VA Class:CN105

AHFS Class:

• Selective Serotonin Agonists 28:32.28

Generic Name(s):

• Eletriptan Hydrobromide

Chemical Name:

• 3-[[( R )-1-Methyl-2-pyrrolidinyl]methyl]-5-[2-(phenylsulfonyl)ethyl]indole

Molecular Formula:

• C₂₂H₂₆N₂O₂S

Eletriptan hydrobromide is a selective agonist of serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptors (“triptan”).1,2,3,4,5,11,12,13,14,15

Vascular Headaches

Migraine

Eletriptan hydrobromide is used for the acute treatment of attacks of migraine with or without aura in adults.1,2,3,4,5,6,6,7,15,16,17 The manufacturer states that eletriptan should not be used for the management of hemiplegic or basilar migraine or for the prophylaxis of migraine.1 Safety and efficacy have not been established for the management of cluster headaches.1

Efficacy of eletriptan administered at the recommended dosage of 20 or 40 mg has been evaluated for the acute treatment of migraine attacks in several randomized, placebo-controlled studies in adult outpatients with moderate to severe headaches.1,2,3,4,5,6,15,16,17 In these studies, 47-54 or 54-65% of patients receiving eletriptan 20 or 40 mg, respectively, achieved a response (mild to no pain) 2 hours after treatment, compared with 19-40% of patients receiving placebo.1,2,3,4,5,15,16,17 The drug also relieved manifestations of migraine other than headache (including nausea, photophobia, and phonophobia) and reduced the need for supplemental migraine therapy.1,2,3,4,5,16,17

Eletriptan appears to be at least as effective as oral sumatriptan in alleviating the pain associated with migraine 2 hours after treatment.2,3,5,15 In several comparative studies, response rates 2 hours after treatment were substantially higher in patients receiving eletriptan 40 mg (64-67%) than in patients receiving sumatriptan 50 mg (50%) or 100 mg (53-59%).2,5,16 In another study, similar response rates were reported for eletriptan 20 or 40 mg (54 or 65%, respectively) and sumatriptan 100 mg (55%).15 In all comparative studies to date, sumatriptan tablets were encapsulated for the purpose of blinding, while eletriptan tablets were not.2,5,15,16 The encapsulated sumatriptan formulations were reportedly bioequivalent to conventional sumatriptan tablets;2,5,16 however, in another study, encapsulation of sumatriptan delayed absorption of the drug during the first 2 hours after dosing compared with conventional sumatriptan tablets.8,15,18 Results of a pooled analysis suggest that headache response rates 2 hours after treatment may be lower with eletriptan 20 mg than with sumatriptan 100 mg.8

The US Headache Consortium considers 5-HT_1B/1D receptor agonists (e.g., eletriptan) an appropriate treatment choice for the acute management of moderate to severe migraine headaches in patients without contraindications to these drugs and recommends use of 5H-T_1B/1D receptor agonists, dihydroergotamine, or ergotamine in patients with more severe migraine attacks as well as in patients in whom previous therapy with nonsteroidal anti-inflammatory agents (NSAIAs) or fixed-combination preparations such as acetaminophen, aspirin, and caffeine has been ineffective.9,10

For further information on management and classification of migraine headache, see Vascular Headaches: General Principles in Migraine Therapy, under Uses in Sumatriptan 28:32.28.

General

Eletriptan hydrobromide is administered orally without regard to meals.1,2,3,4,5,6,7,15,22 Dosage of eletriptan hydrobromide is expressed in terms of eletriptan.1

Vascular Headaches

Migraine

For the acute treatment of migraine attacks with or without aura in adults, single oral eletriptan doses of 20 or 40 mg were effective in clinical studies,1,2,3,4,5,6,7,8,15 although the 40-mg dose was effective in a greater proportion of patients.1,3 Because individuals vary in their response to eletriptan, dosage selection should be individualized.1 In clinical studies, doses exceeding 40 mg were effective but were associated with an increased risk of adverse effects.1,2 The maximum single dose of eletriptan should not exceed 40 mg.1

