ADVERSE REACTIONS
Serious cardiac events, including some that have been fatal, have occurred following use of 5-HT1 agonists. These events are extremely rare and most have been reported in patients with risk factors predictive of CAD. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia and ventricular fibrillation (see CONTRAINDICATIONS, WARNINGS and PRECAUTIONS).
Incidence in Controlled Clinical Trials:
Among 1554 patients treated with FROVA in four placebo-controlled trials (Trials 1, 3, 4 and 5 in Table 1), only 1% (16) patients withdrew because of treatment-emergent adverse events. In a long term, open-label study where patients were allowed to treat multiple migraine attacks with FROVA for up to 1 year, 5% (26/496) patients discontinued due to treatment-emergent adverse events.
The treatment-emergent adverse events that occurred most frequently following administration of frovatriptan 2.5 mg (i.e., in at least 2% of patients), and at an incidence ≥1% greater than with placebo, in the four placebo-controlled trials were dizziness, paresthesia, headache, dry mouth, fatigue, flushing, hot or cold sensation and chest pain.
Table 2 lists treatment-emergent adverse events reported within 48 hours of drug administration that occurred with frovatriptan 2.5 mg at an incidence of ≥ 2% and more often than on placebo, in the first attack in four placebo-controlled trials (Trials 1, 3, 4 and 5 in Table 1). These studies involved 2392 patients (1554 frovatriptan 2.5 mg and 838 placebo). The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these incidence estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ.
Table 2: Treatment-Emergent Adverse Events (Incidence ≥ 2% and Greater Than Placebo) of Patients in Four Placebo-Controlled Migraine Trials | Adverse events | Frovatriptan 2.5 mg
(n=1554) | Placebo
(n=838) |
|---|
|
Central & peripheral nervous system
Dizziness
Headache
Paresthesia
|
8%
4%
4%
|
5%
3%
2%
|
|
Gastrointestinal system disorders
Mouth dry
Dyspepsia
|
3%
2%
|
1%
1%
|
|
Body as a whole – general disorders
Fatigue
Hot or cold sensation
Chest pain
|
5%
3%
2%
|
2%
2%
1%
|
|
Musculo-skeletal
Skeletal pain
|
3%
|
2%
|
|
Vascular
Flushing
|
4%
|
2%
|
Other events that occurred at ≥2% on frovatriptan that were equally or more common in the placebo group were somnolence and nausea.
FROVA is generally well tolerated. The incidence of adverse events in clinical trials did not increase when up to 3 doses were used within 24 hours. The majority of adverse events were mild or moderate and transient. The incidence of adverse events in four placebo-controlled clinical trials was not affected by gender, age or concomitant medications commonly used by migraine patients. There were insufficient data to assess the impact of race on the incidence of adverse events.
Other Events Observed in Association with FROVA:
In the paragraphs that follow, the incidence of less commonly reported adverse events in four placebo-controlled trials are presented. Variability associated with adverse event reporting, the terminology used to describe adverse events etc, limit the value of the incidence estimates provided. The incidence of each adverse event is calculated as the number of patients reporting the event at least once divided by the number of patients who used FROVA. All adverse events reported within 48 hours of drug administration in the first attack in four placebo controlled trials involving 2392 patients (1554 frovatriptan 2.5 mg and 838 placebo) are included, except those already listed in Table 2, those too general to be informative, those not reasonably associated with the use of the drug and those which occurred at the same or a greater incidence in the placebo group. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those occurring in at least 1/100 patients, infrequent adverse events are those occurring in between 1/100 and 1/1000 patients, and rare adverse events are those occurring in fewer than 1/1000 patients.
Central and peripheral nervous system: Frequent: dysesthesia and hypoesthesia. Infrequent: tremor, hyperesthesia, migraine aggravated, involuntary muscle contractions, vertigo, ataxia, abnormal gait and speech disorder. Rare: hypertonia, hypotonia, abnormal reflexes and tongue paralysis.
Gastrointestinal: Frequent: vomiting, abdominal pain and diarrhea. Infrequent: dysphagia, flatulence, constipation, anorexia, esophagospasm and saliva increased. Rare: change in bowel habits, cheilitis, eructation, gastroesophageal reflux, hiccup, peptic ulcer, salivary gland pain, stomatitis and toothache.
Body as a whole: Frequent: pain. Infrequent: asthenia, rigors, fever, hot flushes and malaise. Rare: feeling of relaxation, leg pain and edema mouth.
Psychiatric: Frequent: insomnia and anxiety. Infrequent: confusion, nervousness, agitation, euphoria, impaired concentration, depression, emotional lability, amnesia, thinking abnormal and depersonalization. Rare: depression aggravated, abnormal dreaming and personality disorder.
Musculoskeletal: Infrequent: myalgia, back pain, arthralgia, arthrosis, leg cramps and muscle weakness.
Respiratory: Frequent: sinusitis and rhinitis. Infrequent: pharyngitis, dyspnea, hyperventilation and laryngitis.
Vision disorders: Frequent: vision abnormal. Infrequent: eye pain, conjunctivitis and abnormal lacrimation.
Skin and appendages: Frequent: sweating increased. Infrequent: pruritis, and bullous eruption.
Hearing and vestibular disorders: Frequent: tinnitus. Infrequent: ear ache, and hyperacusis.
Heart rate and rhythm: Frequent: palpitation. Infrequent: tachycardia. Rare: bradycardia.
Metabolic and nutritional disorders: Infrequent: thirst and dehydration. Rare: hypocalcemia and hypoglycemia.
Special senses, other disorders: Infrequent: taste perversion.
Urinary system disorders: Infrequent: micturition frequency and polyuria. Rare: nocturia, renal pain and abnormal urine.
Cardiovascular disorders, general: Infrequent: abnormal ECG.
Platelet, bleeding and clotting disorders: Infrequent: epistaxis. Rare: purpura.
Autonomic nervous system: Rare: syncope.
Postmarketing Experience
Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency. Information is often incomplete so that a definite causal relationship to drug exposure can often not be established.
Central and peripheral nervous system: Seizure.
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