Professional Information
Naratriptan (Systemic)
VA CLASSIFICATION
Primary: CN105
Commonly used brand name(s): Amerge.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antimigraine agent—
Indications
General considerations
Naratriptan should only be prescribed for patients who have an established clear diagnosis of migraine {01}.
Accepted
Headache, migraine (treatment)—Naratriptan is indicated to relieve (abort) acute migraine headaches (with or without aura) {01}.
Unaccepted
Naratriptan is not recommended for treatment of basilar artery migraine or hemiplegic migraine {01}.
Naratriptan is not recommended for treatment of cluster headaches {01}. Efficacy and safety of naratriptan in these conditions have not been established {01}.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
371.93 {01}
Mechanism of action/Effect:
Naratriptan's mechanism of action has not been established {01}. It is thought that agonist activity at the 5-hydroxytryptamine (5-HT) 1D and 5-HT 1B receptor subtypes provides relief of headaches {01}. Naratriptan is a highly selective agonist at these receptor subtypes; it has no significant activity at 5-HT 2, 5-HT 3, or 5-HT 4 receptor subtypes or at adrenergic, dopaminergic, histamine, muscarinic, or benzodiazepine receptors {01}. It has been proposed that constriction of cerebral blood vessels resulting from 5-HT 1D/1B receptor stimulation reduces the pulsation that may be responsible for the pain of migraine headaches {01}. It has also been proposed that naratriptan may relieve migraine headaches by decreasing the release of pro-inflammatory neuropeptides {01}.
Absorption:
Oral—Rapid; bioavailability is 70% {01}. The rate and extent of the absorption of naratriptan are not affected by administration with food {01}. The rate of absorption is slower during a migraine attack {01}.
Protein binding:
Low (28 to 31%), at plasma concentrations of 50 to 1000 nanograms per mL (nanograms/mL) {01}.
Biotransformation:
Hepatic {01}. In vitro studies indicate that naratriptan is metabolized by cytochrome P450 isoenzymes into inactive metabolites {01}.
Half-life:
Approximately 6 hours {01}.
Time to peak concentration:
Within 2 to 3 hours (3 to 4 hours during a migraine attack) {01}.
Elimination:
Renal—80% (50% of the dose as unchanged; 30% as metabolites) {01}.
Precautions to Consider
Carcinogenicity/Tumorigenicity
Lifetime carcinogenicity studies were done in mice and rats receiving naratriptan by oral gavage {01}. In mice receiving doses of 200 mg per kg of body weight (mg/kg) per day (reflects an area under the plasma concentration–time curve [AUC] exposure of 110 times the exposure in humans receiving the maximum recommended human dose [MRHD]), no evidence of tumorigenicity was found {01}. Two studies were done in rats, one receiving a standard diet and the other a nitrate-supplemented diet {01}. Rats receiving the standard and nitrate-supplemented diet with doses of naratriptan 5, 20, and 90 mg/kg per day reflected plasma concentration AUC exposures of 7, 40, and 236 times the MRHD and 7, 29, 180 times the MRHD at week 13, respectively {01}. There was an increase in the incidence of thyroid follicular hyperplasia and thyroid follicular adenomas in high-dosed male rats in both studies {01}. However, there was only an increase in thyroid follicular hyperplasia in the high-dosed female rats {01}. Also, in the standard and nitrate supplement studies, the exposure to achieve the no-effect dose for thyroid tumors was 40 and 29 times the MRHD, respectively {01}. In the standard study, there was an increase in the incidence of the benign c-cell adenomas in the thyroid of the high-dosed male rats {01}. The incidence of benign lymphocytic thymoma was increased in all of the females in the nitrate-supplemented diet study {01}.
Mutagenicity
Naratriptan demonstrated no mutagenic effects in the Ames test or in the in vitro thymidine locus mouse lymphoma gene mutation assays {01}. There was no evidence of clastogenic activity in the in vitro human lymphocyte assay or in the in vivo mouse micronucleus cytogenetics assay {01}. A mutagenic product (WHO nitrosation assay) is formed in vitro from nitrosated naratriptan, and has been found in stomachs of rats receiving a nitrate-supplemented diet {01}. It was not determined in the two rat studies whether the nitrosated product is systemically absorbed. However, no changes were found in the stomachs of the rats {01}.
