Frovatriptan Succinate

FROVA is indicated for the acute treatment of migraine with or without aura in adults.

• Use only if a clear diagnosis of migraine has been established. If a patient has no response for the first migraine attack treated with FROVA, reconsider the diagnosis of migraine before FROVA is administered to treat any subsequent attacks.
• FROVA is not indicated for the prevention of migraine attacks.
• Safety and effectiveness of FROVA have not been established for cluster headache.

Mechanism Of Action

Frovatriptan binds with high affinity to 5-HT1B/1D receptors. The therapeutic activity of FROVA 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.

Pharmacokinetics

The pharmacokinetics of frovatriptan are similar in migraine patients and healthy subjects.

Mean maximum blood concentrations (Cmax) in patients are achieved approximately 2 - 4 hours after administration of a single oral dose of frovatriptan 2.5 mg. The absolute bioavailability of an oral dose of frovatriptan 2.5 mg in healthy subjects is about 20% in males and 30% in females. Food has no significant effect on the bioavailability of frovatriptan, but delays tmax by one hour.

Binding of frovatriptan to serum proteins is low (approximately 15%). Reversible binding to blood cells at equilibrium is approximately 60%, resulting in a blood: plasma ratio of about 2:1 in both males and females. The mean steady state volume of distribution of frovatriptan following intravenous administration of 0.8 mg is 4.2 L/kg in males and 3.0 L/kg in females.

in vitro, cytochrome P450 1A2 appears to be the principal enzyme involved in the metabolism of frovatriptan. Following administration of a single oral dose of radiolabeled frovatriptan 2.5 mg to healthy male and female subjects, 32% of the dose was recovered in urine and 62% in feces. Radiolabeled compounds excreted in urine were unchanged frovatriptan, hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, together with several other minor metabolites. Desmethyl frovatriptan has lower affinity for 5-HT1B/1D receptors compared to the parent compound. The N-acetyl desmethyl metabolite has no significant affinity for 5-HT receptors. The activity of the other metabolites is unknown.

After an intravenous dose, mean clearance of frovatriptan was 220 and 130 mL/min in males and females, respectively. Renal clearance accounted for about 40% (82 mL/min) and 45% (60 mL/min) of total clearance in males and females, respectively. The mean terminal elimination half-life of frovatriptan in both males and females is approximately 26 hours.

Special Populations

The AUC of frovatriptan in patients with mild (Child-Pugh 5-6) to moderate (Child-Pugh 7-9) hepatic impairment was about twice that of young, healthy subjects, but within the range observed in healthy elderly subjects and was considerably lower than the values attained with higher doses of frovatriptan (up to 40 mg), which were not associated with any serious adverse effects. There is no clinical or pharmacokinetic experience with FROVA in patients with severe hepatic impairment.

The pharmacokinetics of frovatriptan following a single oral dose of 2.5 mg was not different in patients with renal impairment (5 males and 6 females, creatinine clearance 16 -73 mL/min) compared to subjects with normal renal function.

Mean AUC of frovatriptan was 1.5-to 2-fold higher in healthy elderly subjects (age 65 - 77 years) compared to those in healthy younger subjects (age 21 -37 years). There was no difference in tmax or t½ between the two populations.

There was no difference in the mean terminal elimination half-life of frovatriptan in males and females. Bioavailability was higher, and systemic exposure to frovatriptan was approximately 2-fold greater, in females than males, irrespective of age.

The effect of race on the pharmacokinetics of frovatriptan has not been examined.

Drug Interaction Studies

Frovatriptan is not an inhibitor of human monoamine oxidase (MAO) enzymes or cytochrome P450 (isozymes 1A2, 2C9, 2C19, 2D6, 2E1, 3A4) in vitro at concentrations up to 250 to 500-fold higher than the highest blood concentrations observed in man at a dose of 2.5 mg. No induction of drug metabolizing enzymes was observed following multiple dosing of frovatriptan to rats or on addition to human hepatocytes in vitro. Although no clinical trials have been performed, it is unlikely that frovatriptan will affect the metabolism of co-administered drugs metabolized by these mechanisms.

Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives compared to tho se not taking oral contraceptives.

The AUC and Cmax of frovatriptan (2 x 2.5 mg dose) were reduced by approximately 25% when co -administered with ergotamine tartrate [see CONTRAINDICATIONS, DRUG INTERACTIONS].

Propranolol increased the AUC of frovatriptan 2.5 mg in males by 60% and in females by 29%. The C max of frovatriptan was increased 23% in males and 16% in females in the presence of propranolol. The tmax as well as half-life of frovatriptan, though slightly longer in the females, were not affected by concomitant administration of propranolol.

The pharmacokinetic profile of frovatriptan was unaffected when a single oral dose of frovatriptan 2.5 mg was administered to healthy female subjects receiving the MAO-A inhibitor, moclobemide, at an oral dose of 150 mg bid for 8 days.

