AHFS Class:

• Selective Serotonin Agonists 28:32.28

Generic Name(s):

• Almotriptan Malate

Chemical Name:

• Hydroxybutanedioate-1-[[[3-[2-(dimethylamino)ethyl]-1 H -indol-5-yl]methyl]sulfonyl]pyrrolidine

Molecular Formula:

• C₁₇H₂₅N₃O₂S•C₄H₆O₅

Almotriptan malate is a selective agonist of vascular serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptors (“triptan”).1,2,3,5,12

Vascular Headaches

Migraine

Almotriptan malate is used for the acute management of attacks of migraine with or without aura in adults.1 Almotriptan malate also is used for the acute management of migraine headache pain in adolescents 12-17 years of age who have migraine attacks with or without aura that usually last 4 hours or longer without treatment.1 The manufacturer states that the drug is not to be used for the management of hemiplegic or basilar migraine nor for the prophylaxis of migraine.1

Efficacy in adults has been established in 3 randomized, double-blind, placebo-controlled studies principally in women (86%) and white patients (98% or more) with moderate to severe migraine headaches.1,4,5 In these studies, substantially more patients receiving almotriptan achieved a response (mild to no pain) 2 hours after treatment than those receiving placebo.1,4,5 The drug also relieved manifestations of migraine other than headache (including nausea, vomiting, photophobia, and phonophobia), decreased the need for supplemental analgesic therapy, and improved functional ability.4,5,7 In long-term (e.g., 6-12 months) studies, intermittent almotriptan remained effective during subsequent migraine attacks.5,7,8

Efficacy in adolescents has been established in a randomized, double-blind, placebo-controlled study in adolescents 12-17 years of age, mainly girls (60%) and white patients (75%), with moderate to severe migraine headaches.1,17 Patients enrolled in the study had at least a one-year history of migraine attacks with or without aura that usually lasted 4 hours or longer without treatment.1,17 In this study, substantially more patients receiving almotriptan achieved a response (mild or no pain) 2 hours after treatment compared with those receiving placebo; however, the frequency of migraine-associated symptoms (i.e., nausea, photophobia, phonophobia) at 2 hours after treatment was similar in those receiving almotriptan and those receiving placebo.1,17

Limited data suggest that 12.5 mg of almotriptan is at least as effective as 50 or 100 mg of oral sumatriptan in alleviating the pain associated with migraine 2 hours after treatment.5,6,7

The US Headache Consortium considers 5-HT_1B/1D receptor agonists (e.g., almotriptan) 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 5-HT_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 or fixed-combination preparations such as acetaminophen, aspirin, and caffeine has been ineffective.9

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.

Safety and efficacy of almotriptan have not been established for the management of cluster headaches, which are more likely to occur in older, predominantly male patients.1

General

Almotriptan malate is administered orally without regard to meals.1,5,10,16 Dosage of almotriptan malate is expressed in terms of almotriptan.1 The recommended dose of almotriptan for management of acute migraine attacks in adults and adolescents 12-17 years of age is a single dose of 6.25 or 12.5 mg.1 In clinical studies in adults, single oral almotriptan doses of 6.25 and 12.5 mg were effective for the management of acute migraine pain and associated symptoms, although the 12.5-mg dose was effective in a greater proportion of patients.1,4,5 In a clinical study in adolescents, the 12.5-mg dose provided no additional benefit in pain relief compared with the 6.25-mg dose.1,17 Because individuals vary in their response to almotriptan, dosage selection should be individualized,1 weighing the possible benefit of the 12.5-mg dose with the potential for an increased risk of adverse effects.7 In clinical studies, doses exceeding 12.5 mg did not lead to substantially greater response.1,17

If the headache returns, a second oral dose of up to 12.5 mg may be administered after 2 hours.1 The manufacturer recommends that no more than 2 doses (maximum total dosage of 25 mg) be administered within a 24-hour period.1 Controlled trials have not established the effectiveness of a second dose when an initial dose was ineffective, and the manufacturer states that a diagnosis of migraine headache should be reconsidered prior to administration of a second dose in patients who fail to respond to an initial dose of almotriptan.1 The safety of treating an average of more than 4 headaches per 30-day period has not been established.1

Dosage adjustment is recommended when almotriptan is used concomitantly with a potent inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4.1 (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Special Populations

Clearance of almotriptan is substantially reduced in patients with severe renal impairment (creatinine clearance: 10-30 mL/min), and it is anticipated that clearance will be decreased in patients with hepatic impairment.1 Therefore, an initial dosage of 6.25 mg and a maximum dosage of 12.5 mg over a 24-hour period are recommended by the manufacturer in patients with renal or hepatic impairment.1

