VA Class:CN105

AHFS Class:

• Selective Serotonin Agonists 28:32.28

Generic Name(s):

• Naratriptan Hydrochloride

Chemical Name:

• N -methyl-3-(1-methyl-4-piperidinyl)-1 H -indole-5-ethanesulfonamide monohydrochloride

Molecular Formula:

• C₁₇H₂₅N₃O₂S•HCl

Naratriptan hydrochloride is a selective agonist of serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptors (“triptan”).1,2,3,11

Vascular Headaches

Migraine

Naratriptan hydrochloride is used for the acute treatment of attacks of migraine with or without aura in adults.1 The manufacturer states that naratriptan 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 naratriptan administered at the recommended dosage of 1 or 2.5 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.1,4 In these studies, 50-54 or 60-66% of patients receiving naratriptan 1 or 2.5 mg, respectively, achieved a response (mild or no headache pain) 4 hours after treatment, compared with 27-34% of patients receiving placebo.1,4 The drug also relieved manifestations of migraine other than headache (including nausea, photophobia, and phonophobia) and reduced the need for supplemental migraine therapy.1,4

The US Headache Consortium considers 5-HT_1B/1D receptor agonists (e.g., naratriptan) 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 (NSAIAs) 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.

General

Naratriptan hydrochloride is administered orally.1 Dosage of naratriptan hydrochloride is expressed in terms of naratriptan.1

Vascular Headaches

Migraine

For the acute treatment of migraine attacks with or without aura in adults, single oral naratriptan doses of 1 or 2.5 mg were effective in clinical studies, although the 2.5-mg dose was effective in a greater proportion of patients.1 Because individuals vary in their response to naratriptan, dosage selection should be individualized, weighing the possible benefit of the 2.5-mg dose with the potential for an increased risk of adverse effects.1

If headache recurs or only a partial response is achieved following an initial dose, the dose may be repeated once after 4 hours.1 However, following failure of a given attack of migraine to respond to the first dose of naratriptan, the diagnosis of migraine should be reconsidered prior to administration of a second dose.1 The maximum dosage of naratriptan to be administered in any 24-hour period is 5 mg.1 The safety of treating an average of more than 4 headaches per 30-day period has not been established.1

Special Populations

For patients with mild or moderate renal or hepatic impairment, the manufacturer recommends a maximum dosage of 2.5 mg of naratriptan per 24-hour period and consideration of a reduced initial dosage.1 Use of naratriptan is contraindicated in patients with severe renal or hepatic impairment.1 (See Cautions: Contraindications.)

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

Severe renal impairment (e.g., creatinine clearance less than 15 mL/minute) or severe hepatic impairment (e.g., Child-Pugh grade C).1

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

Known hypersensitivity to naratriptan or any ingredient in the formulation.1

Warnings/Precautions

Careful Diagnosis of Migraine

Naratriptan should be used only in patients in whom a clear diagnosis of migraine has been established.1 Following failure of a given attack of migraine to respond to the first dose of naratriptan, the diagnosis of migraine should be reconsidered prior to administration of a second dose.1 Care should be taken to exclude other potentially serious neurologic disorders before naratriptan 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.1,12 Myocardial ischemia/infarction or coronary vasospasm (e.g., Prinzmetal variant angina) may occur even in patients without a history of coronary artery disease.12 Use of naratriptan 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.12

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.1,12 However, the manufacturer states that patients experiencing symptoms suggestive of angina after receiving naratriptan 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 naratriptan 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.1,12 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.1,12 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 Effects

Cerebral or subarachnoid hemorrhage and stroke, sometimes fatal, have occurred in patients receiving 5-HT₁ receptor agonists.1,12 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.1,12 (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 naratriptan.1,12 (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.12 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 naratriptan.1,12

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.1,12 (See Cautions: Contraindications.) Increases in blood pressure have been observed following administration of naratriptan and may be more pronounced in geriatric patients and patients with hypertension.1

Increases in mean pulmonary arterial pressure and mean aortic pressure following naratriptan administration have been observed in 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).1,10 Serotonin syndrome also may occur in patients receiving 5-HT₁ receptor agonists concomitantly with monoamine oxidase (MAO) inhibitors or tricyclic antidepressants.12 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).1,10 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.10 If manifestations of serotonin syndrome occur, treatment with naratriptan and any concurrently administered serotonergic agents should be discontinued and supportive and symptomatic treatment should be initiated.1,33

Sensitivity Reactions

Hypersensitivity reactions, including anaphylaxis or anaphylactoid reactions, may occur in patients receiving naratriptan; such reactions may be life-threatening or fatal.1

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

Specific Populations

Pregnancy

Category C.1 (See Users Guide.)

Lactation

Naratriptan and/or its metabolites are distributed into milk in rats.1,8 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

Geriatric Use

Use in geriatric patients is not recommended.1 There is a greater frequency of coronary artery disease in this patient population.1 The risk of adverse effects may be increased in those with renal or hepatic impairment.1,8 Increases in blood pressure may be more pronounced in geriatric patients.1

Renal and Hepatic Impairment

Clearance of naratriptan is reduced approximately 50% in patients with moderate renal impairment (creatinine clearance of 18-39 mL/minute) and 30% in patients with moderate hepatic impairment (Child-Pugh grade A or B).1 Naratriptan should be used with caution in such patients; dosage adjustment is recommended.1 (See Dosage and Administration: Special Populations.) Use is contraindicated in patients with severe renal or hepatic impairment.1 (See Cautions: Contraindications.)