If headache recurs following an initial dose, additional doses of eletriptan may be administered at intervals of not less than 2 hours, up to a maximum adult dosage of 80 mg in any 24-hour period.1,15 However, additional doses of eletriptan are unlikely to provide benefit in patients who do not respond to the first dose of the drug for the same headache.1,15 The safety of treating an average of more than 3 headaches per 30-day period has not been established.1

Special Populations

Use of eletriptan is contraindicated in patients with severe hepatic impairment.1 The manufacturer states that dosage adjustment is not necessary in mild to moderate hepatic impairment.1,15

Contraindications

Known or suspected ischemic heart disease (e.g., angina pectoris, myocardial infarction, silent ischemia), coronary vasospasm (e.g., Prinzmetal variant angina), uncontrolled hypertension, other serious underlying cardiovascular disease, cerebrovascular syndromes (e.g., stroke syndrome, transient ischemic attacks), peripheral vascular disease, or ischemic bowel disease.1,15 Basilar or hemiplegic migraine.1 Treatment within the previous 24 hours with another 5-HT₁ receptor agonist or with an ergot alkaloid (e.g., ergotamine, dihydroergotamine, methysergide [no longer commercially available in the US]).1 Severe hepatic impairment (Child-Pugh grade C).1,19 Known hypersensitivity to eletriptan or any ingredient in the formulation.1

Warnings/Precautions

Careful Diagnosis of Migraine

Eletriptan should be used only in patients in whom a clear diagnosis of migraine has been established.1 Care should be taken to exclude other potentially serious neurologic disorders before eletriptan is administered to patients not previously diagnosed with migraine or to patients who present with atypical symptoms.1,23

Interactions with CYP3A4 Inhibitors

Eletriptan should not be used within at least 72 hours of treatment with potent inhibitors of the cytochrome P-450 (CYP) 3A4 isoenzyme (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir). (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)1

Cardiac Effects

Serious cardiac events, including acute myocardial infarction and fatal or life-threatening cardiac rhythm disturbances (e.g., ventricular tachycardia or fibrillation), have occurred within a few hours following administration of 5-HT₁ receptor agonists.1,23 Myocardial ischemia/infarction or coronary vasospasm (e.g., Prinzmetal variant angina) may occur even in patients without a history of coronary artery disease.1,23 Use of eletriptan is contraindicated in patients with ischemic or vasospastic heart disease.1 (See Cautions: Contraindications.) Therapy with 5-HT₁ receptor agonists should be discontinued if disturbances in cardiac rhythm occur.23

Although sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw occur frequently following administration of 5-HT₁ receptor agonists, these sensations usually are noncardiac in origin.1,23 However, the manufacturer states that patients experiencing symptoms suggestive of angina after receiving eletriptan should be evaluated for the presence of coronary artery disease or predisposition to Prinzmetal variant angina before receiving additional doses of the drug.1 If administration of eletriptan is resumed and such symptoms recur, electrocardiographic evaluation should be performed.1

Patients with multiple cardiovascular risk factors (e.g., postmenopausal women; men older than 40 years of a patients with risk factors such as hypertension, hypercholesterolemia, smoking, obesity, diabetes, or family history of coronary artery disease) who have not previously received therapy with a 5-HT₁ receptor agonist should undergo cardiovascular evaluation prior to initiation of 5-HT₁ receptor agonist therapy.1,23 If the evaluation provides evidence of coronary artery disease or coronary artery vasospasm, the drug should not be administered.1 For patients with a satisfactory cardiovascular evaluation, the manufacturer states that consideration should be given to administration of the first dose in a medically supervised setting with electrocardiographic monitoring performed immediately following administration of the dose.1 Periodic cardiovascular evaluation is recommended for patients with risk factors for coronary artery disease who are receiving intermittent long-term therapy with 5-HT₁ receptor agonists, including eletriptan.1,19

For further information on the systematic approach to administering 5-HT₁ receptor agonists in patients with risk factors for the development of coronary artery disease, see Cautions: Precautions and Contraindications, in Sumatriptan 28:32.28.

