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Naratriptan

Pronunciation

(NAR a trip tan)

Index Terms

  • NAratriptan HCl
  • Naratriptan Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Amerge: 1 mg, 2.5 mg

Generic: 1 mg, 2.5 mg

Brand Names: U.S.

  • Amerge

Pharmacologic Category

  • Antimigraine Agent
  • Serotonin 5-HT1B, 1D Receptor Agonist

Pharmacology

Selective agonist for serotonin (5-HT1B and 5-HT1D receptors) in cranial arteries; causes vasoconstriction and reduces sterile inflammation associated with antidromic neuronal transmission correlating with relief of migraine

Absorption

Well absorbed

Distribution

Vdss: 170 L

Metabolism

Hepatic via CYP

Excretion

Urine (50% of total dose as unchanged drug; 30% of total dose as metabolites)

Onset of Action

~1-2 hours (Bomhof, 1999; Tfelt-Hansen, 2000)

Time to Peak

2-3 hours

Half-Life Elimination

6 hours; Increased in renal impairment (moderate impairment; mean: 11 hours; range: 7 to 20 hours); Increased in hepatic impairment (moderate impairment: 8 to 16 hours)

Protein Binding

Plasma: 28% to 31%

Special Populations: Renal Function Impairment

Naratriptan clearance is reduced 50% with moderate impairment (CrCl 18 to 39 mL/minute); mean Cmax increased ~40%.

Special Populations: Hepatic Function Impairment

Naratriptan clearance is decreased 30% in patients with moderate impairment (Child-Pugh class A or B).

Special Populations: Elderly

Clearance is decreased ~26% in healthy elderly subjects (65-77 years) compared to younger patients.

Special Populations: Gender

Cmax is 50% higher in women.

Use: Labeled Indications

Migraines: Acute treatment of migraine attacks with or without aura in adults.

Use: Unlabeled

Short-term prevention of menstrually-associated migraines (MAMs)

Contraindications

Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction [MI], or documented silent ischemia); coronary artery vasospasm, including Prinzmetal’s angina; Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders; history of stroke, transient ischemic attack (TIA), or history of hemiplegic or basilar migraine; peripheral vascular disease; ischemic bowel disease; uncontrolled hypertension; recent use (within 24 hours) of another 5-HT1 agonist, ergotamine-containing medication, or ergot-type medication (eg, dihydroergotamine or methysergide); severe renal impairment (CrCl <15 mL/minute) or severe hepatic impairment; hypersensitivity to naratriptan or any component of the formulation

Canadian labeling: Additional contraindications (not in U.S. labeling): Severe hypertension, cardiac arrhythmias (especially tachycardias); valvular heart disease, congenital heart disease, atherosclerotic disease; management of ophthalmoplegic migraine

Documentation of allergenic cross-reactivity for triptans is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Note: If the first dose is ineffective, diagnosis needs to be re-evaluated. The safety of treating >4 migraines/month has not been established.

Acute migraine: Oral: Initial: 1-2.5 mg; if headache recurs or does not fully resolve, a second dose may be administered after 4 hours (maximum: 5 mg daily).

Dosing: Geriatric

U.S. labeling: Refer to adult dosing. Dosing should generally start at the lower end of the dosing range due to possible increased incidence of hepatic, renal, and cardiac impairment.

Canadian labeling: Use is not recommended

Dosing: Renal Impairment

Mild-to-moderate renal impairment:

U.S. labeling: Initial: 1 mg; do not exceed 2.5 mg in 24 hours.

Canadian labeling: Initial: 1 mg; do not exceed 2 mg in 24 hours

Severe renal impairment (CrCl <15 mL/minute): Use is contraindicated.

Dosing: Hepatic Impairment

Mild-to-moderate hepatic impairment (Child-Pugh grade A or B):

U.S. labeling: Initial: 1 mg; do not exceed 2.5 mg in 24 hours

Canadian labeling: Initial: 1 mg; do not exceed 2 mg in 24 hours

Severe hepatic impairment (Child-Pugh grade C): Use is contraindicated.

Extemporaneously Prepared

A 0.5 mg/mL oral suspension may be made using tablets. Crush fifty 2.5 mg tablets and reduce to a fine powder. In small amounts, add 125 mL of Ora-Plus® and mix well after each addition. Transfer to a calibrated bottle, rinse mortar with vehicle, then add quantity of Ora-Sweet® or Ora-Sweet® SF sufficient to make 250 mL. Label "shake well" and "refrigerate". Stable 90 days refrigerated.

Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.

Administration

Administer orally as soon as symptoms appear; may take with or without food. Do not crush or chew tablet; swallow whole with water.

Storage

Store at 20°C to 25°C (68°F to 77°F).

Drug Interactions

Analgesics (Opioid): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Anti-Parkinson Agents (Monoamine Oxidase Inhibitor): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity if selegiline or rasagiline is combined with a serotonin modulator. Use of transdermal selegiline with serotonin modulators is contraindicated. Consider therapy modification

Antipsychotic Agents: Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

Droxidopa: Serotonin 5-HT1D Receptor Agonists may enhance the hypertensive effect of Droxidopa. Monitor therapy

Ergot Derivatives: May enhance the vasoconstricting effect of Serotonin 5-HT1D Receptor Agonists. Serotonin 5-HT1D Receptor Agonists may enhance the vasoconstricting effect of Ergot Derivatives. Avoid combination

Linezolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Management: Due to a risk of serotonin syndrome/serotonin toxicity, discontinue serotonin modulators 2 weeks prior to the administration of linezolid. If urgent initiation of linezolid is needed, discontinue serotonin modulators immediately and monitor closely. Consider therapy modification

Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination

Metoclopramide: Serotonin Modulators may enhance the adverse/toxic effect of Metoclopramide. This may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Monitor therapy

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Tedizolid. Monitor therapy

SUMAtriptan: Serotonin 5-HT1D Receptor Agonists may enhance the adverse/toxic effect of SUMAtriptan. Avoid combination

Tedizolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

TraMADol: Serotonin Modulators may enhance the adverse/toxic effect of TraMADol. The risk of seizures may be increased. TraMADol may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Adverse Reactions

1% to 10%:

Central nervous system: Pain (4%), fatigue (2%), dizziness (1% to 2%), drowsiness (1% to 2%), paresthesia (1% to 2%), hot and cold flashes (1%), sensation of pressure (1%; chest/neck/throat/jaw), vertigo (1%)

Gastrointestinal: Nausea (4% to 5%), vomiting (1%), xerostomia (1%)

Neuromuscular & skeletal: Neck pain (2%)

Ophthalmic: Photophobia (1%)

Respiratory: Constriction of the pharynx (2%), ENT infection (1%)

<1% (Limited to important or life-threatening): Abnormal bilirubin levels, abnormal hepatic function tests, anaphylactoid reaction, anaphylaxis, anemia, angina pectoris, angioedema, bradycardia, cerebral infarction, colonic ischemia, coronary artery vasospasm, depression, ECG changes (atrial fibrillation, atrial flutter, premature ventricular contractions, PR prolongation, or QTc prolongation), glycosuria, hallucination, heart murmur, hypersensitivity reaction (some cases severe, including circulatory collapse), hypertension, hypothyroidism, ischemic heart disease, ketonuria, myocardial infarction, palpitations, seizure, serotonin syndrome, skin rash, subarachnoid hemorrhage, subconjunctival hemorrhage, syncope, thrombocytopenia, transient ischemic attacks, ventricular fibrillation, ventricular tachycardia

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactic/Anaphylactoid reactions: Anaphylaxis, anaphylactoid, and hypersensitivity reactions (including angioedema) have occurred; may be life-threatening or fatal. Use is contraindicated in patients with known hypersensitivity to naratriptan.

• Cardiac events: Coronary artery vasospasm, transient ischemia, myocardial infarction, ventricular tachycardia/fibrillation, cardiac arrest, and death have been reported with 5-HT1 agonist administration; some events have occurred within a few hours of administration. Discontinue if these events occur. Patients who experience sensations of chest pain/pressure/tightness or symptoms suggestive of angina following dosing should be evaluated for coronary artery disease (CAD) or Prinzmetal's angina before receiving additional doses; if dosing is resumed and similar symptoms recur, monitor with ECG. Use is contraindicated in patients with ischemic or vasospastic CAD and Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. Additionally, the Canadian labeling contraindicates use in patients with valvular heart disease, cardiac arrhythmias (especially tachycardias), and congenital heart disease.

• Cerebrovascular events: Cerebral/subarachnoid hemorrhage and stroke (some fatal) have been reported with 5-HT1 agonist administration. Use is contraindicated in patients with a history of stroke or transient ischemic attack.