Pregnancy/Reproduction
Fertility—
A reproductive toxicity study in male and female rats receiving doses of naratriptan up to 10, 60, 170, or 340 mg/kg per day (AUC exposure approximately 11, 70, 230, and 470 times the MRHD) found a treatment-related decrease in the number of females exhibiting normal estrous cycles at doses of 170 mg/kg per day or greater {01}. In female rats receiving doses up to 60 mg/kg per day or greater, an increase in preimplantation loss was observed {01}. In the high-dose group males, testicular and/or epididymal atrophy along with spermatazoa depletion resulted in reduced mating success {01}. Also, the preimplantation loss in females may have been due to the testicular and/or epididymal atrophy {01}. However, the exposures achieved at approximately 11, 70, and 230 times the MRHD of naratriptan resulted in no preimplantation loss, anestrus, and testicular effects, respectively {01}.
A study in rats receiving 10, 60, or 340 mg/kg per day for 6 months found changes in the female reproductive tract including atrophic or cystic ovaries at the highest dose {01}. However, in rats receiving 60 mg/kg per day (85 times the MRHD) of naratriptan, no effect was observed {01}.
Pregnancy—
Adequate and well-controlled trials have not been done in pregnant women {01}.
In a reproductive toxicity study, rats and rabbits receiving oral doses of naratriptan equivalent to maternal plasma exposure of 11, 70, and 230 times the MRHD had evidence of developmental toxicity, such as embryo lethality, fetal abnormalities, pup mortality, and offspring growth retardation {01}.
In pregnant rats doses of naratriptan of up to 10, 60, or 340 mg/kg per day (maternal plasma exposures [AUC] approximately 11, 70, and 470 times the MRHD, respectively) given during the organogenesis period resulted in an increase in dose-related embryonic death {01}. The increased incidence of embryo lethality was statistically significant at the highest dose only {01}. However, the incidence of fetal structural variations, such as incomplete or irregular ossification of skull bones, sternebrae, and ribs were increased at all the doses {01}. The highest dose was found to be maternally toxic, which resulted in a lower than normal maternal weight gain during gestation {01}.
In pregnant Dutch rabbits receiving doses of naratriptan of up to 1, 5, or 30 mg/kg per day (approximately 4, 20, and 120 times the MRHD on a mg per square meter of body surface area [mg/m 2] basis, respectively), during the organogenesis period, an increase in incidences of fused sternebrae at the highest dose was observed. In addition, at all the doses there was evidence of an increase in embryonic death, and fetal variations, such as major blood vessel variations, incomplete skeletal ossification, and supernumary ribs {01}. The highest dose in this study was also found to be maternally toxic, which resulted in a lower maternal weight gain during gestation {01}. A study in pregnant New Zealand white rabbits, during the organogenesis period, receiving naratriptan doses of 1, 5, or 30 mg/kg (maternal exposure approximately 2.5, 19, and 140 times the MRHD) per day found decreased fetal weights and increased incidences of fetal skeletal variations at all doses {01}. In contrast with the Dutch rabbits, the maternal weight gain in the New Zealand white rabbits was lower at doses of naratriptan of 5 mg/kg or greater {01}.
In female rats receiving 10, 60, 340 mg/kg doses of naratriptan during late gestation and lactation, behavioral impairment, such as tremors, was observed {01}. At doses of 60 mg/kg per day or greater of naratriptan, a decrease in offspring viability and growth was observed. However, maternal toxicity occurred only at the highest doses {01}. The maternal exposure achieved at approximately 11 times the MRHD of naratriptan did not cause any developmental effects {01}.
FDA Pregnancy Category C {01}.
Breast-feeding
It is not known whether naratriptan is distributed into human breast milk {01}.
