RIZATRIPTAN Drug Interactions: What You Need to Know

INTERACTIONS

7.1 Propranolol The dose of rizatriptan benzoate should be adjusted in propranolol-treated patients, as propranolol has been shown to increase the plasma AUC of rizatriptan by 70% <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 ) and Clinical Pharmacology ( 12.3 )]</span> .

7.2 Ergot-Containing Drugs Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and rizatriptan benzoate within 24 hours is contraindicated <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .

7.3 Other 5-HT 1 Agonists Because their vasospastic effects may be additive, co-administration of rizatriptan benzoate and other 5-HT 1 agonists within 24 hours of each other is contraindicated <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .

7.4 SSRIs/SNRIs and Serotonin Syndrome Cases of serotonin syndrome have been reported during co-administration of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.7 )]</span> .

7.5 Monoamine Oxidase Inhibitors Rizatriptan benzoate is contraindicated in patients taking MAO-A inhibitors and non-selective MAO inhibitors. A specific MAO-A inhibitor increased the systemic exposure of rizatriptan and its metabolite <span class="opacity-50 text-xs">[see Contraindications ( 4 ) and Clinical Pharmacology ( 12.3 )]</span> .

Drug

Interactions [See also Drug Interactions ( 7 )]. Monoamine oxidase inhibitors: Rizatriptan is principally metabolized via monoamine oxidase, ‘A’ subtype (MAO-A). Plasma concentrations of rizatriptan may be increased by drugs that are selective MAO-A inhibitors (e.g., moclobemide) or nonselective MAO inhibitors [type A and B] (e.g., isocarboxazid, phenelzine, tranylcypromine, and pargyline). In a drug interaction study, when rizatriptan benzoate 10 mg was administered to subjects (n=12) receiving concomitant therapy with the selective, reversible MAO-A inhibitor, moclobemide 150 mg t.i.d., there were mean increases in rizatriptan AUC and C max of 119% and 41% respectively; and the AUC of the active N-monodesmethyl metabolite of rizatriptan was increased more than 400%. The interaction would be expected to be greater with irreversible MAO inhibitors. No pharmacokinetic interaction is anticipated in patients receiving selective MAO-B inhibitors [see Contraindications ( 4 ) and Drug Interactions ( 7.5 )] . Propranolol: In a study of concurrent administration of propranolol 240 mg/day and a single dose of rizatriptan 10 mg in healthy adult subjects (n=11), mean plasma AUC for rizatriptan was increased by 70% during propranolol administration, and a four-fold increase was observed in one subject. The AUC of the active N-monodesmethyl metabolite of rizatriptan was not affected by propranolol [see Dosage and Administration ( 2.4 ) and Drug Interactions ( 7.1 )] . Nadolol/Metoprolol : In a drug interactions study, effects of multiple doses of nadolol 80 mg or metoprolol 100 mg every 12 hours on the pharmacokinetics of a single dose of 10 mg rizatriptan were evaluated in healthy subjects (n=12). No pharmacokinetic interactions were observed. Paroxetine : In a study of the interaction between the selective serotonin reuptake inhibitor (SSRI) paroxetine 20 mg/day for two weeks and a single dose of rizatriptan benzoate 10 mg in healthy subjects (n=12), neither the plasma concentrations of rizatriptan nor its safety profile were affected by paroxetine [see Warnings and Precautions ( 5.7 ), Drug Interactions ( 7.4 ), and Patient Counseling Information ( 17 )] . Oral contraceptives : In a study of concurrent administration of an oral contraceptive during 6 days of administration of rizatriptan benzoate (10 to 30 mg/day) in healthy female volunteers (n=18), rizatriptan did not affect plasma concentrations of ethinyl estradiol or Norethindrone.

Rizatriptan benzoate orally disintegrating tablets are contraindicated in patients with:

• Ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), or other significant underlying cardiovascular disease [see Warnings and Precautions ( 5.1 )] .
• Coronary artery vasospasm including Prinzmetal's angina [see Warnings and Precautions ( 5.1 )].
• History of stroke or transient ischemic attack (TIA) [s ee Warnings and Precautions ( 5.4 )] .
• Peripheral vascular disease (PVD) [see Warnings and Precautions ( 5.5 )] .
• Ischemic bowel disease [see Warnings and Precautions ( 5.5 )] .
• Uncontrolled hypertension [see Warnings and Precautions ( 5.8 )] .
• Recent use (i.e., within 24 hours) of another 5-HT 1 agonist, ergotamine-containing medication, or ergot-type medication (such as dihydroergotamine or methysergide) [see Drug Interactions ( 7.2 and 7.3 )] .
• Hemiplegic or basilar migraine [see Indications and Usage ( 1 )] .
• Concurrent administration or recent discontinuation (i.e., within 2 weeks) of a MAO-A inhibitor [see Drug Interactions ( 7.5 ) and Clinical Pharmacology ( 12.3 )] .
• Hypersensitivity to rizatriptan benzoate tablets or rizatriptan benzoate orally disintegrating tablets or any of the excipients (angioedema and anaphylaxis seen) [see Adverse Reactions ( 6.2 )].
• History of ischemic heart disease or coronary artery vasospasm ( 4 )
• History of stroke or transient ischemic attack ( 4 )
• Peripheral vascular disease ( 4 )
• Ischemic bowel disease ( 4 )
• Uncontrolled hypertension ( 4 )
• Recent (within 24 hours) use of another 5-HT 1 agonist (e.g., another triptan), or of an ergotamine-containing medication ( 4 )
• Hemiplegic or basilar migraine ( 4 )
• MAO-A inhibitor used in the past 2 weeks ( 4 )
• Hypersensitivity to rizatriptan or any of the excipients ( 4 )

