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Frovatriptan


General


Pronunciation

(froe va TRIP tan)


Brand Names: U.S.

  • Frova

Indications


Use: Labeled Indications

Migraines: Acute treatment of migraine with or without aura in adults.


Contraindications


Ischemic coronary artery disease (eg, angina pectoris, history of MI, documented silent ischemia); coronary artery vasospasm, including Prinzmetals angina; Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders; history of stroke, transient ischemic attack, or history of hemiplegic or basilar migraine; peripheral vascular disease; ischemic bowel disease; uncontrolled hypertension; recent use (within 24 hours) of another 5-HT1 agonist, an ergotamine containing or ergot-type medication (eg, dihydroergotamine, methysergide); hypersensitivity to frovatriptan or any component of the formulation.

Canadian labeling: Additional contraindications (not in U.S. labeling): Cardiac arrhythmias, valvular heart disease (especially tachycardia), congenital heart disease, atherosclerotic disease; management of ophthalmoplegic migraine; severe hepatic impairment; Raynaud's syndrome

Documentation of allergenic cross-reactivity for triptans is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.


Dosing and Administration


Dosing: Adult

Note: If the first dose is ineffective, diagnosis needs to be re-evaluated. The safety of treating >4 migraines/month has not been established.

Migraine: Oral:

U.S. labeling: Initial: 2.5 mg; if headache recurs, a second dose may be administered after 2 hours have elapsed since the first dose (maximum: 7.5 mg daily)

Canadian labeling: Initial: 2.5 mg; if headache recurs, a second dose may be administered after 4 hours have elapsed since the first dose (maximum: 5 mg daily)


Dosing: Geriatric

Refer to adult dosing.


Dosing: Renal Impairment

No dosage adjustment necessary.


Dosing: Hepatic Impairment

Mild-to-moderate impairment: No dosage adjustment necessary.

Severe impairment:

U.S. labeling: Use with caution (has not been studied).

Canadian labeling: Use is contraindicated.


Administration

Administer orally with fluids as soon as symptoms appear.


Storage

Store at 25 é ░C (77 é ░F); excursions are permitted between 15 é ░C and 30 é ░C (59 é ░F and 86 é ░F). Protect from moisture.


Dosage Forms/Strengths


Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Frova: 2.5 mg

Generic: 2.5 mg


Drug Interactions

Analgesics (Opioid): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Anti-Parkinson Agents (Monoamine Oxidase Inhibitor): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity if selegiline or rasagiline is combined with a serotonin modulator. Use of transdermal selegiline with serotonin modulators is contraindicated. Consider therapy modification

Antipsychotic Agents: Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

Droxidopa: Serotonin 5-HT1D Receptor Agonists may enhance the hypertensive effect of Droxidopa. Monitor therapy

Ergot Derivatives: May enhance the vasoconstricting effect of Serotonin 5-HT1D Receptor Agonists. Serotonin 5-HT1D Receptor Agonists may enhance the vasoconstricting effect of Ergot Derivatives. Exceptions: Nicergoline. Avoid combination

Linezolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Management: Due to a risk of serotonin syndrome/serotonin toxicity, discontinue serotonin modulators 2 weeks prior to the administration of linezolid. If urgent initiation of linezolid is needed, discontinue serotonin modulators immediately and monitor closely. Consider therapy modification

Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination

Metoclopramide: Serotonin Modulators may enhance the adverse/toxic effect of Metoclopramide. This may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Monitor therapy

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid. Monitor therapy

SUMAtriptan: Serotonin 5-HT1D Receptor Agonists may enhance the adverse/toxic effect of SUMAtriptan. Avoid combination

Tedizolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

TraMADol: Serotonin Modulators may enhance the adverse/toxic effect of TraMADol. The risk of seizures may be increased. TraMADol may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy


Monitoring Parameters

Headache severity, blood pressure, signs/symptoms suggestive of angina; perform a cardiovascular evaluation in triptan-na â »ve patients who have multiple cardiovascular risk factors (eg, increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD), monitor ECG with first dose in patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation and consider periodic cardiovascular evaluation in such patients if they are intermittent long-term users; signs/symptoms of serotonin syndrome and hypersensitivity reactions.


