Frova

The following adverse reactions are described elsewhere in other sections of the labeling:

• Myocardial ischemia, myocardial infarction, and Prinzmetal's angina [see WARNINGS AND PRECAUTIONS]
• Arrhythmias [see WARNINGS AND PRECAUTIONS]
• Chest, throat, neck and/or jaw pain/tightness/pressure [see WARNINGS AND PRECAUTIONS]
• Cerebrovascular events [see WARNINGS AND PRECAUTIONS]
• Other vasospasm reactions [see WARNINGS AND PRECAUTIONS]
• Medication overuse headache [see WARNINGS AND PRECAUTIONS]
• Serotonin syndrome [see WARNINGS AND PRECAUTIONS]
• Increases in blood pressure [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity reactions [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

FROVA was evaluated in four randomized, double-blind, placebo-controlled, short-term trials. These trials involved 2392 patients (1554 on FROVA 2.5 mg and 838 on placebo). In these short-term trials, patients were predominately female (88%) and Caucasian (94%) with a mean age of 42 years (range 18 -69).The treatment-emergent adverse events that occurred most frequently following administration of FROVA 2.5 mg (i.e., in at least 2% of patients), and at an incidence ≥ 1% greater than with placebo, were dizziness, paresthesia, headache, dry mouth, fatigue, flushing, hot or cold sensation, dyspepsia, skeletal pain, and chest pain. In a long term, open-label study where 496 patients were allowed to treat multiple migraine attacks with FROVA 2.5 mg for up to 1 year, 5% of patients (n=26) discontinued due to treatment-emergent adverse events.

Table 1 lists treatment-emergent adverse events reported within 48 hours of drug administration that occurred with FROVA 2.5 mg at an incidence of ≥ 2% and more often than on placebo, in the four placebo-controlled trials. 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 1 : Treatment-Emergent Adverse Events Reported within 48 Hours (Incidence ≥ 2% and Greater Than Placebo) of Patients in Four Pooled Placebo-Controlled Migraine Trials

The incidence of adverse events in clinical trials did not increase when up to 3 doses were used within 24 hours. The incidence of adverse events in 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.

The incidence of frequently reported adverse events in four placebo-controlled trials are presented below. Events are further classified within body system categories. Frequent adverse events are those occurring in at least 1/100 patients.

Central and peripheral nervous system: dysesthesia and hypoesthesia.

Gastrointestinal: vomiting, abdominal pain and diarrhea.

Body as a whole: pain.

Psychiatric: insomnia and anxiety.

Respiratory: sinusitis and rhinitis.

Vision disorders: vision abnormal.

Skin and appendages: sweating increased.

Hearing and vestibular disorders: tinnitus.

Heart rate and rhythm: palpitation.

Postmarketing Experience

The following adverse reactions were identified during post approval use of FROVA. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Central and peripheral nervous system: Seizure.

Common side effects include:

• dizziness
• fatigue (tiredness)
• headache (other than a migraine headache)
• paresthesia (feeling of tingling)
• dry mouth
• flushing (hot flashes)
• feeling hot or cold
• chest pain
• dyspepsia (indigestion)
• skeletal pain (pain in joints or bones)

Tell your doctor about any symptoms that you develop while taking Frova. If you feel dizziness or fatigue, take extra care or avoid driving and operating machinery.

In very rare cases, patients taking this class of medicines experience serious heart problems, stroke, or increased blood pressure. If you develop pain, tightness, heaviness, or pressure in your chest, throat, neck, or jaw, contact your doctor right away.

Also contact your doctor right away if you develop a rash or itching after taking this medication. 

Do not take frovatriptan within 24 hours before or after using another migraine headache medicine, including:

• sumatriptan injection, almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, zolmitriptan; or

• ergot medicine--dihydroergotamine, ergotamine, ergonovine, methylergonovine.

Frovatriptan may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Vascular Headaches

Acute treatment of migraine attacks with or without aura.1 4 5

Not recommended for management of hemiplegic or basilar migraine or for prophylaxis of migraine.1

Safety and efficacy not established for management of cluster headaches.1

Appears to be metabolized principally via CYP1A2.1 3 10

Does not inhibit CYP1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 or MAO isoenzymes in vitro; does not induce drug metabolizing enzymes.1 Pharmacokinetic interaction with drugs metabolized by these isoenzymes unlikely.1 9

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (increased plasma frovatriptan concentrations) with concomitant use of CYP1A2 inhibitors; however, effects not considered clinically relevant.8 10

Specific Drugs

Storage

Oral

25°C (may be exposed to 15–30°C).1 Protect from moisture and light.1

It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it.