AND PRECAUTIONS Myocardial ischemia, myocardial infarction, and Prinzmetal's angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors ( 5.1 ) Arrhythmias: Discontinue dosing if occurs ( 5.2 ) Chest/throat/neck/jaw pain, tightness, pressure, or heaviness; Generally not associated with myocardial ischemia; Evaluate patients at high risk ( 5.3 ) Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue dosing if occurs ( 5.4 ) Gastrointestinal ischemic events, peripheral vasospastic reactions: Discontinue dosing if occurs ( 5.5 ) Medication overuse headache: Detoxification may be necessary ( 5.6 ) Serotonin syndrome: Discontinue dosing if occurs ( 5.7 )

5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetals Angina Keep rizatriptan benzoate orally disintegrating tablets and all medicines out of the reach of children.

General

Information about the safe and effective use of rizatriptan benzoate orally disintegrating tablets. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use rizatriptan benzoate for a condition for which it was not prescribed. Do not give rizatriptan benzoate orally disintegrating tablets to other people, even if they have the same symptoms that you have. It may harm them.

This Patient

Information leaflet summarizes the most important information about rizatriptan benzoate orally disintegrating tablets. If you would like more information, talk to your doctor. You can ask your pharmacist or doctor for information about rizatriptan benzoate orally disintegrating tablets that is written for health professionals. For more information, call Unichem Pharmaceuticals (USA), Inc. at 1-866-562-4616 What are the ingredients in rizatriptan benzoate orally disintegrating tablets? Active ingredient in rizatriptan benzoate orally disintegrating tablets: rizatriptan benzoate. Inactive ingredients in rizatriptan benzoate orally disintegrating tablets: colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, microcrystalline cellulose, orange flavor, sucralose. * The brand names mentioned are registered trademarks of their respective manufacturers.

This Patient

Information has been approved by the U.S. Food and Drug Administration. Additional patient information leaflets can be obtained by calling Unichem at 1-866-562-4616. Manufactured by: UNICHEM LABORATORIES LTD.

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5.2 Arrhythmias Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT 1 agonists. Discontinue rizatriptan benzoate if these disturbances occur.

5.3 Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure As with other 5-HT 1 agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck and jaw commonly occur after treatment with rizatriptan benzoate and are usually non-cardiac in origin. However, if a cardiac origin is suspected, patients should be evaluated. Patients shown to have CAD and those with Prinzmetal&apos;s variant angina should not receive 5-HT 1 agonists.

5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT 1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT 1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack). Discontinue rizatriptan benzoate if a cerebrovascular event occurs. 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. Rizatriptan benzoate should not be administered to patients with a history of stroke or transient ischemic attack <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .

5.5 Other Vasospasm Reactions 5-HT 1 agonists, including rizatriptan benzoate, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud&apos;s syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT 1 agonist, the suspected vasospasm reaction should be ruled out before receiving additional rizatriptan benzoate doses. Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT 1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT 1 agonists have not been clearly established

5.6 Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or a combination of 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 Serotonin Syndrome Serotonin syndrome may occur with triptans, including rizatriptan benzoate particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors <span class="opacity-50 text-xs">[see Drug Interactions ( 7.5 )]</span> . 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). The onset of symptoms can occur within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Rizatriptan benzoate treatment should be discontinued if serotonin syndrome is suspected <span class="opacity-50 text-xs">[see Drug Interactions ( 7.4 ) and Patient Counseling Information ( 17 )]</span> .

5.8 Increase in Blood Pressure Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients with and without a history of hypertension receiving 5-HT 1 agonists, including rizatriptan benzoate. In healthy young adult male and female patients who received maximal doses of rizatriptan benzoate (10 mg every 2 hours for 3 doses), slight increases in blood pressure (approximately 2-3 mmHg) were observed. Rizatriptan benzoate is contraindicated in patients with uncontrolled hypertension <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .