frovatriptan succinate 2.5 MG Oral Tablet
Generic Name: FROVATRIPTAN SUCCINATE
Brand Name: frovatriptan succinate
- Substance Name(s):
- FROVATRIPTAN SUCCINATE
DRUG INTERACTIONS
7 7.1 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 frovatriptan succinate within 24 hours of each other is contraindicated [see Contraindications (4)].
7.2 5-HT1B/1D Agonists Because their vasospastic effects may be additive, co-administration of frovatriptan succinate and other 5-HT1 agonists (e.g., triptans) within 24 hours of each other is contraindicated [see Contraindications (4)].
7.3 Selective Serotonin Reuptake Inhibitors / Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome Cases of serotonin syndrome have been reported during combined use of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7)].
OVERDOSAGE
10 The elimination half-life of frovatriptan is 26 hours [see Clinical Pharmacology (12.3)].
Therefore, monitoring of patients after overdose with frovatriptan should continue for at least 48 hours or while symptoms or signs persist.
There is no specific antidote to frovatriptan.
It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of frovatriptan.
DESCRIPTION
11 Frovatriptan succinate tablets contain frovatriptan succinate, a selective 5-hydroxytryptamine1 (5-HT1B/1D) receptor subtype agonist, as the active ingredient.
Frovatriptan succinate is chemically designated as R-(+) 3-methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole monosuccinate monohydrate and it has the following structure: The molecular formula is C18H23N3O5.H2O, representing a molecular weight of 379.4.
Frovatriptan succinate is a white to off-white powder that is soluble in water and very slightly soluble in methanol.
Each frovatriptan succinate tablet for oral administration contains 3.91 mg frovatriptan succinate, equivalent to 2.5 mg of frovatriptan base.
Each tablet also contains the inactive ingredients anhydrous lactose, colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium starch glycolate (potato), talc, titanium dioxide and triacetin.
structure
CLINICAL STUDIES
14 The efficacy of frovatriptan succinate in the acute treatment of migraine headaches was demonstrated in four randomized, double-blind, placebo-controlled, short-term outpatient trials.
In these trials, patients received doses of frovatriptan from 0.5 mg to 40 mg.
In these controlled short-term trials, patients were predominately female (88%) and Caucasian (94%) with a mean age of 42 years (range 18 to 69).
Patients were instructed to treat a moderate to severe headache.
Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed for up to 24 hours after dosing.
The associated symptoms nausea, vomiting, photophobia and phonophobia were also assessed.
Maintenance of response was assessed for up to 24 hours post dose.
In two of the trials a second dose of frovatriptan succinate was provided after the initial treatment, to treat recurrence of the headache within 24 hours.
Other medication, excluding other 5-HT1 agonists and ergotamine containing compounds, was permitted from 2 hours after the first dose of frovatriptan succinate.
The frequency and time to use of additional medications were also recorded.
In all four placebo-controlled trials, the percentage of patients achieving a headache response 2 hours after treatment was significantly greater for those taking frovatriptan 2.5 mg compared to those taking placebo (Table 2).
Lower doses of frovatriptan (1 mg or 0.5 mg) were not effective at 2 hours.
Higher doses (5 mg to 40 mg) of frovatriptan showed no added benefit over 2.5 mg but did cause a greater incidence of adverse events.
Table 2 Percentage of Patients with Headache Response (Mild or No Headache) 2 Hours Following Treatmenta Trial Frovatriptan 2.5 mg Placebo 1 42%* (n=90) 22% (n=91) 2 39%* (n=187) 21% (n=99) 3 46%** (n=672) 27% (n=347) 4 37%** (n=438) 23% (n=225) a ITT observed data, excludes patients who had missing data or were asleep; *p<0.05, **p<0.001 in comparison with placebo The estimated probability of achieving an initial headache response by 2 hours following treatment is depicted in Figure 1.
Figure 1 Estimated Probability of Achieving Initial Headache Response Within 2 Hours Figure 1 shows a Kaplan-Meier plot of the probability over time of obtaining headache response (no or mild pain) following treatment with frovatriptan succinate tablets 2.5 mg or placebo.
The probabilities displayed are based on pooled data from the four placebo-controlled trials described in Table 2.
Patients who did not achieve a response were censored at 24 hours.
In patients with migraine-associated nausea, photophobia and phonophobia at baseline there was a decreased incidence of these symptoms in frovatriptan succinate treated patients compared to placebo.
The estimated probability of patients taking a second dose or other medication for their migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.
Figure 2 Estimated Probability of Patients Taking a Second Dose or Other Medication for Migraine Over the 24 Hours Following the Initial Dose of Study Treatment Figure 2 is a Kaplan-Meier plot showing the probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study medication based on the data from the four placebo-controlled trials described in Table 2.
The plot includes those patients who had a response to the initial dose and those who did not.