Contraindications

Known or suspected ischemic heart disease (e.g., angina pectoris, history of myocardial infarction, documented silent ischemia), coronary artery vasospasm (e.g., Prinzmetal variant angina), uncontrolled hypertension, or other serious underlying cardiovascular disease.1 Cerebrovascular syndromes (e.g., stroke of any type, transient ischemic attack), peripheral vascular disease, or ischemic bowel disease.1 Hemiplegic or basilar migraine.1 Recent (i.e., 24 hours or less) treatment with another 5-HT₁ receptor agonist or an ergotamine-containing or ergot-type drug.1 (See Drug Interactions.) Known hypersensitivity to almotriptan or any ingredient in the formulation.1

Warnings/Precautions

Careful Diagnosis of Migraine

Almotriptan should be used only in patients in whom a clear diagnosis of migraine has been established.1 If the first attack of migraine treated with almotriptan fails to respond to the drug, the diagnosis of migraine should be reconsidered before almotriptan is administered to treat subsequent attacks.1 Care should be taken to exclude other potentially serious neurologic disorders before almotriptan is administered to patients not previously diagnosed with migraine or to patients who present with atypical symptoms.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.1,5,22 Myocardial ischemia/infarction or coronary vasospasm (e.g., Prinzmetal variant angina) may occur even in patients without a history of coronary artery disease.1,22 Use of almotriptan 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.22

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.1,22 However, the manufacturer states that patients experiencing symptoms suggestive of angina after receiving almotriptan 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 almotriptan 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.1,22 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.1,22 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.1

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 Events

Cerebral or subarachnoid hemorrhage and stroke, sometimes fatal, have occurred in patients receiving 5-HT₁ receptor agonists.1,22 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 of 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.1,22 (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, including almotriptan.1,22 (See Cautions: Contraindications.) Transient or permanent blindness and partial vision loss also have been reported very rarely in patients receiving 5-HT₁ receptor agonists, although visual disorders may occur as manifestations of migraine attacks.1 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 almotriptan.1

Substantial increases in systemic blood pressure, including hypertensive crisis with acute impairment of organ systems, have been reported rarely in patients with or without a history of hypertension receiving 5-HT₁ receptor agonists, including almotriptan.1,5,22 (See Cautions: Contraindications and also see Cautions: Cardiovascular Effects, in Sumatriptan 28:32.28.) Small, but not clinically important, increases in mean systolic and diastolic blood pressure have been observed in patients with controlled hypertension and in normotensive individuals within 4 hours after oral administration of almotriptan 12.5 mg.1

Increases in mean pulmonary arterial pressure have been observed following administration of another 5-HT₁ receptor agonist in patients 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).1,11 Serotonin syndrome also may occur in patients receiving 5-HT₁ receptor agonists concomitantly with monoamine oxidase (MAO) inhibitors or tricyclic antidepressants.22 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).1,11 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.1,11 If manifestations of serotonin syndrome occur, treatment with almotriptan 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.22,31,32 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.22,31,32

Sensitivity Reactions

Hypersensitivity

Hypersensitivity reactions (e.g., anaphylaxis) have been reported in patients receiving almotriptan.1

Sulfonamide Hypersensitivity

The potential for cross-sensitivity between almotriptan, which contains a sulfonyl group, and sulfonamides has not been systematically evaluated.1 Therefore, almotriptan should be used with caution in patients with known hypersensitivity to sulfonamides.1

Ocular Effects

Accumulation of almotriptan 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. (See Users Guide.)

Lactation

Almotriptan is distributed into milk in rats; it is not known whether almotriptan is distributed into human milk.1 Caution is advised if used in nursing women.1

Pediatric Use

Safety and efficacy of almotriptan have not been established in children younger than 12 years of age.1 Safety and tolerability of almotriptan in adolescents 12-17 years of age is similar to that in adults.1 Serious adverse events have been reported during postmarketing experience in a limited number of pediatric patients receiving 5-HT₁ receptor agonists.1

Geriatric Use

Experience in those 65 years of age and older is insufficient to determine whether they respond differently from younger adults; cautious dosage selection is recommended.1

Hepatic Impairment

Although pharmacokinetics have not been evaluated in patients with hepatic impairment, reduced clearance would be expected.1 Almotriptan should be used with caution in such patients; dosage adjustment is recommended.1 (See Dosage and Administration: Special Populations and see Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Renal Impairment

Clearance of almotriptan is decreased in patients with moderate renal impairment.1 Almotriptan should be used with caution in such patients; dosage adjustment is recommended.1 (See Dosage and Administration: Special Populations and see Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Common Adverse Effects