Clinical Studies

The efficacy of FROVA 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 -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 FROVA 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 FROVA. 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 FROVA 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

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 FROVA 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 FROVA 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 commonl y used by migraine patients.

FROVA
(FRO-va)
(Frovatriptan Succinate) Tablets

Read this Patient Information before you start taking FROVA and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor. You and your doctor should discuss FROVA when you start taking your medication and at regular check-ups.

What is FROVA?

FROVA is a prescription medicine used to treat migraine headaches with or without aura in adults.

FROVA is not used to treat other types of headaches.

FROVA is not used to prevent or decrease the number of migraine headaches.

It is not known if FROVA is safe and effective to treat cluster headaches.

It is not known if FROVA is safe and effective in children under 18 years of age.

Who should not take FROVA?

Do not take FROVA if you have:

• heart problems, a history of heart problems, or problems with the electrical system of your heart
• had a stroke, transient ischemic attacks (TIAs), or problems with your blood circulation
• hemiplegic migraines or basilar migraines. If you are not sure if you have these types of migraines, ask your healthcare provider.
• narrowing of blood vessels to your legs, arms, or stomach (peripheral vascular disease)
• uncontrolled high blood pressure
• taken any of the following medicines in the last 24 hours:
  • almotriptan (AXERT®)
  • eletriptan (RELPAX®)
  • naratriptan (AMERGE®)
  • rizatriptan (MAXALT®, MAXALT-MLT®)
  • sumatriptan (IMITREX®, SUMAVEL® DosePro®, ALSUMA®)
  • sumatriptan and naproxen (TREXIMET®)
  • zolmitriptan (ZOMIG®)
  • Ergotamine or ergotamine-type medicines (BELLERGAL®, CAFERGOT® , ERGOMAR®, WIGRAINE®, D.H.E.45®, MIGRANAL®, SANSERT®) Ask your healthcare provider if you are not sure if your medicine is listed above.
• an allergy to frovatriptan or any of the ingredients in FROVA. See the end of this leaflet for a complete list of ingredients in FROVA.

What should I tell my doctor before taking FROVA?

Before you take FROVA, tell your doctor about all of your medical conditions, including if you:

• have high blood pressure
• have high cholesterol
• have diabetes
• smoke
• are overweight
• are a female who has gone through menopause
• have heart disease or a family history of heart disease or stroke
• are pregnant or plan to become pregnant
• are breastfeeding or plan to breastfeed

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.

Especially tell your doctor if you take:

• propranolol
• selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), two types of drugs for depression or other disorders. Common SSRIs are CELEXA® (citalopram HBr), LEXAPRO® (escitalopram oxalate), PAXIL® (paroxetine), PROZAC®/SARAFEM® (fluoxetine), SYMBAX® (olanzapine/fluoxetine), ZOLOFT® (sertraline), and fluvoxamine. Common SNRIs are CYMBALTA® (duloxetine) and EFFEXOR® (venlafaxine).

These medicines may affect how FROVA works, or FROVA may affect how these medicines work.

Ask your doctor or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them to show your doctor or pharmacist when you get a new medicine.

How should I take FROVA?

• Certain people should take their first dose of FROVA in their doctor's office or in another medical setting. Ask your doctor if you should take your first dose in a medical setting.
• Take FROVA exactly as your doctor tells you.
• If you do not get any relief after your first FROVA tablet, do not take a second tablet without first talking with your doctor.
• If your headache comes back or you only get some relief from your headache, you may take a second FROVA tablet 2 hours after the first tablet.
• Do not take more than 3 FROVA tablets in a 24-hour period.
• It is not known if it is safe and effective to take FROVA for more than 4 headaches in 30 days.
• If you take too much FROVA, call your doctor or go to the nearest hospital emergency room right away.
• You should write down when you have headaches and when you take FROVA so you can talk with your doctor about how FROVA is working for you.

What should I avoid while taking FROVA?

FROVA can cause dizziness, weakness, or drowsiness. If you have these symptoms do not drive a car, use machinery, or do anything where you need to be alert.

What are the possible side effects of FROVA?

FROVA can cause serious side effects.