The protocols did not permit remedication within 2 hours of the initial dose.
Efficacy was unaffected by a history of aura; gender; age, or concomitant medications commonly used by migraine patients.
figure-1 figure-2
HOW SUPPLIED
16 /STORAGE AND HANDLING Frovatriptan succinate tablets, containing 2.5 mg of frovatriptan (base) as the succinate, are available as white to off-white, circular, film coated tablets debossed with ‘72’ on one side and ‘G’ on the other side.
The tablets are available in: Blister card of 9 tablets, 1 blister card per carton (NDC 68462-694-97) Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Protect from moisture.
RECENT MAJOR CHANGES
Warnings and Precautions (5.6) 11/2012
GERIATRIC USE
8.5 Geriatric use Mean blood concentrations of frovatriptan in elderly patients were 1.5- to 2-times higher than those seen in younger adults [see Clinical Pharmacology (12.3)].
No dosage adjustment is necessary.
DOSAGE FORMS AND STRENGTHS
3 2.5 mg Tablets: White to off-white, circular, film coated tablets debossed with ‘72’ on one side and ‘G’ on the other side.
Tablets: 2.5 mg (3)
MECHANISM OF ACTION
12.1 Mechanism of Action Frovatriptan binds with high affinity to 5-HT1B/1D receptors.
The therapeutic activity of frovatriptan succinate is thought to be due to the agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.
INDICATIONS AND USAGE
1 Frovatriptan succinate is indicated for the acute treatment of migraine with or without aura in adults.
Limitations of Use •Use only if a clear diagnosis of migraine has been established.
If a patient has no response for the first migraine attack treated with frovatriptan succinate, reconsider the diagnosis of migraine before frovatriptan succinate is administered to treat any subsequent attacks.
•Frovatriptan succinate is not indicated for the prevention of migraine attacks.
•Safety and effectiveness of frovatriptan succinate have not been established for cluster headache.
Frovatriptan succinate is a serotonin (5-HT1B/1D) receptor agonist (triptan) indicated for the acute treatment of migraine with or without aura in adults (1) Limitations of Use •Use only after a clear diagnosis of migraine has been established (1) •Not indicated for the prophylactic therapy of migraine (1) •Not indicated for the treatment of cluster headache (1)
PEDIATRIC USE
8.4 Pediatric use The safety and effectiveness in pediatric patients have not been established.
Therefore, frovatriptan succinate is not recommended for use in patients under 18 years of age.
There are no additional adverse reactions identified in pediatric patients based on postmarketing experience that were not previously identified in adults.
PREGNANCY
8.1 Pregnancy Pregnancy Category C: There are no adequate and well-controlled trials in pregnant women; therefore, frovatriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
When pregnant rats were administered frovatriptan during the period of organogenesis at oral doses of 100, 500 and 1000 mg/kg/day (equivalent to 130, 650 and 1300 times the maximum recommended human dose [MRHD] of 7.5 mg/day on a mg/m2 basis) there were dose related increases in incidences of fetuses with dilated ureters, unilateral and bilateral pelvic cavitation, hydronephrosis, and hydroureters.
A no-effect dose for renal effects was not established.
This signifies a syndrome of related effects on a specific organ in the developing embryo in all treated groups, which is consistent with a slight delay in fetal maturation.
This delay was also indicated by a treatment related increased incidence of incomplete ossification of the sternebrae, skull and nasal bones in all treated groups.
Reduced fetal weights and an increased incidence of embryolethality were observed in treated rats; an increase in embryolethality occurred in both the embryo-fetal developmental study and in the prenatal-postnatal developmental study.
No increase in embryolethality was observed at the lowest dose level studied (100 mg/kg/day, equivalent to 130 times the MRHD on a mg/m2 basis).
When pregnant rabbits were dosed throughout organogenesis at oral doses up to 80 mg/kg/day (equivalent to 210 times the MRHD on a mg/m2 basis), no effects on fetal development were observed.
NUSRING MOTHERS
8.3 Nursing mothers It is not known whether frovatriptan is excreted in human milk.
Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from frovatriptan succinate, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
In rats, oral dosing with frovatriptan resulted in levels of frovatriptan and/or its metabolites in milk up to four times higher than in plasma.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS •Myocardial ischemia/infarction or Prinzmetal’s angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors (5.1) •Arrhythmias: Discontinue frovatriptan succinate if occurs (5.2) •Chest/throat/neck/jaw pain, tightness, pressure, or heaviness: Generally not associated with myocardial ischemia; evaluate high risk patients for coronary artery disease (5.3) •Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue frovatriptan succinate if occurs (5.4) •Gastrointestinal ischemic reactions and peripheral vasospastic reactions: Discontinue frovatriptan succinate if occurs (5.5) •Medication overuse headache: Detoxification may be necessary (5.6) •Serotonin syndrome: Discontinue frovatriptan succinate if occurs (5.7, 7.3) 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina Frovatriptan succinate is contraindicated in patients with ischemic or vasospastic CAD.
