ALMOTRIPTAN MALATE Drug Interactions: What You Need to Know

INTERACTIONS

• Do not use almotriptan tablets and ergotamine-containing or ergot-type medications within 24 hours of each other ( 4.5 , 7.1 )
• Do not use almotriptan tablets and other 5-HT 1 agonist (e.g., triptans) within 24 hours of each other ( 4.6 , 7.2 )
• SSRI or SNRI: life-threatening serotonin syndrome reported during combined use with triptans ( 5.5 , 7.3 )
• Ketoconazole: use single dose of almotriptan tablets 6.25 mg; maximum almotriptan tablets daily dose 12.5 mg ( 7.4 )

7.1 Ergot-Containing Drugs These drugs have been reported to cause prolonged vasospastic reactions. Because, in theory, vasospastic effects may be additive, ergotamine-containing or ergot-type medications (like dihydroergotamine, ergotamine tartrate, or methysergide) and almotriptan tablets (almotriptan malate) should not be used within 24 hours of each other <span class="opacity-50 text-xs">[see Contraindications (4.5) ]</span> . 7.2 5-HT 1 Agonists (e.g., Triptans) Concomitant use of other 5-HT 1 agonists (e.g., triptans) within 24 hours of treatment with almotriptan tablets is contraindicated <span class="opacity-50 text-xs">[see Contraindications (4.6) ]</span> .

7.3 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors Cases of life-threatening serotonin syndrome have been reported during combined use of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.5) , Clinical Pharmacology (12.3) ]</span> .

7.4 Ketoconazole and Other Potent CYP3A4 Inhibitors Co-administration of almotriptan and oral 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 concomitantly with other potent CYP3A4 inhibitors <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . In patients concomitantly using potent CYP3A4 inhibitors, the recommended starting dose of almotriptan tablets is 6.25 mg. The maximum daily dose should not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan tablets and potent CYP3A4 inhibitors should be avoided in patients with renal or hepatic impairment <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

Ischemic heart disease, coronary artery vasospasm, or other significant underlying cardiovascular disease ( 4.1 ) Cerebrovascular syndromes (e.g., history of stroke or TIA) ( 4.2 ) Peripheral vascular disease (including ischemic bowel disease) ( 4.3 ) Uncontrolled hypertension ( 4.4 ) Do not use almotriptan malate within 24 hours of an ergotamine-containing, or ergot-type medication, or of another 5-HT 1 agonist, e.g., another triptan ( 4.5 , 4.6 ) Hemiplegic or basilar migraine ( 4.7 ) Known hypersensitivity to almotriptan malate ( 4.8 )

4.1 Ischemic or Vasospastic Coronary Artery Disease, or Other Significant Underlying Cardiovascular Disease Do not use 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&apos;s variant angina, or other significant underlying cardiovascular disease <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> .

4.2 Cerebrovascular Syndromes Do not use almotriptan malate tablets in patients with cerebrovascular syndromes including (but not limited to) stroke of any type as well as transient ischemic attacks <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span> .

4.3 Peripheral Vascular Disease Do not use almotriptan malate tablets in patients with peripheral vascular disease including (but not limited to) ischemic bowel disease <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 )]</span> .

4.4 Uncontrolled Hypertension Because almotriptan malate may increase blood pressure, do not use almotriptan malate tablets in patients with uncontrolled hypertension <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.7 )]</span> .

4.5 Ergotamine-Containing and Ergot-Type Medications Do not use almotriptan malate tablets and ergotamine-containing or ergot-derived medications like dihydroergotamine, ergotamine tartrate, or methysergide within 24 hours of each other <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span> .

4.6 Concomitant Use With 5-HT 1 Agonists (e.g., Triptans) Almotriptan malate tablets and other 5-HT 1 agonists (e.g., triptans) should not be administered within 24 hours of each other <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 ) and ( 5.2 )]</span> .

4.7 Hemiplegic or Basilar Migraine Do not use almotriptan malate tablets in patients with hemiplegic or basilar migraine.

4.8 Hypersensitivity Almotriptan malate tablets are contraindicated in patients with known hypersensitivity to almotriptan or any of its inactive ingredients.

AND PRECAUTIONS

• Serious adverse cardiac events, including acute myocardial infarction and life-threatening disturbances of cardiac rhythm ( 5.1 )
• It is strongly recommended that almotriptan tablets not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of risk factors. In very rare cases, serious cardiovascular events have been reported in association with almotriptan tablet use in the absence of known cardiovascular disease. If almotriptan tablets are considered, patients should first have a cardiovascular evaluation. If the evaluation is satisfactory, first dose should take place in a physician’s office setting ( 5.1 )
• Sensations of pain, tightness, pressure, and heaviness in the chest, throat, neck, and jaw: generally not associated with myocardial ischemia, but patients with signs or symptoms suggestive of angina should be evaluated for the presence of CAD ( 5.2 )
• Cerebrovascular events, some fatal ( 5.3 )
• Gastrointestinal ischemic events and peripheral vasospastic reactions (e.g., Raynaud’s syndrome) ( 5.4 )
• Potentially life-threatening serotonin syndrome, particularly in combination with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). Monitor patients for neurologic changes and gastrointestinal symptoms if concomitant treatment is clinically warranted ( 5.5 , 7.3 )
• Medication overuse headache: Detoxification may be necessary ( 5.6 )
• Increase in blood pressure, very rarely associated with significant clinical events ( 4.4 , 5.7 )
• Use with caution in patients with a known hypersensitivity to sulfonamides ( 5.8 )

5.1 Risk of Myocardial Ischemia and Infarction and Other Adverse Cardiac Events Cardiac Events and Fatalities with 5-HT 1 Agonists Serious adverse cardiac events, including acute myocardial infarction, have been reported within a few hours following administration of almotriptan tablets (almotriptan malate). Life-threatening disturbances of cardiac rhythm and death have been reported within a few hours following the administration of other triptans. Considering the extent of use of triptans in patients with migraine, the incidence of these events is extremely low. Almotriptan tablets can cause coronary vasospasm; at least one of these events occurred in a patient with no cardiac history and with documented absence of coronary artery disease. Because of the close proximity of the events to use of almotriptan tablets, a causal relationship cannot be excluded. Patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of coronary artery disease (CAD) or a predisposition to Prinzmetal’s variant angina before receiving additional doses of medication, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur.

Premarketing

Experience with Almotriptan Tablets in Adults Among the 3865 subjects/patients who received almotriptan tablets in premarketing clinical trials, one patient was hospitalized for observation after a scheduled electrocardiogram (ECG) was found to be abnormal (negative T-waves on the left leads) 48 hours after taking a single 6.25 mg dose of almotriptan. The patient, a 48-year-old female, had previously taken three other doses for earlier migraine attacks. Myocardial enzymes at the time of the abnormal ECG were normal. The patient was diagnosed as having had myocardial ischemia and that she had a family history of coronary disease. An ECG performed 2 days later was normal, as was a follow-up coronary angiography. The patient recovered without incident.

Postmarketing

Experience with Almotriptan Tablets in Adults Serious cardiovascular events have been reported in association with the use of almotriptan tablets. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to definitively determine the proportion of the reported cases that were actually caused by almotriptan or to reliably assess causation in individual cases [see Adverse Reactions (6.3) ] . Patients with Documented Coronary Artery Disease Because of the potential of this class of compound (5-HT 1 agonists) to cause coronary vasospasm, almotriptan tablets should not be given to patients with documented ischemic or vasospastic coronary artery disease [see Contraindications (4.1) ] . Patients with Risk Factors for CAD It is strongly recommended that almotriptan tablets not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient’s medical history, electrocardiographic or other investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, almotriptan tablets should not be administered [see Contraindications (4.1) ] . For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of almotriptan tablets take place in the setting of a physician’s office or similar medically staffed and equipped facility unless the patient has previously received almotriptan tablets. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an ECG during the interval immediately following almotriptan tablets, in these patients with risk factors. It is recommended that patients who are intermittent long-term users of almotriptan tablets and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use almotriptan tablets. The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to almotriptan tablets. The ability of cardiac diagnostic procedures to detect all cardiovascular diseases or predisposition to coronary artery vasospasm is modest at best. Cardiovascular events associated with triptan treatment have occurred in patients with no cardiac history and with documented absence of coronary artery disease.

5.2 Sensations of Pain, Tightness, Pressure in the Chest and/or Throat, Neck, and Jaw As with other 5-HT 1 agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw have been reported after treatment with almotriptan tablets.

