Generic Name: Almotriptan Malate
Class: Selective Serotonin Agonists
VA Class: CN105
Chemical Name: Hydroxybutanedioate-1-[[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]sulfonyl]pyrrolidine
Molecular Formula: C17H25N3O2S•C4H6O5
CAS Number: 181183-52-8

Introduction

Selective serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptor agonist (“triptan”).1 2 3 5 12

Uses for Axert

Vascular Headaches

Acute treatment of migraine attacks with or without aura in adults.1 9

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 without treatment.1 17 Efficacy in reducing migraine-associated symptoms (nausea, photophobia, phonophobia) in adolescents not established.1 17

Slideshow: Living with Your Migraines: Tips for Treatment and Prevention

Not recommended for management of hemiplegic or basilar migraine or for prophylaxis of migraine.1

Safety and efficacy not established for management of cluster headaches.1

Axert Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.1 5 10 16

Dosage

Available as almotriptan malate; dosage is expressed in terms of almotriptan.1

Dosage adjustment recommended when used concomitantly with potent CYP3A4 inhibitors.1 (See Drugs Affecting Hepatic Microsomal Enzymes under Interactions.)

Pediatric Patients

Vascular Headaches
Migraine
Oral

Adolescents 12–17 years of age: 6.25 or 12.5 mg as a single dose;1 individualize dosage selection, since individual response may vary.1 In clinical study, 12.5-mg dose provided no additional pain relief compared with 6.25-mg dose.1 17

If headache recurs, dose may be repeated after 2 hours.1

Following failure to respond to first dose, reconsider diagnosis of migraine prior to administration of a second dose.1

Adults

Vascular Headaches
Migraine
Oral

6.25 or 12.5 mg as a single dose;1 4 5 individualize dosage selection,1 weighing the possible benefit (greater effectiveness)1 4 5 and risks (increased adverse effects)7 of the 12.5-mg dose.7 In clinical studies, doses >12.5 mg did not lead to substantially greater response.1

If headache recurs, dose may be repeated after 2 hours.1

Following failure to respond to first dose, reconsider diagnosis of migraine prior to administration of a second dose.1

Prescribing Limits

Pediatric Patients

Vascular Headaches
Migraine
Oral

Adolescents 12–17 years of age: Maximum 12.5 mg as a single dose; do not exceed 2 doses (maximum total dosage of 25 mg) in any 24-hour period.1

Safety of treating an average of >4 headaches per 30-day period has not been established.1

Adults

Vascular Headaches
Migraine
Oral

Maximum 12.5 mg as a single dose; do not exceed 2 doses (maximum total dosage of 25 mg) in any 24-hour period.1

Safety of treating an average of >4 headaches per 30-day period has not been established.1

Special Populations

Hepatic Impairment

Initial dose of 6.25 mg; maximum dosage of 12.5 mg over a 24-hour period.1

Renal Impairment

Initial dose of 6.25 mg; maximum dosage of 12.5 mg over a 24-hour period.1

Geriatric Patients

Cautious dosage selection recommended; generally start at low end of dosing range due to greater frequency of decreased hepatic, renal, or cardiac function and of concomitant illnesses or other drug therapy in geriatric population.1

In geriatric patients with normal renal function for their age, dosage is the same as that recommended for younger adults.1

Cautions for Axert

Contraindications

  • Known or suspected ischemic heart disease (e.g., angina pectoris, history of MI, documented silent ischemia).1

  • Coronary artery vasospasm (e.g., Prinzmetal variant angina).1

  • Uncontrolled hypertension.1

  • Other serious underlying cardiovascular disease.1

  • Cerebrovascular syndromes (e.g., stroke of any type, TIA).1

  • Peripheral vascular disease or ischemic bowel disease.1

  • Hemiplegic or basilar migraine.1

  • Treatment within previous 24 hours with another 5-HT1 receptor agonist or an ergot alkaloid.1 (See Specific Drugs under Interactions.)