Common Adverse Effects

Adverse effects occurring in 2% or more of patients receiving naratriptan include paresthesia,1 nausea,1,4,7 dizziness,1 drowsiness,1 malaise/fatigue,1 and throat/neck symptoms (e.g., pain, pressure).1

Ergot Alkaloids and Other 5-HT1 Receptor Agonists

Potential pharmacologic interaction (additive vasospastic effects) when naratriptan 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 is contraindicated.1

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

Potential pharmacologic interaction (potentially life-threatening serotonin syndrome).1,10 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.10 (See Serotonin Syndrome under Cautions: Warnings/Precautions.)

Oral Contraceptives

Potential pharmacokinetic interaction (decreased clearance and volume of distribution, resulting in slightly increased concentrations of naratriptan).1

Pharmacokinetics

Absorption

Bioavailability

Naratriptan is well absorbed, with oral bioavailability of about 70%.1

Peak plasma concentrations are attained within 2-3 hours after oral administration.1 Absorption may be slower during a migraine attack, with peak plasma concentrations attained in 3-4 hours.1

Food

Food does not affect pharmacokinetics of naratriptan.1

Distribution

Extent

Naratriptan is distributed into milk in animals.1

Plasma Protein Binding

28-31%.1

Elimination

Metabolism

In vitro, naratriptan is metabolized by a wide range of CYP isoenzymes into inactive metabolites.1

Elimination Route

Naratriptan is eliminated principally in urine, with approximately 50% of a dose excreted as unchanged drug and 30% as metabolites.1

Half-life

6 hours.1

Special Populations

In patients with moderate hepatic impairment (Child-Pugh grade A or B), clearance is decreased by approximately 30%.1

In patients with moderate renal impairment (creatinine clearance of 18-39 mL/minute), clearance is decreased by approximately 50%.1

Description

Naratriptan hydrochloride is a selective agonist of serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptors.1,2,3,11 Naratriptan is structurally and pharmacologically related to other selective 5-HT_1B/1D receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, rizatriptan, sumatriptan, zolmitriptan).1,2,11 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.1,2 However, current data suggest that 5-HT₁ receptor agonists, including naratriptan, may ameliorate migraine through selective constriction of certain intracranial blood vessels, inhibition of neuropeptide release, and reduced transmission in the trigeminal pain pathway.1,2,3

Naratriptan is eliminated principally in urine, with approximately 50% of an administered dose excreted as unchanged drug and 30% as metabolites.1 In vitro, naratriptan is metabolized by a wide range of cytochrome P-450 (CYP) isoenzymes to numerous inactive metabolites.1

Advice to Patients

Importance of informing clinicians of any atypical migraine symptoms.1,8

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 naratriptan and of not taking naratriptan again until evaluated by clinician.1,12

Importance of adhering to prescribed directions for use.1 Provide copy of manufacturer's patient information.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.1,31

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).1,10

Importance of informing patients of risk of serotonin syndrome, particularly with concurrent use of naratriptan and a selective serotonin-reuptake inhibitor (SSRI) or selective serotonin- and norepinephrine-reuptake inhibitor (SNRI).1,10 Importance of seeking immediate medical attention if symptoms of serotonin syndrome develop.1,10

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.)

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. GlaxoSmithKline. Amerge^® (naratriptan hydrochloride) tablets prescribing information. Research Triangle Park, NC; 2012 Mar.

2. Goadsby PJ, Hargreaves RJ. Mechanisms of action of serotonin 5-HT_1B/1Dagonists: insights into migraine pathophysiology using rizatriptan. Neurology . 2000; 55(Suppl 2):S8-S14. [PubMed 11089513]

3. Dulli DA. Naratriptan: an alternative for migraine. Ann Pharmacother . 1999; 33:704-11. [PubMed 10410185]

4. Klassen A, Elkind A, Asgharnejad M et al. Naratriptan is effective and well tolerated in the acute treatment of migraine. Results of a double-blind, placebo-controlled parallel-group study. Headache . 1997; 37:640-5. [PubMed 9439085]

5. 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]

6. 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]

7. Mathew NT, Asgharnejad M, Peykamian M et al. Naratriptan is effective and well tolerated in the acute treatment of migraine: results of a double-blind, placebo-controlled, crossover study. Neurology . 1997; 49:1485-90. [PubMed 9409334]

8. GlaxoSmithKline, Research Triangle Park, NC; Personal communication.

9. Matchar DB, Young WB, Rosenberg JH et al. Evidence-based guidelines for migraine headache in the primary care setting: pharmacologic management of acute attacks. St. Paul, MN; 2001. From the American Academy of Neurology web site. [Web]

10. 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]).

11. 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]

12. 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]