Nausea,1 paresthesia,1 and dry mouth1 are the most common adverse effects of almotriptan in adults.1 In adolescents, the most common adverse effects are dizziness,1,17 somnolence,1,17 headache,1 paresthesia,1,17 nausea,1,17 and vomiting.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of cytochrome P-450 (CYP) 3A4 isoenzyme (e.g., ketoconazole, itraconazole, ritonavir, erythromycin): potential pharmacokinetic interaction (decreased almotriptan metabolism).1

Concomitant oral administration of almotriptan and ketoconazole (a potent CYP3A4 inhibitor) increased exposure (peak plasma concentrations and area under the concentration-time curve [AUC]) to almotriptan by approximately 60%.1,18 Increased exposure to almotriptan is expected when other potent CYP3A4 inhibitors are used concomitantly with almotriptan.1

The recommended initial dose of almotriptan in patients receiving concomitant therapy with a potent CYP3A4 inhibitor is 6.25 mg, and the maximum total dosage should not exceed 12.5 mg within any 24-hour period.1 The manufacturer states that concomitant use of almotriptan and potent CYP3A4 inhibitors should be avoided in patients with renal or hepatic impairment.1

Alcohol

Pharmacokinetic and pharmacologic interactions are unlikely.15

Ergot Alkaloids and Other 5-HT1 Receptor Agonists

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

Monoamine Oxidase Inhibitors

Potential pharmacokinetic interaction (decreased almotriptan metabolism); no dosage adjustment is required.1

Propranolol

Pharmacokinetic interaction is unlikely.1,5

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

Potential pharmacologic interaction (potentially life-threatening serotonin syndrome).1,5,11 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.1,11 (See Serotonin Syndrome under Cautions: Warnings/Precautions.)

Potential pharmacokinetic interaction with fluoxetine (increased plasma almotriptan concentrations); no adjustment of almotriptan dosage is required.1,14

Verapamil

Potential pharmacokinetic interaction (increased plasma almotriptan concentration); no adjustment of almotriptan dosage is required.1,5,13

Pharmacokinetics

Absorption

Bioavailability

Well absorbed from GI tract.19 Absolute bioavailability is approximately 70%.1,19,20 Peak plasma concentrations attained within 1-3 hours after oral administration.1,19,20 Rate and extent of absorption in adolescents 12-17 years of age is similar to that in adults.1

Food

Food does not affect pharmacokinetics.1,10

Distribution

Extent

Appears to be widely distributed throughout the body.20 Distributed into milk in rats; not known whether distributed into milk in humans.1

Plasma Protein Binding

Approximately 35%.1

Elimination

Metabolism

Metabolized to inactive metabolites principally via MAO-mediated oxidative deamination, CYP3A4, and CYP2D6, with minor contribution of flavin monooxygenase.1,19

Elimination Route

Excreted in urine (75%) and feces (13%), with 40% of dose recovered in urine as unchanged drug.1

Half-life

3-4 hours.1,19,20

Special Populations

Pharmacokinetics not evaluated in patients with hepatic impairment.1 Based on mechanism of almotriptan clearance, maximum decrease in clearance of 60% would be expected.1

In patients with moderate to severe renal impairment, clearance is reduced by approximately 40 or 65%, respectively; peak plasma concentrations increased by approximately 80% in these patients.1

In healthy geriatric patients, clearance is decreased, resulting in increases in half-life and AUC compared with younger adults; not considered clinically important.1

Description

Almotriptan malate is a selective agonist of vascular serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptors.1,2,3,5 Almotriptan is structurally and pharmacologically related to other selective 5-HT_1B/1D receptor agonists (e.g., eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan).2,3,12 Because the mechanisms involved in the pathogenesis of migraine are not clearly understood,2 the precise mechanism of action of almotriptan in the management of acute migraine has yet to be established.7 However, like other 5-HT₁ agonists, it has been suggested that almotriptan may ameliorate migraine through selective constriction of certain cranial blood vessels, inhibition of neuropeptide release, and reduced transmission in the trigeminal pain pathway.1,3,5,12

Almotriptan is eliminated principally by renal excretion with approximately 40% of an administered dose excreted as unchanged drug in urine.1,5 In addition, approximately 27 or 12% of a dose is metabolized by monoamine oxidase-A (MAO-A) or the cytochrome P-450 (CYP) 3A4 and 2D6 isoenzymes, respectively, to inactive metabolites.1,3,5

Advice to Patients

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 the chest, throat, neck, or jaw) occur after taking almotriptan and of not taking almotriptan again until evaluated by clinician.1,22

