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In very rare cases, patients taking this class of medicines experience serious side effects including death. These effects include:
- heart problems
- increased blood pressure
Tell your doctor right away if you feel tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw after taking Axert.
Some people may have a reaction called serotonin syndrome, which can be life-threatening, when they use Axert. In particular, this reaction may occur when they use Axert together with certain types of antidepressants known as SSRIs or SNRIs. Symptoms may include:
- mental changes (hallucinations, agitation, or coma)
- fast heartbeat
- changes in blood pressure
- high body temperature or sweating
- tight muscles
- trouble walking
Call your doctor immediately if you have any of these symptoms after taking Axert.Do not take Axert if you:
- have ever had heart disease.
- have uncontrolled high blood pressure.
- have hemiplegic or basilar migraine. If you are not sure, ask your doctor.
- have taken another serotonin receptor agonist (e.g., another triptan) in the last 24 hours. These include naratriptan (Amerge), rizatriptan (Maxalt), sumatriptan (Imitrex, Treximet), or zolmitriptan (Zomig).
- have taken ergotamine-type medicines in the last 24 hours. These include ergotamine (Bellergal-S, Cafergot, Ergomar, Wigraine), dihydroergotamine (D.H.E. 45), or methysergide (Sansert).
- had an allergic reaction to Axert or any of its ingredients.
Axert Food Interactions
Grapefruit and grapefruit juice may interact with Axert and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor.
Axert and Pregnancy
Tell your doctor if you are pregnant or plan to become pregnant.
The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.
This medication falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.
How should I take Axert (almotriptan)?
Your doctor may want to give your first dose of this medicine in a hospital or clinic setting to quickly treat any serious side effects that occur.
Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.
Take almotriptan as soon as you notice migraine symptoms.
After taking a tablet: If your headache goes away and comes back, take a second tablet 2 hours after the first. Do not take more than 2 tablets of almotriptan tablets in 24 hours. If your symptoms have not improved, contact your doctor before taking any more tablets.
Call your doctor if your headache does not go away at all after taking the first almotriptan tablet.
Never use more than your recommended dose. Overuse of migraine headache medicine can make headaches worse.
Contact your doctor if you have more than four headaches in one month (30 days). Tell your doctor if this medicine seems to stop working as well in treating your migraine attacks.
If you use almotriptan long-term, your heart function may need to be checked using an electrocardiograph or ECG (sometimes called an EKG). This will help your doctor determine if it is still safe for you to take almotriptan.
Store at room temperature away from moisture, heat, and light.
Precautions While Using Axert
It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it.
Check with your doctor if you used this medicine and your migraine did not go away, or if your migraine got worse or started occurring more often.
You should not take this medicine if you have used other triptan or ergot-type migraine medicines within the past 24 hours. Some examples of triptan medicines are frovatriptan (Frova®), naratriptan (Amerge®), rizatriptan (Maxalt®), sumatriptan (Imitrex®, Treximet®), and zolmitriptan (Zomig®). Some examples of ergot-type medicines are dihydroergotamine (D.H.E. 45®, Migranal®), ergotamine (Bellergal®, Cafergot®, Ergomar®, or Wigraine®), and methysergide (Sansert®).
This medicine may cause problems if you have heart disease. If your doctor thinks you might have a problem with this medicine, he or she may want you to take your first dose in the doctor’s office or clinic.
This medicine may increase your risk of having a heart attack, angina, or stroke. This is more likely to occur if you or a family member already have heart disease, if you smoke, if you are male and over 40 years of age, or if you are female and have gone through menopause. Call your doctor right away if you have any symptoms of a heart problem, such as chest pain or discomfort, an irregular heartbeat, nausea or vomiting, pain or discomfort in the shoulders, arms, jaw, back, or neck, shortness of breath, or sweating. Call your doctor right away if you have any symptoms of a stroke, such as confusion, difficulty with speaking, double vision, headaches, an inability to move the arms, legs, or facial muscles, an inability to speak, or slow speech.