Adverse Reactions


1% to 10%:

Cardiovascular: Flushing (4%), hot or cold flashes (3%), chest pain (2%), palpitations (1%)

Central nervous system: Dizziness (8%), fatigue (5%), headache (4%), paresthesia (4%), drowsiness ( ≥2%), anxiety (1%), dysesthesia (1%), hypoesthesia (1%), insomnia (1%), pain (1%)

Dermatologic: Diaphoresis (1%)

Gastrointestinal: Xerostomia (3%), nausea ( ≥2%), dyspepsia (2%), abdominal pain (1%), diarrhea (1%), vomiting (1%)

Neuromuscular & skeletal: Musculoskeletal pain (3%)

Ophthalmic: Visual disturbance (1%)

Otic: Tinnitus (1%)

Respiratory: Rhinitis (1%), sinusitis (1%)

<1% (Limited to important or life-threatening): Abnormal gait, abnormal lacrimation, abnormal reflexes, amnesia, anaphylactoid reactions, anaphylaxis, anorexia, ataxia, bradycardia, bullous rash, cheilitis, chest tightness, confusion, conjunctivitis, dehydration, depersonalization, depression, dysgeusia, ECG changes, emotional lability, epistaxis, esophageal spasm, euphoria, eye pain, gastroesophageal reflux disease, hyperacusis, hyperesthesia, hypersensitivity reaction (including angioedema), hypertonia, hyperventilation, hypocalcemia, hypoglycemia, hypotonia, involuntary muscle movements, jaw tightness, lack of concentration, laryngitis, myocardial infarction, nocturia, osteoarthritis, peptic ulcer, personality disorder, pharyngitis, polyuria, purpura, renal pain, rigors, salivary gland pain, seizure, sialorrhea, significant cardiovascular event, speech disturbance, stomatitis, syncope, tachycardia, tightness in chest and throat, tongue paralysis


Warnings/Precautions


Special Populations: Hepatic Function Impairment

In patients with mild (Child-Pugh class 5 to 6) to moderate (Child-Pugh class 7 to 9) hepatic function impairment, AUC increased 2 " ëtimes that of healthy subjects.


Special Populations: Elderly

AUC was 1.5- to 2-fold higher in elderly subjects.


Special Populations: Gender

Bioavailability was higher and systemic exposure was approximately 2-fold greater in females than males.


Warnings/Precautions

Concerns related to adverse effects:

- Anaphylactic/Anaphylactoid reactions: Anaphylaxis, anaphylactoid, and hypersensitivity reactions (including angioedema) have occurred; may be life-threatening or fatal. Use is contraindicated in patients with known hypersensitivity to frovatriptan.

- Cardiac events: Coronary artery vasospasm, transient ischemia, myocardial infarction, ventricular tachycardia/fibrillation, cardiac arrest, and death have been reported with 5-HT1 agonist administration; some events have occurred within a few hours of administration. Discontinue if these events occur. Patients who experience sensations of chest pain/pressure/tightness or symptoms suggestive of angina following dosing should be evaluated for coronary artery disease or Prinzmetals angina before receiving additional doses; if dosing is resumed and similar symptoms recur, monitor with ECG. Use is contraindicated in patients with ischemic or vasospastic CAD and Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.

- Cerebrovascular events: Cerebral/subarachnoid hemorrhage and stroke (some fatal) have been reported with 5-HT1 agonist administration. Use is contraindicated in patients with a history of stroke or transient ischemic attack.

- Elevated blood pressure: Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has also been reported on rare occasions in patients with and without a history of hypertension. Monitor blood pressure; use is contraindicated in patients with uncontrolled hypertension.