There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of frovatriptan succinate.
Some of these reactions occurred in patients without known CAD.
Frovatriptan succinate may cause coronary artery vasospasm (Prinzmetal’s angina), even in patients without a history of CAD.
Perform a cardiovascular evaluation in triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving frovatriptan succinate.
Do not administer Frovatriptan succinate if there is evidence of CAD or coronary artery vasospasm [see Contraindications (4)].
For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administrating the first frovatriptan succinate dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following frovatriptan succinate administration.
For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of frovatriptan succinate.
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-HT1 agonists.
Discontinue frovatriptan succinate if these disturbances occur.
Frovatriptan succinate is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see Contraindications (4)].
5.3 Chest, Throat, Neck, and Jaw Pain/Tightness/Pressure Sensations of pain, tightness, pressure, and heaviness have been reported in the chest, throat, neck, and jaw after treatment with frovatriptan succinate and are usually non-cardiac in origin.
However, perform a cardiac evaluation if these patients are at high cardiac risk.
The use of frovatriptan succinate is contraindicated in patients with CAD and those with Prinzmetal’s angina [see Contraindications (4)].
5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, stroke and other cerebrovascular events have been reported in patients treated with 5-HT1 agonists, and some have resulted in fatalities.
In a number of cases, it appears possible that the cerebrovascular events were primary, the agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not.
Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical of migraine, other potentially serious neurological conditions need to be excluded.
Frovatriptan succinate is contraindicated in patients with a history of stroke or TIA [see Contraindications (4)].
5.5 Other Vasospasm Reactions Frovatriptan succinate, 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’s syndrome.
In patients who experience symptoms or signs suggestive of a vasospastic reaction following the use of any 5-HT1 agonist, rule out a vasospastic reaction before using frovatriptan succinate [see Contraindications (4)].
Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists.
Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists have not been clearly established.
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 Serotonin Syndrome Serotonin syndrome may occur with frovatriptan succinate, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase (MAO) inhibitors [see Drug Interactions (7.3)].
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 usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication.
Discontinue frovatriptan succinate if serotonin syndrome is suspected.
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 treated with 5-HT1 agonists, including patients without a history of hypertension.
Monitor blood pressure in patients treated with frovatriptan succinate.
Frovatriptan succinate is contraindicated in patients with uncontrolled hypertension [see Contraindications (4)].
5.9 Anaphylactic/Anaphylactoid Reactions There have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving frovatriptan succinate.
Such reactions can be life threatening or fatal.
In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens.
Frovatriptan succinate is contraindicated in patients with a history of hypersensitivity reaction to frovatriptan succinate [see Contraindications (4)].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information) Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospastic Reactions, and Cerebrovascular Events Inform patients that frovatriptan succinate may cause serious cardiovascular adverse reactions such as myocardial infarction or stroke, which may result in hospitalization and even death.
Although serious cardiovascular reactions can occur without warning symptoms, instruct patients to be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and instruct them to ask for medical advice when observing any indicative sign or symptoms.
Instruct patients to seek medical advice if they have symptoms of other vasospastic reactions [see Warnings and Precautions (5.1, 5.2, 5.4, 5.5, and 5.8)].
Anaphylactic/Anaphylactoid Reactions Inform patients that anaphylactic/anaphylactoid reactions have occurred in patients receiving frovatriptan succinate.
Such reactions can be life threatening or fatal.
In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens [see Contraindications (4)].
Medication Overuse Headache Inform patients that use of drugs to treat acute migraines for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [see Warnings and Precautions (5.6)].
Serotonin Syndrome Inform patients about the risk of serotonin syndrome with the use of frovatriptan succinate or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7) and Drug Interactions (7.3)].
Pregnancy Inform patients that frovatriptan succinate should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].
Nursing Mothers Inform patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations (8.3)].
DOSAGE AND ADMINISTRATION
2 Dosing Information The recommended dose is a single tablet of frovatriptan succinate (frovatriptan 2.5 mg) taken orally with fluids.
If the migraine recurs after initial relief, a second tablet may be taken, providing there is an interval of at least 2 hours between doses.
The total daily dose of frovatriptan succinate should not exceed 3 tablets (3 x 2.5 mg per 24 hour period).
There is no evidence that a second dose of frovatriptan succinate is effective in patients who do not respond to a first dose of the drug for the same headache.
The safety of treating an average of more than 4 migraine attacks in a 30-day period has not been established.
•1 tablet taken with fluids.
Second tablet may be taken 2 hours after initial dose if headache recurs following initial relief.
Total dose not to exceed 3 tablets in any 24-hour period (2)