Do not take this medicine if you have used other triptan or ergot-type migraine medicines within the past 24 hours. Some examples of triptan medicines are almotriptan (Axert®), eletriptan (Relpax®), naratriptan (Amerge®), sumatriptan (Imitrex®, Treximet®), or zolmitriptan (Zomig®). Some examples of ergot-type medicines are dihydroergotamine (D.H.E. 45®, Migranal®), ergotamine (Bellergal®, Cafergot®, Ergomar®, Wigraine®), or methysergide (Sansert®).

This medicine may cause serious allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash, itching, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth while you are using this medicine.

Check with your doctor if you have used frovatriptan and your migraine got worse or started occurring more often.

This medicine may increase your risk of having abnormal heart rhythm, heart attack, angina, or stroke. This is more likely to occur if you or a family member already has heart disease, if you have diabetes, high blood pressure, or if you smoke. Call your doctor right away if you have any symptoms of a heart problem, such as chest pain or discomfort, an uneven heartbeat, nausea or vomiting, pain or discomfort in the shoulders, arms, jaw, back, or neck, shortness of breath, or sweating. Call your doctor right away if you have any symptoms of a stroke, such as confusion, difficulty with speaking, double vision, headaches, an inability to move the arms, legs, or facial muscles, an inability to speak, or slow speech.

Check with your doctor right away if you have chest discomfort, jaw or neck tightness after taking this medicine. Also, tell your doctor if you have sudden or severe abdominal or stomach pain or bloody diarrhea after using this medicine.

Check with your doctor right away if you have blurred vision, difficulty with reading, or any other change in vision while you are using this medicine. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

Using frovatriptan alone or in combination with other migraine medicines for 10 or more days per month may lead to worsening of headache. You may keep a headache diary to record the headache frequency and drug use.

Make sure your doctor knows about all the other medicines you are using. Frovatriptan may cause a serious condition called serotonin syndrome when taken with some medicines. This includes medicines to treat depression, such as amitriptyline (Elavil®), citalopram (Celexa®), duloxetine (Cymbalta®), escitalopram (Lexapro®), fluoxetine (Prozac®, Sarafem®, Symbyax®), fluvoxamine (Luvox®), olanzapine (Zyprexa®), paroxetine (Paxil®), sertraline (Zoloft®), or venlafaxine (Effexor®). Check with your doctor right away if you have agitation, confusion, diarrhea, excitement while talking that is not normal, fever, overactive reflexes, poor coordination, restlessness, shivering, sweating, trembling or shaking that you cannot control, or twitching. These could be symptoms of serotonin syndrome.

Drinking alcoholic beverages can make headaches worse or cause new headaches to occur. People who suffer from severe headaches should probably avoid alcoholic beverages, especially during a headache.

Some people feel drowsy or dizzy during or after a migraine, or after taking frovatriptan to relieve a migraine. As long as you are feeling drowsy or dizzy, do not drive, use machines, or do anything else that could be dangerous until you know how this medicine affects you.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Dizziness.
• Feeling tired or weak.
• Headache.
• Dry mouth.
• Flushing.
• Feeling of warmth.
• Feeling of heaviness or pressure.
• Upset stomach.
• Bone or joint pain.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

2.5 mg Tablets:  Round, white, film-coated tablets debossed with 2.5 on one side and "E" on the other side.

Frova tablets, containing 2.5 mg of Frovatriptan (base) as the succinate salt, are available as round, white, film-coated tablets debossed with 2.5 on one side and “E” on the other side. The tablets are available in:

Blister card of 9 tablets, 1 blister card per carton (NDC 63481-025-09)

Store Frova tablets at controlled room temperature, 25°C (77°F) excursions permitted to 15 - 30°C (59°F - 86°F) [see USP Controlled Room Temperature].  Protect from moisture.

2.5 mg Tablets:  Round, white, film-coated tablets debossed with 2.5 on one side and "E" on the other side.

Frova (Frovatriptan succinate) tablets contain Frovatriptan succinate, a selective 5-hydroxy-tryptamine1 (5-HT1B/1D) receptor subtype agonist (triptan), 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 empirical formula is C14H17N3O.C4H6O4.H2O, representing a molecular weight of 379.4. Frovatriptan succinate is a white to off-white powder that is soluble in water.

Each Frova 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 lactose NF, microcrystalline cellulose NF, colloidal silicon dioxide NF, sodium starch glycolate NF, magnesium stearate NF, hypromellose USP, polyethylene glycol 3000 USP, triacetin USP, and titanium dioxide USP.

Frova tablets, containing 2.5 mg of Frovatriptan (base) as the succinate salt, are available as round, white, film-coated tablets debossed with 2.5 on one side and “E” on the other side. The tablets are available in:

Blister card of 9 tablets, 1 blister card per carton (NDC 63481-025-09)

Store Frova tablets at controlled room temperature, 25°C (77°F) excursions permitted to 15 - 30°C (59°F - 86°F) [see USP Controlled Room Temperature].  Protect from moisture.