Check with your doctor right away if you have chest discomfort, jaw or neck tightness after taking this medicine. Also, tell your doctor if you have sudden or severe abdominal or stomach pain or bloody diarrhea after using this medicine.
Make sure your doctor knows about all the other medicines you are using. Almotriptan may cause a serious condition called serotonin syndrome when taken with some medicines. This includes medicines to treat depression, such as citalopram (Celexa®), duloxetine (Cymbalta®), escitalopram (Lexapro®), fluoxetine (Prozac®, Sarafem®, or Symbyax®), fluvoxamine (Luvox®), paroxetine (Paxil®), sertraline (Zoloft®), or venlafaxine (Effexor®). Check with your doctor right away if you have agitation, confusion, diarrhea, excitement while talking that is not normal, fever, overactive reflexes, poor coordination, restlessness, shivering, sweating, trembling or shaking that you cannot control, or twitching. These could be symptoms of serotonin syndrome.
Using almotriptan alone or in combination with other migraine medicines for 10 or more days per month may lead to worsening of headache. You may keep a headache diary to record your headache frequency and drug use.
Check with your doctor right away if you have blurred vision, difficulty with reading, or any other change in vision while you are using this medicine. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).
Almotriptan may cause drowsiness, dizziness, or trouble with your vision. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that requires you to be alert and able to see well.
Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.
If OVERDOSE is suspected
If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.
Ischemic or Vasospastic Coronary Artery Disease, or Other Significant Underlying Cardiovascular Disease
Do not use Axert® (almotriptan malate) in patients with ischemic heart disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), or in patients who have symptoms or findings consistent with ischemic heart disease, coronary artery vasospasm, including Prinzmetal's variant angina, or other significant underlying cardiovascular disease [see Warnings and Precautions (5.1)].
Do not use Axert® in patients with cerebrovascular syndromes including (but not limited to) stroke of any type as well as transient ischemic attacks [see Warnings and Precautions (5.3)].
Peripheral Vascular Disease
Do not use Axert® in patients with peripheral vascular disease including (but not limited to) ischemic bowel disease [see Warnings and Precautions (5.4)].
Because Axert® may increase blood pressure, do not use Axert® in patients with uncontrolled hypertension [see Warnings and Precautions (5.7)].
Ergotamine-Containing and Ergot-Type Medications
Do not use Axert® and ergotamine-containing or ergot-derived medications like dihydroergotamine, ergotamine tartrate, or methysergide within 24 hours of each other [see Drug Interactions (7.1)].
Concomitant Use With 5-HT1 Agonists (e.g., Triptans)
Axert® and other 5-HT1 agonists (e.g., triptans) should not be administered within 24 hours of each other [see Warnings and Precautions (5.1) and (5.2)].
Hemiplegic or Basilar Migraine
Do not use Axert® in patients with hemiplegic or basilar migraine.
Axert® is contraindicated in patients with known hypersensitivity to almotriptan or any of its inactive ingredients.
Serious cardiac reactions, including myocardial infarction, have occurred following the use of Axert® (almotriptan malate) Tablets. These reactions are extremely rare and most have been reported in patients with risk factors predictive of CAD. Reactions reported in association with triptans have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation [see Contraindications (4.1) and Warnings and Precautions (5.1)].
The following adverse reactions are discussed in more detail in other sections of the labeling:
- Risk of Myocardial Ischemia and Infarction and Other Adverse Cardiac Events [see Warnings and Precautions (5.1)]
- Sensations of Pain, Tightness, Pressure in the Chest and/or Throat, Neck, and Jaw [see Warnings and Precautions (5.2)]
- Cerebrovascular Events and Fatalities [see Warnings and Precautions (5.3)]
- Other Vasospasm-Related Events, Including Peripheral Vascular Ischemia and Colonic Ischemia [see Warnings and Precautions (5.4)]
- Serotonin Syndrome [see Warnings and Precautions (5.5)]
- Increases in Blood Pressure [see Warnings and Precautions (5.7)]
Adverse events were assessed in controlled clinical trials that included 1840 adult patients who received one or two doses of Axert® and 386 adult patients who received placebo. The most common adverse reactions 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 1 year, 5% (63 out of 1347 patients) withdrew due to adverse experiences.
