimus, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, paritaprevir, sildenafil, simvastatin, ticagrelor, triazolam, and ulipristal.(1,3,5)

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

Selected Sensitive Cyp3a4 Substrates/Schisandra

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

MECHANISM OF ACTION: Schisandra is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,2)

CLINICAL EFFECTS: Concurrent use of Schisandra may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(3-7)

PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(8)

PATIENT MANAGEMENT: If Schisandra must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor the CYP3A4 substrate and adjust its dose as appropriate.(3-7) The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(8)

DISCUSSION: A study in 12 healthy volunteers found that Schisandra led to an increase in midazolam area-under-curve (AUC) and maximum concentration (Cmax) of 2.05- and 1.65-fold, respectively, compared to midazolam administered alone.(3) In a study of 18 healthy volunteers, sirolimus AUC and Cmax increased by 2.07-fold and 1.96-fold, respectively when given with Schisandra compared to sirolimus administered alone.(4) The effect of Schisandra on tacrolimus has been examined in several small pharmacokinetic studies in healthy volunteers as well as liver and kidney transplant patients. Compared to tacrolimus given alone, tacrolimus AUC when administered with Schisandra was consistently increased by 2.1-fold, while the increase in Cmax varied between 1.83- and 2.11-fold in the transplant studies(5-6) and 3-fold in the study on healthy subjects.(7) In the study with kidney transplant patients, a decrease in tacrolimus dose of 40.9 % was required to bring tacrolimus levels into the therapeutic range.(5)

*Ischemic coronary artery disease (e.g., angina pectoris, history of myocardial infarction, documented silent ischemia), coronary artery vasospasm (e.g., Prinzmetal variant angina), or uncontrolled hypertension.

*Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.

*Cerebrovascular syndromes (e.g., history of stroke, transient ischemic attack, or history or current evidence of hemiplegic or basilar migraine), peripheral vascular disease, or ischemic bowel disease.

*Recent (i.e., 24 hours or less) treatment with another 5-HT1 receptor agonist or an ergotamine-containing or ergot-type drug.

*Recent (i.e., 72 hours or less) use of the following strong CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, clarithromycin, ritonavir, or nelfinavir.

*Known hypersensitivity to eletriptan; angioedema and anaphylaxis reported.

• Acute myocardial infarction
• Angina
• Cerebral ischemia
• Cerebrovascular accident
• Coronary artery disease
• Coronary artery spasm
• Hemiplegic migraine
• Ischemic bowel disease
• Myocardial ischemia
• Peripheral vascular disease
• Prinzmetal angina
• Serotonin syndrome
• Severe uncontrolled hypertension

• Hypertension
• Raynaud's phenomenon
• Tachyarrhythmia

There are no moderate contraindications for this drug.

The most common adverse reactions (incidence >=5% and greater than placebo) with eletriptan include asthenia, nausea, dizziness, and somnolence.

Less Frequent

• Chest pain

Rare or Very Rare

• Acute myocardial infarction
• Anaphylaxis
• Angina
• Angioedema
• Atrial fibrillation
• Atrioventricular block
• Cardiac arrhythmia
• Cerebrovascular accident
• Coronary artery spasm
• Hypertension
• Hypertensive crisis
• Intracerebral hemorrhage
• Ischemic bowel disease
• Myocardial ischemia
• Peripheral ischemia
• Peripheral vasoconstriction
• Prinzmetal angina
• Seizure disorder
• Serotonin syndrome
• Subarachnoid intracranial hemorrhage
• Ventricular arrhythmias
• Ventricular fibrillation
• Ventricular tachycardia

More Frequent

• Dizziness
• Drowsy
• General weakness
• Nausea

Less Frequent

• Abdominal pain with cramps
• Chest tightness
• Dyspepsia
• Dysphagia
• Flushing
• Medication overuse headache
• Palpitations
• Paresthesia
• Xerostomia

Rare or Very Rare

• Jaw pain
• Polyuria
• Raynaud's phenomenon
• Vomiting

No enhanced messaging available.

Safety and efficacy have not been established in pediatric patients younger than 18 years of age. In a study involving 274 adolescents (11-17 years of age), the headache response rate at 2 hours for eletriptan 40 mg was not different from placebo (57% for both groups). Adverse reactions in the study were similar to those observed in adults.

There are insufficient human data on the use of eletriptan in pregnancy to determine a drug-associated risk for major birth defects and miscarriage. In animal reproductive studies, eletriptan was associated with developmental toxicity (e.g., reduced fetal and pup weights, increased fetal structural abnormalities, decreased pup viability) when administered during the period of pregnancy and lactation at clinically relevant doses.

Linked data from the Medical Birth Registry of Norway to the Norwegian Prescription Database revealed that of 189 women who redeemed an eletriptan prescription during the first trimester of pregnancy, 4 gave birth to infants with major congenital malformations while 11 infants with major congenital malformations were born to 174 women who redeemed an eletriptan prescription before, but not during, pregnancy.

Eletriptan is distributed into human milk; the effects of eletriptan on the breastfed infant or milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for eletriptan and any adverse effects on the breastfed infant from the drug or from the underlying maternal condition. Infant exposure to eletriptan can be minimized by avoiding breastfeeding for 24 hours after treatment.

No specific dosage adjustment is recommended in geriatric patients.

Pharmacokinetic profile in patients 65 years of age and older is similar to that in younger adults. No apparent differences in efficacy or safety relative to younger adults have been observed in clinical trials. Increases in blood pressure are more pronounced in geriatric patients.