Naratriptan is distributed in the milk of lactating rats {01}.
Pediatrics
No information is available on the relationship of age to the effects of naratriptan in pediatric patients. Safety and efficacy have not been established.
Adolescents
In clinical trials, 300 children 12 to 17 years of age have been treated with naratriptan (0.25- to 1.5-mg doses); adverse effects were similar to those occurring in patients older than 17 years of age {01}. However, the safety and efficacy of naratriptan in children up to 18 years of age have not been established {01}.
Geriatrics
Use of naratriptan in elderly patients is not recommended {01}.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Dihydroergotamine or
Ergotamine or
Methysergide or
Other 5-hydroxytryptamine (5HT 1) agonists such as:
Sumatriptan or
Zolmitriptan (a delay of 24 hours between administration of dihydroergotamine, ergotamine, methysergide, or other 5HT 1 and naratriptan is recommended because of the possibility of additive and/or prolonged vasoconstriction {01})
Serotonergics (see Appendix II ), such as:
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline (concurrent use may result in weakness, hyperreflexia, and incoordination; monitoring is recommended {01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Except under special circumstances, this medication should not be used when the following medical problems exist:
» Coronary artery disease, especially:
Angina pectoris
Myocardial infarction, history of
Myocardial ischemia, silent, documented
Prinzmetal's angina or
» Other conditions in which coronary vasoconstriction would be detrimental (naratriptan may cause coronary vasospasms {01})
» Hypertension, uncontrolled (may be exacerbated {01})
» Peripheral vascular disease, including:
Ischemic bowel disease (may be exacerbated {01})
Risk-benefit should be considered when the following medical problems exist
» Cerebrovascular accident, history of (5HT 1 agonists may precipitate a cerebrovascular syndrome; caution should be used when administering to patients at risk for cerebrovascular events {01})
» Coronary artery disease, predisposition to (naratriptan may cause serious coronary adverse effects; patients in whom coronary artery disease is a possibility on the basis of age or the presence of other risk factors, such as diabetes, hypercholesterolemia, obesity, a strong family history of coronary artery disease, or tobacco smoking should be evaluated for the presence of cardiovascular disease before naratriptan is prescribed; even after a satisfactory evaluation, the advisability of administering the patient's first dose under medical supervision should be considered {01})
» Hepatic function impairment, severe or
» Renal function impairment, severe (studies have shown a decrease in naratriptan clearance in patients with moderate hepatic and renal impairment; caution is recommended; a dosage adjustment is recommended in patients with severe hepatic and renal impairment {01})
» Hypersensitivity to naratriptan
» Hypertension, controlled (may precipitate an increase in systolic and diastolic pressure {01})
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Electrocardiogram (ECG) (monitoring is recommended for long-term intermittent users of naratriptan {01})
Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent
Chest pain, severe{01}
heaviness, tightness, or pressure in chest, throat, and/or neck{01}
paresthesias{01} (sensation of burning, warmth or heat, numbness, tightness, or tingling)
Incidence less frequent or rare
Arrythmias{01} (irregular heartbeat)
bradycardia{01} (slow heartbeat)
convulsions{01}
decreased blood pressure{01}
increased blood pressure{01}
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Dizziness
drowsiness
malaise (increased tiredness)
nausea and/or vomiting{01}
Incidence less frequent
Anxiety{01}
arthralgia (joint pain)
blurred vision
chills and/or fever{01}
constipation{01}
diarrhea{01}
gastroenteritis (diarrhea; nausea; stomach pain)
increased thirst{01}
muscle or joint stiffness, tightness, or rigidity{01}
muscle pain or spasms{01}
palpitations{01} (pounding heartbeat)
polyuria{01} (sudden, large increase in frequency and quantity of urine)
pruritus{01} (itching of the skin)
sleep disorders{01} (difficulty sleeping)
skin rash{01}
stomach discomfort and/or pain{01}
syncope{01} (fainting)
tremors{01} (trembling or shaking of hands or feet)
Incidence rare
Acne
anemia (unusual tiredness or weakness)
bone or skeletal pain{01}
confusion{01}
eye problems, including dry eyes{01}
eye pain and/or discomfort{01}
fluid imbalance
mood or mental changes, including agitation{01}
hallucinations
and panic disorders{01}
restlessness{01}
taste perversion{01} (change in taste sensation)
Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).
Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and/or chronic
Increased blood pressure{01}
lightheadedness{01}
loss of coordination{01}
tension in neck{01}
tiredness{01}
Treatment of overdose
Monitoring:
Electrocardiogram (ECG) monitoring should be performed in patients who present with symptoms of chest pain or other symptoms consistent with angina {01}.
Patients should be monitored for at least 24 hours after an overdose of naratriptan {01}.
Supportive care:
Maintaining an open airway and breathing, maintaining proper fluid and electrolyte balance and/or correcting hypertension. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation {01}.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Naratriptan— (Systemic) .
In providing consultation, consider emphasizing the following» selected information ( = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Hypersensitivity to naratriptan
Use in the elderly—Use is not recommended
Other medical problems, especially cerebrovascular accident (history of), coronary artery disease, predisposition to coronary artery disease, or other conditions that may be adversely affected by coronary artery constriction, hepatic function impairment (severe), peripheral vascular disease, renal function impairment (severe), hypertension
Proper use of this medication
» Not administering if atypical headache symptoms are present; checking with physician instead
Administering after onset of headache pain
Additional benefit may be obtained if the patient lies down in a quiet, dark room after administering medication
» Not taking additional doses if first dose does not provide substantial relief; taking alternate medication as previously advised by physician, then checking with physician as soon as possible
» Taking additional doses, if needed, for return of migraine headache after initial relief was obtained, provided that prescribed limits (quantity used and frequency of administration) are not exceeded
» Compliance with prophylactic therapy, if prescribed
» Proper dosing
» Proper storage
Precautions while using this medication
Avoiding alcohol, which aggravates headache
» Caution when driving or doing anything else requiring alertness because of possible drowsiness, dizziness, lightheadedness, impairment of physical or mental abilities
Side/adverse effects
Signs of potential side effects, especially chest pain, severe; heaviness, tightness, or pressure in chest and/or neck; paresthesias; upper respiratory tract infection; arrythmias; hypertension; bradycardia; and convulsions
Oral Dosage Forms
NARATRIPTAN HYDROCHLORIDE TABLETS
Note: The dosing and strengths of the dosage form available are expressed in terms of naratriptan base (not the hydochloride salt).
Usual adult dose
Antimigraine agent
Oral, 1 or 2.5 mg (base) as a single dose. If necessary, additional doses may be taken at intervals of at least four hours {01}.
A starting dose of less than 2.5 mg is recommended for patients with mild to moderate hepatic or renal impairment {01}.
Usual adult prescribing limits
5 mg in twenty-four hours {01}.
2.5 mg in patients with mild or moderate hepatic or renal impairment {01}.
Usual pediatric dose
Safety and efficacy have not been established in children up to 18 years of age {01}.
Usual geriatric dose
Use is not recommended {01}.
Strength(s) usually available
U.S.—
1 mg (base) (Rx) [Amerge{01} (croscarmellose sodium) (hydroxypropyl methylcellulose) (lactose) (magnesium stearate) (microcrystalline cellulose) (triacetin) (titanium dioxide) (iron oxide yellow) (indigo carmine aluminum lake (FD&C Blue No. 2))]
2.5 mg (base) (Rx) [Amerge{01} (croscarmellose sodium) (hydroxypropyl methylcellulose) (lactose) (magnesium stearate) (microcrystalline cellulose) (triacetin) (titanium dioxide) (iron oxide yellow) (indigo carmine aluminum lake (FD&C Blue No. 2))]
Packaging and storage:
Store below 25 ºC (77 ºF) {01}.
Auxiliary labeling:
• Take with a full glass of water.
Developed: 07/07/1998
References
- Amerge package insert (Glaxo Wellcome—US), New 2/98, Rec 2/98.
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