Adverse events were assessed in controlled clinical trials that included 362 adolescent patients who received Axert® and 172 adolescent patients who received placebo. The most common adverse reactions during treatment with Axert® were dizziness, somnolence, headache, paresthesia, nausea, and vomiting. In a long-term, open-label study where patients were allowed to treat multiple attacks for up to 1 year, 2% (10 out of 420 adolescent patients) withdrew due to adverse events.
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Axert® Clinical Trials
Table 1 lists the adverse events that occurred in at least 1% of the adult patients treated with Axert®, and at an incidence greater than in patients treated with placebo, regardless of drug relationship.
|System/Organ Class |
|Axert® 6.25 mg |
|Axert® 12.5 mg |
|Nervous System Disorders|
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.
Table 2 lists the adverse reactions reported by 1% or more of Axert®-treated adolescents age 12 to 17 years in 1 placebo-controlled, double-blind clinical trial.
|System/Organ Class |
|Axert® 6.25 mg |
|Axert® 12.5 mg |
|Nervous System Disorders|
Other Adverse Reactions Observed in Axert® Clinical Trials
In the paragraphs that follow, the frequencies of less commonly reported adverse clinical reactions are presented. The reports include adverse reactions in 5 adult controlled studies and 1 adolescent controlled study. Variability associated with adverse reaction reporting, the terminology used to describe adverse reactions, etc., limit the value of the quantitative frequency estimates provided. Reaction frequencies are calculated as the number of patients who used Axert® and reported a reaction divided by the total number of patients exposed to Axert® (n=3047, all doses). All reported reactions are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Reactions are further classified within system organ class and enumerated in order of decreasing frequency using the following definitions: frequent adverse reactions are those occurring in 1/100 or more patients, infrequent adverse reactions are those occurring in fewer than 1/100 to 1/1000 patients, and rare adverse reactions 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, Dyspepsia, Gastroenteritis, and Increased thirst. Rare: Colitis, Gastritis, Esophageal reflux, and Increased salivation.
Metabolic: Infrequent: Hyperglycemia and Increased serum creatine phosphokinase. Rare: Increased gamma glutamyl transpeptidase and Hypercholesteremia.
Musculo-Skeletal: Infrequent: Myalgia. Rare: Arthralgia, Arthritis, Myopathy, and Muscle weakness.
Nervous: Frequent: Dizziness and Somnolence. Infrequent: Tremor, Vertigo, Anxiety, Hypoesthesia, Restlessness, CNS stimulation, and Shakiness. Rare: Change in dreams, Impaired concentration, Abnormal coordination, Depressive symptoms, Euphoria, Hyperreflexia, Hypertonia, Nervousness, Neuropathy, Nightmares, Nystagmus, and Insomnia.
Respiratory: Infrequent: Pharyngitis, Rhinitis, Dyspnea, Laryngismus, Sinusitis, and Bronchitis. Rare: Hyperventilation, Laryngitis, Sneezing, and Epistaxis.
Skin: Infrequent: Diaphoresis, Pruritus, and Rash. Rare: Dermatitis and Erythema.
Special Senses: Infrequent: Ear pain and Tinnitus. Rare: Diplopia, Dry eyes, Eye pain, Otitis media, Parosmia, Scotoma, Conjunctivitis, Eye irritation, Hyperacusis, and Taste alteration.
Urogenital: Infrequent: Dysmenorrhea.