Cerebrovascular Effects

Cerebral or subarachnoid hemorrhage and stroke, sometimes fatal, have occurred in patients receiving 5-HT₁ receptor agonists.1,23 In a number of cases, it appears possible that the cerebrovascular event was the primary event, and the 5-HT₁ receptor agonist was administered in the mistaken belief that the patient's symptoms were caused by a migraine attack.1 Patients with migraine may be at increased risk for certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack).1 Therapy with 5-HT₁ receptor agonists should be discontinued in patients experiencing a cerebrovascular event.1,23 (See Cautions: Contraindications.)

Other Cardiovascular or Vasospastic Effects

Noncoronary vasospastic reactions, including peripheral vascular ischemia, GI ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud's syndrome, have been reported in patients receiving 5-HT₁ receptor agonists.1,23 (See Cautions: Contraindications.) Transient or permanent blindness and partial vision loss also have been reported in patients receiving 5-HT₁ receptor agonists, although visual disorders may occur as manifestations of migraine attacks.23 Patients experiencing signs or symptoms suggestive of vasospastic reactions following administration of any 5-HT₁ receptor agonist should be evaluated to rule out vasospastic reactions before receiving additional doses of eletriptan.1,23

Substantial increases in blood pressure, including hypertensive crisis with acute impairment of organ systems, have been reported rarely following administration of 5-HT₁ receptor agonists in patients with or without a history of hypertension.1,23 (See Cautions: Contraindications.) Transient increases in blood pressure have been observed following administration of eletriptan doses of 60 mg or greater and may be more pronounced in patients with renal impairment and geriatric patients.1

Increases (18%) in mean pulmonary arterial pressure have been observed following administration of another 5-HT₁ receptor agonist to patients with suspected coronary artery disease who were undergoing cardiac catheterization.1

Serotonin Syndrome

Potentially life-threatening serotonin syndrome has been reported in patients receiving 5-HT₁ receptor agonists, particularly in those receiving concomitant therapy with selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs).1,21 Serotonin syndrome also may occur in patients receiving 5-HT₁ receptor agonists concomitantly with monoamine oxidase (MAO) inhibitors or tricyclic antidepressants.23 Symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1,21 If concurrent therapy with a 5-HT₁ receptor agonist and an SSRI or SNRI is clinically warranted, the patient should be observed carefully, particularly during initiation of therapy, when dosage is increased, or when another serotonergic agent is initiated.1,21 If manifestations of serotonin syndrome occur, treatment with eletriptan and any concurrently administered serotonergic agents should be discontinued and supportive and symptomatic treatment should be initiated.33

Medication Overuse Headache

Excessive use of drugs indicated for the management of acute migraine attacks (e.g., use of 5-HT₁ receptor agonists, ergotamine, opiates, or certain analgesic combinations on a regular basis for 10 or more days per month) may result in migraine-like daily headaches or a marked increase in the frequency of migraine attacks.1,31,32 Detoxification, including withdrawal of the overused drugs; treatment of withdrawal symptoms (which often include transient worsening of headaches); and consideration of prophylactic therapy for migraine attacks may be necessary.1,31,32

Sensitivity Reactions

Serious allergic reactions, including angioedema, have been reported in patients receiving eletriptan.1

Ocular Effects

Accumulation of eletriptan and/or its metabolites in melanin-rich tissues (such as the eye) may occur over time, resulting in potential toxicity in these tissues with extended use.1

Specific Populations

Pregnancy

Category C.1 (See Users Guide.)