Because

5-HT 1 agonists may cause coronary vasospasm, patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of CAD or a predisposition to Prinzmetal’s variant angina before receiving additional doses of medication, and should be monitored electrocardiographically if dosing is resumed and similar symptoms occur. Patients shown to have CAD and those with Prinzmetal’s variant angina should not receive 5-HT 1 agonists [see Contraindications (4.1) and Warnings and Precautions (5.1) ] .

5.3 Cerebrovascular Events and Fatalities Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with other triptans and some events have resulted in fatalities. In a number of cases, it appeared possible that the cerebrovascular events were primary, the triptan having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, and transient ischemic attack) <span class="opacity-50 text-xs">[see Contraindications (4.2) ]</span> .

5.4 Other Vasospasm-Related Events, Including Peripheral Vascular Ischemia and Colonic Ischemia Triptans, including almotriptan tablets, may cause vasospastic reactions other than coronary artery vasospasm, such as peripheral and gastrointestinal vascular ischemia with abdominal pain and bloody diarrhea. Very rare reports of transient and permanent blindness and significant partial vision loss have been reported with the use of triptans. Visual disorders may also be part of a migraine attack. Patients who experience symptoms or signs suggestive of decreased arterial flow following the use of any triptan, such as ischemic bowel syndrome or Raynaud’s syndrome, are candidates for further evaluation <span class="opacity-50 text-xs">[see Contraindications (4.3) ]</span> .

5.5 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome may occur with triptans, including almotriptan tablets, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with almotriptan tablets and an SSRI (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms 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 gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) <span class="opacity-50 text-xs">[see Drug Interactions (7.3) ]</span> .

5.6 Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.

5.7 Increases in Blood Pressure As with other triptans, significant elevations in systemic blood pressure have been reported on rare occasions with almotriptan tablet use in patients with and without a history of hypertension; very rarely these increases in blood pressure have been associated with significant clinical events. Almotriptan tablets are contraindicated in patients with uncontrolled hypertension <span class="opacity-50 text-xs">[see Contraindications (4.4) ]</span> . In normotensive healthy subjects and patients with hypertension controlled by medication, small, but clinically insignificant, increases in mean systolic (0.21 and 4.87 mm Hg, respectively) and diastolic (1.35 and 0.26 mm Hg, respectively) blood pressure relative to placebo were seen over the first 4 hours after oral administration of 12.5 mg of almotriptan.

An

18% increase in mean pulmonary artery pressure was seen following dosing with another triptan in a study evaluating subjects undergoing cardiac catheterization.

5.8 Hypersensitivity to Sulfonamides Caution should be exercised when prescribing almotriptan tablets to patients with known hypersensitivity to sulfonamides. The chemical structure of almotriptan contains a sulfonyl group, which is structurally different from a sulfonamide. Cross-sensitivity to almotriptan in patients allergic to sulfonamides has not been systematically evaluated.

5.9 Impaired Hepatic or Renal Function Almotriptan tablets should be administered with caution to patients with diseases that may alter the absorption, metabolism, or excretion of drugs, such as those with impaired hepatic or renal function <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) , (2.3) and Clinical Pharmacology (12.3) ]</span> .

5.10 Binding to Melanin-Containing Tissues When pigmented rats were given a single oral dose of 5 mg/kg of radiolabeled almotriptan, the elimination half-life of radioactivity from the eye was 22 days. This finding suggests that almotriptan and/or its metabolites may bind to melanin in the eye. Because almotriptan could accumulate in melanin-rich tissues over time, there is the possibility that it could cause toxicity in these tissues with extended use. However, no adverse retinal effects related to treatment with almotriptan were noted in a 52-week toxicity study in dogs given up to 12.5 mg/kg/day (resulting in exposure [AUC] to parent drug approximately 20 times that in humans receiving the maximum recommended human dose of 25 mg/day). Although no systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic monitoring are offered, prescribers should be aware of the possibility of long-term ophthalmologic effects.

5.11 Corneal Opacities Three male dogs (out of a total of 14 treated) in a 52-week toxicity study of oral almotriptan developed slight corneal opacities that were noted after 51 weeks, but not after 25 weeks of treatment. The doses at which this occurred were 2 mg/kg/day, 5 mg/kg/day, and 12.5 mg/kg/day. The opacity reversed after a 4-week drug-free period in the affected dog treated with the highest dose. Systemic exposure (plasma AUC) to parent drug at 2 mg/kg/day was approximately 2.5 times the exposure in humans receiving the maximum recommended human daily dose of 25 mg. A no-effect dose was not established.