• CNS depression: May cause CNS depression, such as dizziness, weakness, or drowsiness, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Elevated blood pressure: Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has also been reported on rare occasions in patients with and without a history of hypertension. Monitor blood pressure; use is contraindicated in patients with uncontrolled hypertension; the Canadian labeling also contraindicates use in patients with severe hypertension.

• Headaches: Acute migraine agents (eg, triptans, opioids, ergotamine, or a combination of the agents) used for 10 or more days per month may lead to worsening of headaches (medication overuse headache); withdrawal treatment may be necessary in the setting of overuse.

• Vasospasm-related events: Peripheral vascular ischemia and colonic ischemia, gastrointestinal vascular ischemia and infarction, splenic infarction, and Raynaud’s syndrome have been reported with 5-HT1 agonist administration.

• Visual effects: Partial vision loss and blindness (transient and permanent) have been reported with use of 5-HT1 agonists; a causal relationship between these events and 5-HT1 agonist administration has not been clearly determined.

Disease-related concerns:

• Coronary artery disease: Should not be given to patients who have risk factors for CAD (eg, hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, menopause, male >40 years of age) without adequate cardiac evaluation. Use is contraindicated if there is evidence of CAD or coronary artery vasospasm. Patients with suspected CAD should have cardiovascular evaluation to rule out CAD before considering use; if cardiovascular evaluation is “satisfactory,” first dose should be given in the health care provider's office (consider ECG monitoring). Periodic evaluation of cardiovascular status should be done in all patients.

• Hepatic impairment: Use is contraindicated in patients with severe hepatic impairment (Child-Pugh grade C).

• Renal impairment: Use is contraindicated in patients with severe renal impairment (CrCl <15 mL/minute).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Serotonin syndrome: Symptoms of agitation, confusion, hallucinations, hyper-reflexia, myoclonus, shivering, and tachycardia may occur with concomitant proserotonergic drugs (ie, SSRIs/SNRIs or triptans) or agents which reduce naratriptan's metabolism. Concurrent use of serotonin precursors (eg, tryptophan) is not recommended. If concomitant administration with SSRIs is warranted, monitor closely, especially at initiation and with dose increases. Discontinue naratriptan if serotonin syndrome is suspected.

Special populations:

• Elderly: Blood pressure increases may be more pronounced in the elderly.

Other warnings/precautions:

• Appropriate use: Only indicated for the acute treatment of migraine; not indicated for migraine prophylaxis, or for the treatment of cluster headache, hemiplegic, basilar, or ophthalmoplegic (Canadian labeling) migraine. If a patient does not respond to the first dose, the diagnosis of migraine should be reconsidered; rule out underlying neurologic disease in patients with atypical headache and in patients with no prior history of migraine.

Monitoring Parameters

Headache severity, blood pressure, signs/symptoms suggestive of angina; perform a cardiovascular evaluation in triptan-naïve patients who have multiple cardiovascular risk factors (eg, increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD), monitor ECG with first dose in patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation and consider periodic cardiovascular evaluation in such patients if they are intermittent long-term users; signs/symptoms of serotonin syndrome and hypersensitivity reactions.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Pregnancy outcome information for naratriptan is available from a pregnancy registry sponsored by GlaxoSmithKline. As of October 2008, data was available for 55 infants/fetuses exposed to naratriptan, and seven exposed to both naratriptan and sumatriptan. Following naratriptan exposure, there was one infant born with a birth defect; this infant was also exposed to sumatriptan during the first trimester of pregnancy (Cunnington, 2009). The pregnancy registry was closed in January, 2012 and additional information may be obtained from the manufacturer (800-336-2176). Additional information related to the use of naratriptan in pregnancy is limited (Källén, 2011; Nezvalová-Henriksen, 2010; Nezvalová-Henriksen, 2012). Until additional information is available, other agents are preferred for the initial treatment of migraine in pregnancy (Da Silva, 2012; MacGregor, 2012; Williams, 2012).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dizziness, fatigue, loss of strength and energy, flushing, or sensation of warmth. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), signs of a heart attack (angina; pain in arms, back, neck, jaw, or stomach; shortness of breath; cold sweats; severe dizziness; passing out; or severe nausea or vomiting), signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, arrhythmia, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea), arrhythmia, skin discoloration, severe headache, burning or numbness feeling, constipation, diarrhea, severe nausea, severe vomiting, severe abdominal pain, bloody diarrhea, weight loss, leg cramps, sensation of leg heaviness, sensation of cold, shortness of breath, or burning or aching of feet or toes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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