Lactation

Eletriptan is distributed into human milk.1 Caution is advised if used in nursing women.1

Pediatric Use

Safety and efficacy have not been established in children younger than 18 years of age.1 Eletriptan is not recommended for use in patients younger than 18 years of age.1

Geriatric Use

Pharmacokinetic profile in patients 65 years of age and older is similar to that in younger adults, although half-life was increased in geriatric patients during clinical trials.1 No substantial differences in efficacy or safety relative to younger adults have been observed; however, there is limited clinical experience in patients 65 years of age or older.1 Increases in blood pressure may be more pronounced in geriatric patients.1

Hepatic Impairment

Peak plasma concentrations and area under the plasma concentration-time curve (AUC) of eletriptan were increased 18 and 34%, respectively, in patients with mild to moderate hepatic impairment.1 Eletriptan has not been studied in patients with severe hepatic impairment; use in such patients is contraindicated.1

Common Adverse Effects

Adverse effects occurring in 2% or more of patients receiving eletriptan include asthenia,1,2,3,4,5,15,17 headache,1,4,17 nausea,1,2,3,4,5,15,17 paresthesia,1,2,3,15 dizziness,1,2,3,4,5,15,17 somnolence,1,3,4,5,15,17 dry mouth,1,4,17 flushing or feeling of warmth,1 pain/pressure sensations (i.e., chest pain [tightness/pressure], abdominal pain/discomfort/stomach pain/cramps/pressure),1,3,4,5,15 dyspepsia,1 and dysphagia 1,17 (i.e., throat tightness,1 difficulty swallowing1 ).

Drugs Affecting Hepatic Microsomal Enzymes

Because in vitro studies have shown that eletriptan is metabolized via the cytochrome P-450 (CYP) isoenzyme 3A4, concomitant use with drugs that inhibit this enzyme (e.g., fluconazole, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) may increase peak plasma concentrations and area under the plasma concentration-time curve (AUC) of the drug.1,15 Administration of eletriptan within 72 hours of drugs with demonstrated potent CYP3A4 inhibition is not recommended.1

In vitro studies of human liver microsomes indicate that eletriptan has little potential to inhibit or induce CYP isoenzymes 1A2, 2C9, 2E1, or 3A4;1 pharmacokinetic interaction is unlikely.1 The manufacturer states that while eletriptan has an effect on the isoenzyme CYP2D6 at high drug concentrations, such an effect should not interfere with metabolism of other drugs when eletriptan is used at recommended dosages.1,19

Ergot Alkaloids and Other 5-HT1 Receptor Agonists

Potential pharmacologic interaction (additive vasospastic effects) when eletriptan is used concomitantly with ergot alkaloids (e.g., ergotamine, dihydroergotamine, methysergide [no longer commercially available in the US]) or other 5-HT₁ receptor agonists.1,15 Use within 24 hours is contraindicated.1

Monoamine Oxidase (MAO) Inhibitors

Pharmacokinetic interaction is unlikely.1,15

Propranolol

Potential pharmacokinetic interaction (increases in the maximum plasma concentrations and AUC of eletriptan); no dosage adjustment is required.1,11,17,19

Selective Serotonin-reuptake Inhibitors and Selective Serotonin- and Norepinephrine-reuptake Inhibitors

Potential pharmacologic interaction (potentially life-threatening serotonin syndrome).1,8,11,15,21 If concomitant use is clinically warranted, the patient should be observed carefully, particularly during treatment initiation, when dosage is increased, or when another serotonergic agent is initiated.1,19,20,21 (See Serotonin Syndrome under Cautions: Warnings/Precautions.)

Pharmacokinetics

Absorption

Bioavailability

Eletriptan is well absorbed after oral administration.1,2,3,5,14,15 Absolute bioavailability is approximately 50%.1

Peak plasma concentrations are attained approximately 1.5 and 2 hours after oral administration in healthy adults and patients with moderate to severe migraine, respectively.1,2,5,14,15

Food

High-fat meal increases AUC and peak plasma concentrations by approximately 20-30%.1

Distribution

Extent

Distributed into human milk.1

Plasma Protein Binding

Approximately 85%.1

Elimination

Metabolism

Eletriptan is metabolized principally by CYP3A4.1,8,11,15 The N -demethylated metabolite (only known active metabolite) does not appear to contribute substantially to overall effect of parent drug.1,19

Elimination Route

Renal clearance accounts for about 10% of total clearance.1

Half-life

Approximately 4 hours.1,2,3,14,15

Special Populations

In patients with mild to moderate hepatic impairment, peak plasma eletriptan concentrations and AUC are increased 18 and 34%, respectively.1 Eletriptan has not been studied in patients with severe hepatic impairment.1