See FDA-Approved Patient Labeling (Patient Information)

Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospastic Reactions, and Cerebrovascular Events

Inform patients that Frova 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 Frova. 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 Frova 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 Frova 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)].

Applies to frovatriptan: oral tablet

General

The most commonly reported adverse events included dizziness, fatigue, paraesthesia, headache, and vascular flushing.[Ref]

Hypersensitivity

Postmarketing reports: Hypersensitivity reactions including cutaneous disorders, angioedema, and anaphylactic reactions[Ref]

Cardiovascular

Common (1% to 10%): Flushing, chest discomfort
Uncommon (0.1% to 1%): Palpitations, tachycardia, peripheral coldness, hypertension, chest pain
Rare (0.01% to 0.1%): Bradycardia
Postmarketing reports: Myocardial infarction, coronary arteriospasm[Ref]

Nervous system

Common (1% to 10%): Dizziness, headache, paresthesia, dysesthesia, hypoesthesia , somnolence
Uncommon (0.1% to 1%): Dysgeusia, tremor, disturbance in attention. lethargy, sedation, vertigo, involuntary muscle contractions
Rare (0.01% to 0.1%): Amnesia hypertonia hypotonia, hyporeflexia, movement disorder
Postmarketing reports: Seizure[Ref]

Psychiatric

Uncommon (0.1% to 1%): Anxiety, insomnia, confusional state, nervousness, agitation, depression, depersonalization
Rare (0.01% to 0.1%): Abnormal dreams, personality disorder[Ref]

Gastrointestinal

Common (1% to 10%): Dry mouth, dyspepsia, vomiting, nausea, abdominal pain, diarrhea
Uncommon (0.1% to 1%): Dysphagia, flatulence, constipation, anorexia, esophagospasm, increased salivation
Rare (0.01% to 0.1%): Change in bowel habits, chelitis, eructation, gastroesophageal reflux, hiccough, peptic ulcer, salivary gland pain, stomatitis, toothache, lip blister, lip pain , oral mucosal blistering, peptic ulcer, salivary gland pain[Ref]

Musculoskeletal

Common (1% to 10%): Skeletal pain
Uncommon (0.1% to 1%): Musculoskeletal stiffness, musculoskeletal pain, pain in extremity, back pain, arthralgia[Ref]

Respiratory

Common (1% to 10%): Throat tightness
Uncommon (0.1% to 1%): Rhinitis, sinusitis, pharyngolaryngeal pain
Rare (0.01% to 0.1%): Epistasis, hiccups, hyperventilation, respiratory disorder, throat irritation[Ref]

Ocular

Common (1% to 10%): Visual disturbance
Uncommon (0.1% to 1%): Eye pain, eye irritation, photophobia
Rare (0.01% to 0.1%): Night blindness[Ref]

Dermatologic

Common (1% to 10%): Hyperhidrosis
Uncommon (0.1% to 1%): Pruritus
Rare (0.01% to 0.1%): Erythema, piloerection, urticaria, purpura[Ref]

Other

Common (1% to 10%): Fatigue, hot or cold sensation, tinnitus
Uncommon (0.1% to 1%): Ear pain, ear discomfort, ear disorder, ear pruritus, hyperacusis, feeling hot temperature intolerance, asthenia, sluggishness, energy increased, malaise
Rare (0.01% to 0.1%): Pyrexia[Ref]

Genitourinary

Uncommon (0.1% to 1%): Increased micturition frequency, polyuria
Rare (0.01% to 0.1%): Nocturia, renal pain, abnormal urine analysis[Ref]

Metabolic

Uncommon (0.1% to 1%): Dehydration, thirst
Rare (0.01% to 0.1%): Hypoglycemia[Ref]

Hematologic

Rare (0.01% to 0.1%): Lymphadenopathy[Ref]

Hepatic

Rare (0.01% to 0.1%): Increased blood bilirubin[Ref]

Endocrine

Uncommon (0.1% to 1%): Breast tenderness[Ref]

Some side effects of Frova may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Summary of Use during Lactation

No published experience exists with frovatriptan during breastfeeding. If frovatriptan is required by the mother, it is not a reason to discontinue breastfeeding. However, because frovatriptan has a long half-life of 25 to 30 hours, a shorter-acting alternate drug may be preferred, especially while nursing a newborn or preterm infant.[1]

Drug Levels

Maternal Levels. Relevant published information was not found as of the revision date.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

Sumatriptan, Eletriptan

References

1. Amundsen S, Nordeng H, Nezvalova-Henriksen K et al. Pharmacological treatment of migraine during pregnancy and breastfeeding. Nat Rev Neurol. 2015;11:209-19. PMID: 25776823