The following adverse reactions have been identified during postapproval use of Axert®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune System Disorders: Hypersensitivity reactions (including angioedema, anaphylactic reactions and anaphylactic shock)
Psychiatric Disorders: Confusional state, Restlessness
Nervous System Disorders: Hemiplegia, Hypoesthesia, Seizures
Eye Disorders: Blepharospasm, Visual impairment, Vision blurred
Ear and Labyrinth Disorders: Vertigo
Cardiac Disorders: Acute myocardial infarction, Coronary artery vasospasm, Angina pectoris, Tachycardia
Gastrointestinal Disorders: Abdominal discomfort, Abdominal pain, Abdominal pain upper, Colitis, Hypoesthesia oral, Swollen tongue
Skin and Subcutaneous Tissue Disorders: Cold sweat, Erythema, Hyperhidrosis
Musculoskeletal, Connective Tissue, and Bone Disorders: Arthralgia, Myalgia, Pain in extremity
Reproductive System and Breast Disorders: Breast pain
General Disorders: Malaise, Peripheral coldness.
Use in specific populations
Pregnancy Category C
In animal studies, almotriptan produced developmental toxicity (increased embryolethality and fetal skeletal variations, and decreased offspring body weight) at doses greater than those used clinically. There are no adequate and well-controlled studies in pregnant women; therefore, Axert® (almotriptan malate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
When almotriptan (125, 250, 500, or 1000 mg/kg/day) was administered orally to pregnant rats throughout the period of organogenesis, increased incidences of fetal skeletal variations (decreased ossification) were noted at a dose of 250 mg/kg/day or greater and an increase in embryolethality was seen at the highest dose. The no-effect dose for embryo-fetal developmental toxicity in rats (125 mg/kg/day) is approximately 100 times the maximum recommended human dose (MRHD) of 25 mg/day on a body surface area (mg/m2) basis. Similar studies in pregnant rabbits conducted with almotriptan (oral doses of 5, 20, or 60 mg/kg/day) demonstrated increases in embryolethality at the highest dose. The no-effect dose for embryo-fetal developmental toxicity in rabbits (20 mg/kg/day) is approximately 15 times the MRHD on a mg/m2 basis. When almotriptan (25, 100, or 400 mg/kg/day) was administered orally to rats throughout the periods of gestation and lactation, gestation length was increased and litter size and offspring body weight were decreased at the highest dose. The decrease in pup weight persisted throughout lactation. The no-effect dose in this study (100 mg/kg/day) is 40 times the MRHD on a mg/m2 basis.
Labor and Delivery
The effect of Axert® on labor and delivery in humans is unknown.
It is not known whether almotriptan is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Axert® is administered to a nursing woman. Levels of almotriptan in rat milk were up to 7 times higher than in rat plasma.
Safety and efficacy of Axert® in pediatric patients under the age of 12 years have not been established. The pharmacokinetics, efficacy, and safety of Axert® have been evaluated in adolescent patients, age 12 to 17 years [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)].
In a clinical study, Axert® 6.25 mg and 12.5 mg were found to be effective for the relief of migraine headache pain in adolescent patients age 12 to 17 years. Efficacy on migraine-associated symptoms (nausea, photophobia, and phonophobia) was not established. The most common adverse reactions (incidence of ≥1%) associated with Axert® treatment were dizziness, somnolence, headache, paresthesia, nausea, and vomiting [see Adverse Reactions (6.1)]. The safety and tolerability profile of Axert® treatment in adolescents is similar to the profile observed in adults.
Postmarketing experience with other triptans include a limited number of reports that describe pediatric patients who have experienced clinically serious adverse events that are similar in nature to those reported rarely in adults.
Clinical studies of Axert® did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Clearance of almotriptan was lower in elderly volunteers than in younger individuals, but there were no observed differences in the safety and tolerability between the two populations [see Clinical Pharmacology (12.3)]. In general, dose selection for an elderly patient should be cautious, usually starting at the low dose, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. The recommended dose of Axert® for elderly patients with normal renal function for their age is the same as that recommended for younger adults.