  • Known hypersensitivity to almotriptan or any ingredient in the formulation.1

Warnings/Precautions

Careful Diagnosis of Migraine

Use only in patients in whom a clear diagnosis of migraine has been established.1

If first migraine attack treated with almotriptan fails to respond to the drug, reconsider diagnosis before administering almotriptan to treat subsequent attacks.1

Exclude other potentially serious neurologic disorders before administering almotriptan to patients not previously diagnosed with migraine or to those with atypical symptoms.1

Cardiac Effects

Possible myocardial ischemia and/or infarction and coronary vasospasm, even in patients without a history of CAD.1 5 22 Contraindicated in patients with ischemic or vasospastic heart disease.1

Possible fatal or life-threatening cardiac rhythm disturbances (e.g., ventricular tachycardia or fibrillation).1 22 Discontinue if such disturbances occur.22

Tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw occur frequently but usually are noncardiac in origin.1 22 Manufacturer states that patients with symptoms suggestive of angina after receiving almotriptan should be evaluated for the presence of CAD or predisposition to Prinzmetal variant angina before receiving additional doses; if administration is resumed and such signs or symptoms recur, ECG evaluation recommended.1

Patients at Risk for CAD

Perform cardiovascular evaluation prior to initiating therapy in patients with multiple cardiovascular risk factors (e.g., postmenopausal women; men >40 years of age; patients with risk factors such as hypertension, hypercholesterolemia, smoking, obesity, diabetes, family history of CAD) who have not previously received 5-HT1 receptor agonist therapy.1 22

If evaluation provides evidence of CAD or coronary vasospasm, do not administer the drug.1

If results of evaluation are satisfactory, consider administering the initial dose in a medically supervised setting followed immediately by an ECG.1 22

Periodic cardiovascular evaluation recommended in patients with risk factors for CAD if receiving intermittent long-term therapy.1

Cerebrovascular Events

Possible cerebral or subarachnoid hemorrhage and stroke, sometimes fatal.1 22 (See Careful Diagnosis of Migraine under Cautions.) Discontinue therapy if a cerebrovascular event occurs.1 22

Risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA) may be increased in patients with migraine.1

Other Vasospastic Effects

Possible noncoronary vasospastic reactions (e.g., peripheral vascular ischemia, GI ischemia and infarction with abdominal pain and bloody diarrhea, splenic infarction, Raynaud’s syndrome);1 22 transient or permanent blindness and partial vision loss reported very rarely in patients receiving 5-HT1 receptor agonists.1

If signs or symptoms suggestive of vasospasm occur following administration, evaluate patient to rule out vasospastic reaction before administering additional doses.1

Hypertensive Effects

Substantial increases in BP, including hypertensive crisis with acute impairment of organ systems, reported rarely with 5-HT1 receptor agonists in patients with or without history of hypertension.1 5 22

Increases in mean pulmonary arterial pressure observed following administration of a 5-HT1 receptor agonist to patients undergoing cardiac catheterization.1

Serotonin Syndrome

Potentially life-threatening serotonin syndrome reported in patients receiving 5-HT1 receptor agonists, particularly in those receiving SSRIs or SNRIs concomitantly.1 11 (See Specific Drugs under Interactions.) Also may occur in patients receiving MAO inhibitors or tricyclic antidepressants concomitantly.22

Symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1 11

If manifestations of serotonin syndrome occur, discontinue almotriptan and any concurrently administered serotonergic agents and initiate supportive and symptomatic treatment.33

Medication Overuse Headache

Overuse of drugs indicated for 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 days per month) may result in migraine-like daily headaches or a marked increase in frequency of migraine attacks.22 31 32

Detoxification, including withdrawal of overused drugs; treatment of withdrawal symptoms (e.g., transient worsening of headaches); and consideration of prophylactic migraine therapy may be necessary.22 31 32

Sensitivity Reactions

Hypersensitivity

Hypersensitivity reactions (e.g., anaphylaxis) reported.1

Sulfonamide Hypersensitivity

Potential for cross-sensitivity between almotriptan, which contains a sulfonyl group, and sulfonamides not systematically evaluated.1 Use almotriptan with caution in patients with known hypersensitivity to sulfonamides.1

Ocular Effects

Possible accumulation of almotriptan in melanin-rich tissues (e.g., eye) over time, resulting in potential toxicity in these tissues with extended use.1

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; not known whether distributed into milk in humans.1 Caution advised if almotriptan is used.1

Pediatric Use

Safety and efficacy not established in children <12 years of age.1

Safety and tolerability in adolescents 12–17 years of age similar to that in adults.1 Serious adverse events reported in limited number of pediatric patients receiving 5-HT1 receptor agonists.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution; dosage adjustment recommended.1 (See Hepatic Impairment under Dosage and Administration and see Drugs Affecting Hepatic Microsomal Enzymes under Interactions.)

