Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3067
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Axert (Tablet, Coated)
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In controlled clinical trials, single doses of 6.25 mg and
12.5 mg of AXERT (almotriptan malate) Tablets were effective
for the acute treatment of migraines in adults, with the 12.5 mg dose tending
to be a more effective dose (see CLINICAL
STUDIES). Individuals may vary in response to doses of AXERT.
The choice of dose should therefore be made on an individual basis. If
the headache returns, the dose may be repeated after 2 hours, but no more
than two doses should be given within a 24-hour period. Controlled trials
have not adequately established the effectiveness of a second dose if the
initial dose is ineffective. The safety of treating
an average of more than four headaches in a 30-day period has not been established.<br/>Hepatic Impairment: The pharmacokinetics of almotriptan have not been assessed
in this population. The maximum decrease expected in the clearance of almotriptan
due to hepatic impairment is 60%. Therefore, the maximum daily dose should
not exceed 12.5 mg over a 24-hour period, and a starting dose of 6.25 mg should
be used .<br/>Renal Impairment: In patients with severe renal impairment, the clearance of
almotriptan was decreased. Therefore, the maximum daily dose should not exceed
12.5 mg over a 24-hour period, and a starting dose of 6.25 mg should be used
.
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| dailymed-instance:descripti... |
AXERT (almotriptan malate) Tablets contain
almotriptan malate, a selective 5-hydroxytryptamine(5���HT)
receptor agonist. Almotriptan malate is chemically designated as 1-[[[3-[2-(Dimethylamino)ethyl]-1H-indol-5-yl]methyl]sulfonyl]pyrrolidine
(��)-hydroxybutanedioate (1:1), and its structural formula is: Its empirical formula
is CHNOS-CHO,
representing a molecular weight of 469.56. Almotriptan is a white to slightly
yellow crystalline powder that is soluble in water. AXERT for
oral administration contains almotriptan malate equivalent to 6.25 or 12.5
mg of almotriptan. Each compressed tablet contains the following inactive
ingredients: mannitol, cellulose, povidone, sodium starch glycolate, sodium
stearyl fumarate, titanium dioxide, hypromellose, polyethylene glycol, propylene
glycol, iron oxide (6.25 mg only), FD&C Blue No. 2 (12.5 mg only), and
carnauba wax.
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Mechanism of Action: Almotriptan binds with high affinity to 5-HT,
5-HT, and 5-HTreceptors. Almotriptan has weak affinity
for 5-HTand 5-HTreceptors, but has no significant
affinity or pharmacological activity at 5-HT, 5-HT,
5-HT, 5-HT; alpha or beta adrenergic; adenosine (A,
A); angiotensin (AT, AT); dopamine (D,
D); endothelin (ET, ET); or tachykinin
(NK, NK, NK) binding sites. Current
theories on the etiology of migraine headache suggest that symptoms are due
to local cranial vasodilatation and/or to the release of vasoactive and pro-inflammatory
peptides from sensory nerve endings in an activated trigeminal system. The
therapeutic activity of almotriptan in migraine can most likely be attributed
to agonist effects at 5-HTreceptors on the extracerebral,
intracranial blood vessels that become dilated during a migraine attack, and
on nerve terminals in the trigeminal system. Activation of these receptors
results in cranial vessel constriction, inhibition of neuropeptide release,
and reduced transmission in trigeminal pain pathways.<br/>Pharmacokinetics:<br/>General: Almotriptan is well absorbed after oral administration (absolute
bioavailability about 70%) with peak plasma levels 1 to 3 hours after administration;
food does not affect pharmacokinetics. Almotriptan has a mean half-life of
3 to 4 hours. It is eliminated primarily by renal excretion (about 75% of
the oral dose). Almotriptan is minimally protein bound (approximately 35%)
and the mean apparent volume of distribution is approximately 180 to 200 liters.<br/>Metabolism and Excretion: Almotriptan is metabolized by one minor and two major pathways.
Monoamine oxidase (MAO)-mediated oxidative deamination (approximately 27%
of the dose), and cytochrome P450-mediated oxidation (approximately 12% of
the dose) are the major routes of metabolism, while flavin monooxygenase is
the minor route. MAO-A is responsible for the formation of the indoleacetic
acid metabolite, whereas cytochrome P450 (3A4 and 2D6) catalyzes the hydroxylation
of the pyrrolidine ring to an intermediate that is further oxidized by aldehyde
dehydrogenase to the gamma-aminobutyric acid derivative. Both metabolites
are inactive. Approximately 40% of an administered dose
is excreted unchanged in urine. Renal clearance exceeds the glomerular filtration
rate by approximately 3-fold, indicating an active mechanism. Approximately
13% of the administered dose is excreted via feces, both unchanged and metabolized.<br/>Special Populations:<br/>Geriatric: Renal and total clearance, and amount of drug excreted in
the urine were lower in elderly healthy volunteers (age 65 to 76 years) than
in younger healthy volunteers (age 19 to 34 years), resulting in longer terminal
half-life (3.7 h vs. 3.2 h) and a 25% higher area under the plasma concentration-time
curve in the elderly subjects. The differences, however, do not appear
to be clinically significant.<br/>Pediatric: The pharmacokinetics of almotriptan in pediatric patients
have not been evaluated.<br/>Gender: No significant gender differences have been observed in pharmacokinetic
parameters.<br/>Race: No significant differences have been observed in pharmacokinetic
parameters between Caucasian and African-American volunteers.<br/>Hepatic Impairment: The pharmacokinetics of almotriptan have not been assessed
in this population. Based on the known mechanisms of clearance of almotriptan,
the maximum decrease expected in almotriptan clearance due to hepatic impairment
would be 60%(see DOSAGE
AND ADMINISTRATION).<br/>Renal Impairment: The clearance of almotriptan was approximately 65% lower
in patients with severe renal impairment (Cl/F=19.8 L/h; creatinine clearance
between 10 and 30 mL/min) and approximately 40% lower in patients with moderate
renal impairment (Cl/F=34.2 L/h; creatinine clearance between 31 and 71 mL/min)
than in healthy volunteers (Cl/F= 57 L/h). Maximal plasma concentrations of
almotriptan increased by approximately 80% in these patients .<br/>Drug Interactions: (see also PRECAUTIONS,
Drug Interactions) All drug interaction
studies were performed in healthy volunteers using a single 12.5 mg dose of
almotriptan and multiple doses of the other drug.<br/>Monoamine Oxidase Inhibitors: Coadministration of almotriptan and moclobemide (150 mg b.i.d.
for 8 days) resulted in a 27% decrease in almotriptan clearance.<br/>Propanolol: Coadministration of almotriptan and propranolol (80 mg b.i.d.
for 7 days) resulted in no significant changes in the pharmacokinetics of
almotriptan.<br/>Selective Serotonin Reuptake Inhibitors: Coadministration of almotriptan and fluoxetine (60 mg daily
for 8 days), a potent inhibitor of CYP4502D6, had no effect on almotriptan
clearance, but maximal concentrations of almotriptan were increased 18%. This
difference is not clinically significant.<br/>Verapamil: Coadministration of almotriptan and verapamil (120 mg sustained
release tablets b.i.d for 7 days), an inhibitor of CYP3A4, resulted in a 20%
increase in the area under the plasma concentration-time curve, and in a 24%
increase in maximal plasma concentrations of almotriptan. Neither of these
changes is clinically significant.<br/>Ketoconazole and Other Potent CYP3A4
Inhibitors: Coadministration of almotriptan and the potent CYP3A4 inhibitor
ketoconazole (400 mg qd for 3 days) resulted in an approximately 60% increase
in the area under the plasma concentration-time curve and maximal plasma concentrations
of almotriptan. Although the interaction between almotriptan and other potent
CYP3A4 inhibitors (e.g., itraconazole,
ritonavir, and erythromycin) has not been studied, increased exposures to
almotriptan may be expected when almotriptan is used concomitantly with these
medications.
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AXERT (almotriptan malate) Tablets are available
as follows: 6.25 mg: White,
coated, circular, biconvex tablets with red code imprint "2080."Unit
Dose (aluminum blister pack)6 tablets NDC
0062-2080-06 12.5 mg: White,
coated, circular, biconvex tablets with blue stylized "A."Unit
Dose (aluminum blister pack)12 tablets NDC
0062-2085-12 Store at 25��C (77��F); excursions
permitted to 15�����30��C (59�����86��F).
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dailymed-ingredient:carnauba_wax,
dailymed-ingredient:cellulose,
dailymed-ingredient:hypromellose,
dailymed-ingredient:iron_oxide,
dailymed-ingredient:mannitol,
dailymed-ingredient:polyethylene_glycol,
dailymed-ingredient:povidone,
dailymed-ingredient:propylene_glycol,
dailymed-ingredient:sodium_starch_glycolate,
dailymed-ingredient:sodium_stearyl_fumarate,
dailymed-ingredient:titanium_dioxide
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Patients and volunteers receiving single oral doses of 100
to 150 mg of almotriptan did not experience significant adverse events. Six
additional normal volunteers received single oral doses of 200 mg without
serious adverse events. During clinical trials with AXERT (almotriptan
malate) Tablets, one patient ingested 62.5 mg in a 5-hour period and another
patient ingested 100 mg in a 38-hour period. Neither patient experienced adverse
reactions. Based on the pharmacology of 5-HT agonists,
hypertension or other more serious cardiovascular symptoms could occur after
overdosage. Gastrointestinal decontamination (i.e., gastric lavage followed by activated charcoal) should be considered
in patients suspected of an overdose with AXERT. Clinical
and electrocardiographic monitoring should be continued for at least 20 hours,
even if clinical symptoms are not observed. It is unknown
what effect hemodialysis or peritoneal dialysis has on plasma concentrations
of almotriptan.
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almotriptan malate
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Axert (Tablet, Coated)
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Serious cardiac events, including
myocardial infarction and coronary artery vasospasm, have occurred following
the use of AXERT(almotriptan malate) Tablets. These events
are extremely rare and most have been reported in patients with risk factors
predictive of CAD. Events reported in association with drugs in this class
have included coronary artery vasospasm, transient myocardial ischemia, myocardial
infarction, ventricular tachycardia, and ventricular fibrillation (see CONTRAINDICATIONS, WARNINGS,
and PRECAUTIONS).<br/>Incidence in Controlled Clinical Trials: Adverse events were assessed in controlled clinical trials
that included 1840 patients who received one or two doses of AXERT and
386 patients who received placebo. The most common adverse
events during treatment with AXERT were nausea, somnolence,
headache, paresthesia, and dry mouth. In long-term open-label studies where
patients were allowed to treat multiple attacks for up to one year, 5% (63
out of 1347 patients) withdrew due to adverse experiences. Table
2 lists the adverse events that occurred in at least 1% of the patients treated
with AXERT, and at an incidence greater than in patients
treated with placebo, regardless of drug relationship. These events reflect
experience gained under closely monitored conditions of clinical trials in
a highly selected patient population. In actual clinical practice or in other
clinical trials, these frequency estimates may not apply, as the conditions
of use, reporting behavior, and the kinds of patients treated may differ. AXERT is generally well tolerated. Most
adverse events were mild in intensity and were transient, and did not lead
to long-lasting effects. The incidence of adverse events in controlled clinical
trials was not affected by gender, weight, age, presence of aura, or use of
prophylactic medications or oral contraceptives. There were insufficient data
to assess the effect of race on the incidence of adverse events.<br/>Other Events: In this section, the frequencies of less commonly reported
adverse events are presented. However, the role of AXERT in
their causation cannot be reliably determined. Furthermore, variability associated
with adverse event reporting, the terminology used to describe adverse events,
etc., limit the value of the quantitative frequency estimates provided. Event
frequencies are calculated as the number of patients who used AXERT in
controlled clinical trials and reported an event, divided by the total number
of patients exposed to AXERT in these studies. All reported
events are included, except the ones already listed in the previous table,
those unlikely to be drug-related, and those poorly characterized. Events
are further classified within body system categories and enumerated in order
of decreasing frequency using the following definitions: frequentadverse
events are those occurring in at least 1/100 patients; infrequent adverse
events are those occurring in 1/100 to 1/1000 patients; and rare adverse events
are those occurring in fewer than 1/1000 patients. Body: Frequent: headache. Infrequent: abdominal cramp or pain, asthenia, chills, back pain, chest pain,
neck pain, fatigue, and rigid neck. Rare: fever
and photosensitivity reaction. Cardiovascular: Infrequent:
vasodilation, palpitations, and tachycardia. Rare: hypertension and syncope. Digestive:Infrequent: diarrhea,
vomiting, and dyspepsia. Rare: colitis,
gastritis, gastroenteritis, esophageal reflux, increased thirst, and increased
salivation. Metabolic: Infrequent: hyperglycemia and increased serum creatine phosphokinase. Rare: increased gamma glutamyl transpeptidase
and hypercholesteremia. Musculo-Skeletal: Infrequent: myalgia and muscular weakness. Rare: arthralgia, arthritis, and myopathy. Nervous: Frequent: dizziness and somnolence. Infrequent: tremor, vertigo, anxiety, hypesthesia,
restlessness, CNS stimulation, insomnia, and shakiness. Rare: change in dreams, impaired concentration, abnormal coordination,
depressive symptoms, euphoria, hyperreflexia, hypertonia, nervousness, neuropathy,
nightmares, and nystagmus. Respiratory: Infrequent: pharyngitis, rhinitis, dyspnea, laryngismus, sinusitis, bronchitis,
and epistaxis. Rare: hyperventilation,
laryngitis, and sneezing. Skin: Infrequent: diaphoresis, dermatitis, erythema, pruritus, and rash. Special
Senses: Infrequent: ear pain, conjunctivitis,
eye irritation, hyperacusis, and taste alteration. Rare: diplopia, dry eyes, eye pain, otitis media, parosmia, scotoma, and
tinnitus. Urogenital: Infrequent: dysmenorrhea.<br/>Postmarketing Experience: The following section enumerates potentially important adverse
events that have occurred in clinical practice and that have been reported
spontaneously to various surveillance systems. The events enumerated represent
reports arising from both domestic and non-domestic use of almotriptan and
exclude those events already listed elsewhere as adverse reactions, or those
events too general to be informative. Because the reports cite events reported
spontaneously from worldwide postmarketing experience, frequency of events
and the role of almotriptan in their causation cannot be reliably determined.<br/>Cardiovascular: Coronary artery vasospasm, intermediate coronary syndrome,
and myocardial infarction.<br/>Neurological: Seizures have been reported with 5���HTagonists,
including almotriptan.
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AXERT (almotriptan malate) Tablets are indicated
for the acute treatment of migraine with or without aura in adults. AXERT is
not intended for the prophylactic therapy of migraine or for use in the management
of hemiplegic or basilar migraine .
Safety and effectiveness of AXERT have not been established
for cluster headache, which is present in an older, predominantly male population.
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Axert
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