- Headaches: Acute migraine agents (eg, triptans, opioids, ergotamine, or a combination of the agents) used for 10 or more days per month may lead to worsening of headaches (medication overuse headache); withdrawal treatment may be necessary in the setting of overuse.

- Vasospasm-related events: Peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction, splenic infarction, and Raynaud 's syndrome have been reported with 5-HT1 agonist administration.

- Visual effects: Partial vision loss and blindness (transient and permanent) have been reported with use of 5-HT1 agonists; a causal relationship between these events and 5-HT1 agonist administration has not been clearly determined.

Disease-related concerns:

- Coronary artery disease: Should not be given to patients who have risk factors for CAD (eg, hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, menopause, male >40 years of age) without adequate cardiac evaluation. Use is contraindicated if there is evidence of CAD or coronary artery vasospasm. Patients with suspected CAD should have cardiovascular evaluation to rule out CAD before considering use; if cardiovascular evaluation is "satisfactory, " Ł first dose should be given in the healthcare provider's office (consider ECG monitoring). Periodic evaluation of cardiovascular status should be done in all patients.

- Hepatic impairment: Use with caution in severe impairment (has not been studied). The Canadian labeling contraindicates use in severe impairment.

Concurrent drug therapy issues:

- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

- Serotonin syndrome: Symptoms of agitation, confusion, hallucinations, hyper-reflexia, myoclonus, shivering, and tachycardia may occur with concomitant proserotonergic drugs (eg, SSRIs/SNRIs or triptans) or agents which reduce frovatriptan's metabolism. Concurrent use of serotonin precursors (eg, tryptophan) is not recommended. If concomitant administration with SSRIs is warranted, monitor closely, especially at initiation and with dose increases. Discontinue frovatriptan if serotonin syndrome is suspected.

Special populations:

- Elderly: Blood pressure was increased to a greater extent in elderly subjects than in younger subjects.

Other warnings/precautions:

- Appropriate use: Only indicated for treatment of acute migraine; it is not indicated for migraine prophylaxis, or for the treatment of cluster headaches, hemiplegic or basilar migraine. If a patient does not respond to the first dose, the diagnosis of migraine should be reconsidered; rule out underlying neurologic disease in patients with atypical headache, migraine (with no prior history of migraine) or inadequate clinical response to initial dosing.


Pregnancy Risk Factor

C


Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Information related to the use of frovatriptan in pregnancy has not been located. Until additional information is available, other agents are preferred for the initial treatment of migraine in pregnancy (Da Silva, 2012; MacGregor, 2012; Williams, 2012).


Actions


Pharmacology

Selective agonist for serotonin (5-HT1B and 5-HT1D receptors) in cranial arteries; causes vasoconstriction and reduces sterile inflammation associated with antidromic neuronal transmission correlating with relief of migraine.


Distribution

Male: 4.2 L/kg; Female: 3 L/kg


Metabolism

Primarily hepatic via CYP1A2


Excretion

Feces (62%); urine (32%)


Time to Peak

2-4 hours


Half-Life Elimination

~26 hours


Protein Binding

~15%


Patient and Family Education


Patient Education

- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

- Patient may experience dizziness, loss of strength and energy, dry mouth, flushing, sensation of warmth, feeling of heaviness, bone pain, or joint pain. Have patient report immediately to prescriber signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, arrhythmia, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea), signs of severe cardiac abnormalities (chest, throat, neck, or jaw tightness, pain, pressure, or heaviness; break out in a cold sweat; shortness of breath; tachycardia; arrhythmia; or severe dizziness or passing out), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), vision changes, severe nausea, severe vomiting, severe headache, constipation, diarrhea, severe abdominal pain, bloody diarrhea, weight loss, leg cramps, leg pain, sensation of cold, burning or aching in feet or toes, shortness of breath, or burning or numbness feeling (HCAHPS).

- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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