The recommended starting dose of Axert® in patients with hepatic impairment is 6.25 mg. The maximum daily dose should not exceed 12.5 mg over a 24-hour period [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
The recommended starting dose of Axert® in patients with severe renal impairment is 6.25 mg. The maximum daily dose should not exceed 12.5 mg over a 24-hour period [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
Axert® (almotriptan malate) Tablets contain almotriptan malate, a selective 5-hydroxytryptamine1B/1D (5-HT1B/1D) 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 C17H25N3O2S-C4H6O5, 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: carnauba wax, cellulose, FD&C Blue No. 2 (12.5 mg only), hypromellose, iron oxide (6.25 mg only), mannitol, polyethylene glycol, povidone, propylene glycol, sodium starch glycolate, sodium stearyl fumarate and titanium dioxide.
Axert - Clinical Pharmacology
Mechanism of Action
Almotriptan binds with high affinity to 5-HT1D, 5-HT1B, and 5-HT1F receptors. Almotriptan has weak affinity for 5-HT1A and 5-HT7 receptors, but has no significant affinity or pharmacological activity at 5-HT2, 5-HT3, 5-HT4, 5-HT6; alpha or beta adrenergic; adenosine (A1, A2); angiotensin (AT1, AT2); dopamine (D1, D2); endothelin (ETA, ETB); or tachykinin (NK1, NK2, NK3) 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-HT1B/1D receptors 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.
The absolute bioavailability of almotriptan is about 70%, with peak plasma levels occurring 1 to 3 hours after administration; food does not affect pharmacokinetics.
Almotriptan is minimally protein bound (approximately 35%) and the mean apparent volume of distribution is approximately 180 to 200 liters.
Almotriptan is metabolized by two major and one minor 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.
Almotriptan has a mean half-life of 3 to 4 hours. Almotriptan is eliminated primarily by renal excretion (about 75% of the oral dose), with approximately 40% of an administered dose 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.
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.
Monoamine Oxidase Inhibitors
Co-administration of almotriptan and moclobemide (150 mg twice daily for 8 days) resulted in a 27% decrease in almotriptan clearance and an increase in Cmax of approximately 6%. No dose adjustment is necessary.
Co-administration of almotriptan and propranolol (80 mg twice daily for 7 days) resulted in no significant changes in the pharmacokinetics of almotriptan.
Co-administration of almotriptan and fluoxetine (60 mg daily for 8 days), a potent inhibitor of CYP2D6, had no effect on almotriptan clearance, but maximal concentrations of almotriptan were increased 18%. This difference is not clinically significant.
Co-administration of almotriptan and verapamil (120 mg sustained-release tablets twice daily 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. No dose adjustment is necessary.
Ketoconazole and other Potent CYP3A4 Inhibitors
Co-administration of almotriptan and ketoconazole, a potent CYP3A4 inhibitor, resulted in an approximately 60% increase in exposure of almotriptan. Increased exposures to almotriptan may be expected when almotriptan is used with other potent CYP3A4 inhibitors.
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 hours vs. 3.2 hours) 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.
A pharmacokinetics study of almotriptan was conducted in adolescents (12 to 17 years) and adults (18 to 55 years) with or without a history of migraine. No differences were observed in the rate or extent of absorption of almotriptan in adolescents compared with adults.
No significant gender differences were observed in pharmacokinetic parameters.
No significant differences were observed in pharmacokinetic parameters between Caucasian and African-American volunteers.
The pharmacokinetics of almotriptan have not been assessed in patients with hepatic impairment. 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 (2.2)].
The clearance of almotriptan was approximately 65% lower in patients with severe renal impairment (Cl/F=19.8 L/hour; creatinine clearance between 10 and 30 mL/min) and approximately 40% lower in patients with moderate renal impairment (Cl/F=34.2 L/hour; creatinine clearance between 31 and 71 mL/min) than in healthy volunteers (Cl/F=57 L/hour). Maximal plasma concentrations of almotriptan increased by approximately 80% in these patients [see Dosage and Administration (2.3)].