In patients with renal impairment, there are no substantial changes in clearance.1

In geriatric patients, pharmacokinetic profile is similar to that in younger adults, although half-life may be increased.1

Description

Eletriptan hydrobromide is a selective agonist of serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptors.1,2,3,4,5,11,12,13,14,15 Eletriptan is structurally and pharmacologically related to other selective 5-HT_1B/1D receptor agonists (e.g., almotriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan).11,12 Because the mechanisms involved in the pathogenesis of migraine are not clearly understood, the precise mechanism of action of 5-HT₁ receptor agonists in the management of migraine has yet to be established.1,11,12,13 However, current data suggest that 5-HT₁ receptor agonists, including eletriptan, may ameliorate migraine through selective constriction of certain intracranial blood vessels, inhibition of neuropeptide release, and/or reduced transmission in the trigeminal pain pathway.1,8,11,12,13

Eletriptan is well absorbed following oral administration.1,2,3,5,14,15 Peak plasma concentrations are achieved in approximately 1.5 and 2 hours in healthy adults and patients with moderate to severe migraine, respectively.1,2,5,14,15

In vitro, eletriptan is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.1,8,11,15 Since plasma concentrations of the N -demethylated metabolite, the only active metabolite identified for eletriptan, generally are only about 10-20% of the parent drug, the metabolite does not appear to contribute substantially to the overall effect of the parent drug. 1,19 The elimination half-life of eletriptan is approximately 4 hours.1,2,3,14,15 Renal clearance accounts for about 10% of total clearance of eletriptan.1

Advice to Patients

Risk of dizziness or fatigue.1,24

Risk of serious cardiovascular or cerebrovascular events (e.g., myocardial infarction, stroke) or other vasospastic reactions.1 Importance of seeking medical care if symptoms of such reactions (e.g., shortness of breath, weakness, slurring of speech, sudden or severe abdominal pain, difficulty in seeing, or tightness, pain, pressure, or heaviness in chest, throat, jaw, or neck) occur after taking eletriptan and of not taking eletriptan again until evaluated by clinician.1,23,24

Importance of adhering to prescribed directions for use.24 Provide copy of manufacturer's patient information.1,24

Overuse of drugs indicated for the management of acute migraine attacks may exacerbate headaches;1,24 importance of recording headache frequency and drug use to monitor effectiveness of treatment.31

Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease).1,24

Importance of informing patients of risk of serotonin syndrome, particularly with concurrent use of eletriptan and a selective serotonin-reuptake inhibitor (SSRI) or selective serotonin- and norepinephrine-reuptake inhibitor (SNRI).1,21,24 Importance of seeking immediate medical attention if symptoms of serotonin syndrome develop.21,24

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,24

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Pfizer Inc. Relpax® (eletriptan hydrobromide) tablets prescribing information. New York, NY; 2012 Dec.

2. Goadsby PJ, Ferrari MD, Olesen J et al. Eletriptan in acute migraine: a double-blind, placebo-controlled comparison to sumatriptan. Neurology . 2000; 54:156-63. [PubMed 10636142]

3. Stark R, Dahlöf C, Haughie S et al. Efficacy, safety and tolerability of oral eletriptan in the acute treatment of migraine: results of a phase III, multicentre, placebo-controlled study across three attacks. Cephalalgia . 2002; 22:23-32. [PubMed 11993610]

4. Diener HC, Jansen JP, Reches A et al. Efficacy, tolerability and safety of oral eletriptan and ergotamine plus caffeine (Cafergot®) in the acute treatment of migraine: a multicentre, radomised, double-blind, placebo-controlled comparison. Eur Neurol . 2002; 47:99-107. [PubMed 11844898]

5. Sandrini G, Färkkilä M, Burgess G et al. Eletriptan vs sumatriptan : a double-blind, placebo-controlled, multiple migraine attack study. Neurology . 2002; 59:1210-7. [PubMed 12391349]