Importance of adhering to prescribed directions for use, including using the drug only for management of acute attacks of migraine.1 Provide copy of manufacturer's patient information.1

Risk of dizziness, somnolence, visual disturbances, and other CNS symptoms that may impair mental or visual performance; driving, operating machinery, and engaging in other hazardous activities should be avoided until the drug's effects on the individual are known.1

Importance of informing clinician if symptoms suggestive of a hypersensitivity reaction (e.g., rash, itching, difficulty in breathing) occur.1

Overuse of drugs indicated for the management of acute migraine attacks may exacerbate headaches; importance of recording headache frequency and drug use to monitor effectiveness of treatment.22,31

Importance of informing clinicians 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

Importance of informing patients of risk of serotonin syndrome, particularly with concurrent use of almotriptan and a selective serotonin-reuptake inhibitor (SSRI) or selective serotonin- and norepinephrine-reuptake inhibitor (SNRI).1,11 Importance of seeking immediate medical attention if symptoms of serotonin syndrome develop.1,11

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

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

Additional Information

Overview (see Users Guide). For additional information 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. Janssen Pharmaceuticals, Inc. Axert^® (almotriptan malate) tablets prescribing information. Titusville, NJ; 2011 Sep.

2. 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]

3. Palacios JM, Rabasseda X, Castaner J et al. Almotriptan. Drugs Future . 1999; 24:367-74.

4. Pascual J, Falk RM, Piessens F et al. Consistent efficacy and tolerability of almotriptan in the acute treatment of multiple migraine attacks: results of a large, randomized, double-blind, placebo-controlled study. Cephalalgia . 2000; 20:588-96. [PubMed 11075844]

5. Pharmacia Corporation. Axert^® (almotriptan) tablets comprehensive review. Chicago, IL; 2001 Jan.

6. Spierings ELH, Gomez-Mancilla B, Grosz DE et al. Oral almotriptan vs oral sumatriptan in the abortive treatment of migraine. Arch Neurol . 2001; 58:944-50. [PubMed 11405809]

7. Pharmacia & Upjohn. Chicago, IL; Personal communication.

8. Pascaul J, Falk R, Docekal et al. Tolerability and efficacy of almotriptan in the long-term treatment of migraine. Eur Neurol . 2001; 45:206-13. [PubMed 11385257]

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. St. Paul, MN; 2001. From the American Academy of Neurology web site. [Web]

10. Jansat JM, Martinez-Tobed A, Garcia E et al. Effect of food intake on the bioavailability of almotriptan, an antimigraine compound, in healthy volunteers: an open, randomized, crossover, single-dose clinical trial. Int J Clin Pharmacol Ther . 2006; 44:185-90. [PubMed 16625988]

11. 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]

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. Fleishaker JC, Sisson TA, Carel BJ et al. Pharmacokinetic interaction between verapamil and almotriptan in healthy volunteers. Clin Pharmacol Ther . 2000; 67:498-503. [PubMed 10824628]

14. Fleishaker JC, Ryan KK, Carel BJ et al. Evaluation of the potential pharmacokinetic interaction between almotriptan and fluoxetine in healthy volunteers. J Clin Pharmacol . 2001; 41:217-23. [PubMed 11210405]

15. Cabarrocas X, Salva M, Pavesi M et al. Ethanol does not significantly affect the bioavailability of almotriptan: an open, randomized, crossover, single-dose, phase I clinical trial in healthy volunteers. Int J Clin Pharmacol Ther . 2006; 44:443-8. [PubMed 16995333]

16. Ortho-McNeil Pharmaceutical, Inc. Axert^®—Answers to FAQs. From the Ortho-McNeil website. Accessed 2006 Dec 14. [Web]

17. Linder SL, Mathew NT, Cady RK et al. Efficacy and tolerability of almotriptan in adolescents: a randomized, double-blind, placebo-controlled trial. Headache . 2008; 48:1326-36. [PubMed 18484981]

18. Fleishaker JC, Herman BD, Carel BJ et al. Interaction between ketoconazole and almotriptan in healthy volunteers. J Clin Pharmacol . 2003; 43:423-7. [PubMed 12723463]

19. Gras J, Llenas J, Jansat JM et al. Almotriptan, a new anti-migraine agent: a review. CNS Drug Rev . 2002; 8:217-34. [PubMed 12353056]

20. Jansat JM, Costa J, Salva P, Fernandez FJ, Martinez-Tobed A. Absolute bioavailability, pharmacokinetics, and urinary excretion of the novel antimigraine agent almotriptan in healthy male volunteers. J Clin Pharmacol . 2002; 42:1303-10. [PubMed 12463724]

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