Renal Impairment

Use with caution; dosage adjustment recommended.1 (See Renal Impairment under Dosage and Administration and see Drugs Affecting Hepatic Microsomal Enzymes under Interactions.)

Common Adverse Effects

Adults: Nausea,1 paresthesia,1 dry mouth.1

Adolescents: Dizziness,1 17 somnolence,1 17 headache,1 paresthesia,1 17 nausea,1 17 vomiting.1

Interactions for Axert

Metabolized principally by MAO-A, CYP3A4, and CYP2D6.1 19

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (decreased almotriptan metabolism) with concomitant use of CYP3A4 inhibitors.1

When used concomitantly with a potent CYP3A4 inhibitor, recommended initial almotriptan dose is 6.25 mg; do not exceed 12.5 mg within a 24-hour period.1

Avoid concomitant use of almotriptan and potent CYP3A4 inhibitors in patients with renal or hepatic impairment.1

Specific Drugs

Drug

Interaction

Comments

Alcohol

Pharmacokinetic or pharmacologic interaction unlikely15

Antidepressants, SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and SNRIs (e.g., duloxetine, venlafaxine)

Potentially life-threatening serotonin syndrome1 5 11

Potential increase in plasma almotriptan concentrations with concurrent fluoxetine administration1 14

Observe carefully if used concomitantly, particularly during treatment initiation, dosage increases, or when another serotonergic agent is initiated1 11

No dosage adjustment required if fluoxetine is used concomitantly1 14

Ergot alkaloids (e.g., ergotamine, dihydroergotamine, methysergide [no longer commercially available in the US])

Additive vasospastic effects1

Use within 24 hours contraindicated1 5

5-HT1 receptor agonists

Additive vasospastic effects1

Use within 24 hours contraindicated1 5

Itraconazole

Potential decrease in almotriptan metabolism1

Recommended initial almotriptan dose is 6.25 mg; do not exceed 12.5 mg within a 24-hour period1

Avoid concomitant use in patients with renal or hepatic impairment1

Ketoconazole

Decrease in almotriptan metabolism with increased systemic exposure1 18

Recommended initial almotriptan dose is 6.25 mg; do not exceed 12.5 mg within a 24-hour period1

Avoid concomitant use in patients with renal or hepatic impairment1

MAO inhibitors

Potential decrease in almotriptan metabolism1

No dosage adjustment required1

Propranolol

Pharmacokinetic interaction unlikely1 5

Ritonavir

Potential decrease in almotriptan metabolism1

Recommended initial almotriptan dose is 6.25 mg; do not exceed 12.5 mg within a 24-hour period1

Avoid concomitant use in patients with renal or hepatic impairment1

Verapamil

Potential increase in plasma almotriptan concentrations1 5

No dosage adjustment required1 5

Axert 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 or 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

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Binds with high affinity to 5-HT1D, 5-HT1B, and 5-HT1F receptors.1

  • Structurally and pharmacologically related to other selective 5-HT1B/1D receptor agonists (e.g., eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan).2 3 12

  • Precise mechanism of action not established;7 may ameliorate migraine through selective constriction of certain intracranial blood vessels, inhibition of neuropeptide release, and reduced transmission in trigeminal pain pathway.1 3 5 12

Advice to Patients

  • Risk of serious cardiovascular or cerebrovascular events (e.g., MI, 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, or tightness, pain, pressure, or heaviness in chest, throat, neck, or jaw) occur and of not taking almotriptan again until evaluated by clinician.1 22

  • Importance of taking almotriptan exactly as prescribed.1

  • Importance of providing patient a copy of manufacturer’s patient information.1

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

  • Risk of dizziness, somnolence, visual disturbances, and other CNS symptoms that may impair mental or visual performance; avoid driving, operating machinery, and engaging in other hazardous activities until effects on the individual are known.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 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 an SSRI or 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 plan to breast-feed.1

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

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Almotriptan Malate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

6.25 mg (of almotriptan)

Axert

Janssen

12.5 mg (of almotriptan)

Axert

Janssen

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Axert 12.5MG Tablets (JANSSEN PHARMACEUTICALS): 12/$308.98 or 36/$904.98

Axert 6.25MG Tablets (JANSSEN PHARMACEUTICALS): 6/$166.98 or 18/$475.96

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 5, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

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. [IDIS 449430] [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 .

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: ( and , ).

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.

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. [PubMed 21938457]

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

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