6. Smith LA, Oldman AD, McQuay HJ et al. Eletriptan for acute migraine. Cochrane Database Syst Rev . 2001; 3:CD003224.

7. Oldman AD, Smith LA, McQuay HJ et al. Pharmacological treatments for acute migraine: quantitative systematic review. Pain . 2002; 97:247-57. [PubMed 12044621]

8. Ferrari MD, Goadsby PJ, Roon KI et al. Triptans (serotonin, 5-HT_1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials. Cephalalgia . 2002; 22:633-58. [PubMed 12383060]

9. Matchar DB, Young WB, Rosenberg JH et al. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management of acute attacks. From American Academy of Neurology web site. [Web]

10. Silberstein SD, for the US Headache Consortium. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology. Neurology . 2000; 55:754-63. [PubMed 10993991]

11. Deleu D, Hanssens Y. Current and emerging second-generation triptans in acute migraine therapy: a comparative review. J Clin Pharmacol . 2000; 40:687-700. [PubMed 10883409]

12. Tfelt-Hansen P, De Vries P, Saxena PR. Triptans in migraine: a comparative review of pharmacology, pharmacokinetics, and efficacy. Drugs . 2000; 60:1259-87. [PubMed 11152011]

13. Tepper SJ, Rapoport AM, Sheftell FD. Mechanisms of action of the 5-HT_1B/1D receptor agonists. Arch Neurol . 2002; 59:1084-8.. [PubMed 12117355]

14. Milton KA, Scott NR, Allen MJ et al. Pharmacokinetics, pharmacodynamics, and safety of the 5-HT_1B/1D agonist eletriptan following intravenous and oral administration. J Clin Pharmacol . 2002; 42:528-39. [PubMed 12017347]

15. Anon. Eletriptan (Relpax) for migraine. Med Lett Drugs Ther. 2003; 45:33-4.

16. Mathew NT, Schoenen J, Winner P et al. Comparative efficacy of eletriptan 40 mg versus sumatriptan 100 mg. Headache . 2003; 43:214-22. [PubMed 12603639]

17. Sheftell F, Ryan R, Pitman V, for the Eletriptan Steering Committee. Efficacy, safety, and tolerability of oral eletriptan for treatment of acute migraine: a multicenter, double-blind, placebo-controlled study conducted in the United States. Headache . 2003; 43:202-13. [PubMed 12603638]

18. Fuseau E, Petricoul O, Sabin A et al. Effect of encapsulation on absorption of sumatriptan tablets: data from healthy volunteers and patients during a migraine. Clin Ther . 2001; 23:242-51. [PubMed 11293557]

19. Pfizer Inc., New York, NY: Personal communication.

20. Eli Lilly and Company. Sarafem (fluoxetine hydrochloride) capsules prescribing information. Indainapolis, IN; 2000 Jul.

21. Food and Drug Administration. Public health advisory: combined use of 5-hydroxytryptamine receptor agonists (triptans), selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephirne reuptake inhibitors (SNRIs) may result in life-threatening serotonin syndrome. Rockville, MD; 2006 Jul 19. From the FDA website: ([Web], [Web], and [Web]).

22. Pfizer Inc. About Relpax^®—Best way to take Relpax^®. From the Pfizer website: ([Web]) Accessed 2006 Dec 13.

23. Merck and Co., Inc. Maxalt^® (rizatriptan benzoate) tablets and Maxalt-MLT^® (rizatriptan benzoate) orally disintegrating tablets prescribing information. Whitehouse Station, NJ; 2013 Jan.

24. Pfizer. Patient summary of information for Relpax^® (eletriptan hydrobromide). New York, NY; 2012 Jan.

31. Tepper SJ, Tepper DE. Breaking the cycle of medication overuse headache. Cleve Clin J Med . 2010; 77:236-42. [PubMed 20360117]

32. Negro A, Martelletti P. Chronic migraine plus medication overuse headache: two entities or not?. J Headache Pain . 2011; 12:593-601. [PubMedCentral][PubMed 21938457]

33. Bijl D. The serotonin syndrome. Neth J Med . 2004; 62:309-13. [PubMed 15635814]