Call your doctor right away if you have any of the following symptoms after taking FROVA:

• Heart attack or other heart problems. Heart problems may lead to death. Stop taking FROVA and get emergency medical help right away if you have any of the following symptoms of a heart attack or other heart problems:
  • Discomfort in the center of your chest that lasts for more than a few minutes, or that goes away and comes back
  • Chest pain or chest discomfort that feels like heavy pressure, squeezing, or fullness
  • Pain or discomfort in your arms, back, neck, jaw, or stomach
  • Shortness of breath with or without chest discomfort
  • Breaking out in a cold sweat
  • Feeling lightheaded
  • Nausea or vomiting with any of the symptoms included above
• Stroke. Symptoms of stroke include face drooping, slurred speech, and unusual weakness or numbness.
• Changes in color or sensation in your fingers and toes (Raynaud's syndrome).
• Stomach and intestinal problems (gastrointestinal and colonic ischemic events). Symptoms of gastrointestinal and colonic ischemic events include:
  • Sudden or severe stomach pain
  • Stomach pain after meals
  • Weight loss
  • Nausea or vomiting
  • Constipation or diarrhea
  • Bloody diarrhea
  • Fever
• Problems with blood circulation to your legs and feet (peripheral vacular ischemia). Symptoms of peripheral vascular ischemia include:
  • Cramping and pain in your legs or hips
  • Feeling of heaviness or tightness in your leg muscles
  • Burning or aching pain in your feet or toes while resting
  • Numbness, tingling, or weakness in your legs
  • Cold feeling or color changes in one or both legs or feet
• Increased blood pressure
• Allergic reactions. Symptoms of allergic reaction include:
  • Rash
  • Hives
  • Itching
  • Swelling of the face, mouth, throat, or tongue
  • Difficulty breathing
• Medication overuse headache. Some people who use too many FROVA tablets may have worse headaches (medication overuse headache). If your headaches get worse, your doctor may decide to stop your treatment with FROVA.
• Serotonin syndrome. Serotonin syndrome is a rare but serious problem that can happen in people using FROVA, especially if FROVA is used with anti-depressant medicines called SSRIs and SNRIs. Call your doctor right away if you have any of the following symptoms of serotonin syndrome:
  • Mental changes such as seeing things that are not there (hallucinations), agitation, or coma
  • Fast heartbeat
  • Changes in blood pressure
  • High body temperature
  • Tight muscles
  • Trouble walking

The most common side effects of FROVA are:

• 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.

This is not a complete list of side effects. Talk to your doctor if you develop any symptoms that concern you.

How should I store FROVA?

Store FROVA at between 59°F to 86°F (15°C to 30°C). Protect FROVA from moisture. Discard after expiration date printed on package.

Keep FROVA and all medicines out of the reach of children.

General advice about the safe and effective use of FROVA.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use FROVA for a condition for which it was not prescribed. Do not give FROVA to other people, even if they have the same symptoms as you. People may be harmed if they take medicines that have not been prescribed for them.

This leaflet summarizes the most important information about FROVA. If you would like more information about FROVA, talk to your doctor. You can ask your doctor or pharmacist for information on FROVA that is written for healthcare professionals. You can also call 1-800-4623636 or visit our website at www.FROVA.com.

What are the Ingredients in FROVA?

Active ingredient: frovatriptan succinate

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

Frovatriptan is a headache medicine that narrows blood vessels around the brain. Frovatriptan also reduces substances in the body that can trigger headache pain, nausea, sensitivity to light and sound, and other migraine symptoms.

Frovatriptan is used to treat migraine headaches. Frovatriptan will only treat a headache that has already begun. It will not prevent headaches or reduce the number of attacks.

Frovatriptan should not be used to treat a common tension headache, a headache that causes loss of movement on one side of your body, or any headache that seems to be different from your usual migraine headaches. Use this medication only if your condition has been confirmed by a doctor as migraine headaches.

Frovatriptan may also be used for purposes not listed in this medication guide.

Selective serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptor agonist (“triptan”).1 2

Absorption

Bioavailability

Incompletely absorbed from GI tract; absolute bioavailability of 20 and 30% in males and females, respectively.1 9

Peak plasma concentrations attained approximately 2–4 hours after oral administration.1 9

Food

Food does not affect bioavailability but may delay time to peak plasma concentration by 1 hour.1

Distribution

Extent

Distributes into cellular fraction of blood, principally erythrocytes (approximately 60% reversibly bound).9

Animal studies indicate limited capacity to cross blood-brain barrier.9

Distributed into milk in rats; not known whether distributed into milk in humans.1

Plasma Protein Binding

Approximately 15%.1 9

Elimination

Metabolism

Appears to be metabolized principally via CYP1A2 to numerous metabolites, including desmethyl frovatriptan, which exhibits lower affinity for 5-HT1B/1D receptors compared with frovatriptan.1 3

Elimination Route

Excreted in urine (32%) and feces (62%) as unchanged drug and metabolites.1

Half-life

Approximately 26 hours.1 9

Special Populations

In patient with mild to moderate hepatic impairment, AUC is twofold higher than in healthy individuals; pharmacokinetics not studied in patients with severe hepatic impairment.1

In geriatric patients, AUC is 1.5- to 2-fold higher than in younger adults; half-life and time to peak plasma concentrations unchanged.1

• Binds with high affinity to 5-HT1B and 5-HT1D receptors.1

• Structurally distinct from, but pharmacologically related to, other selective 5-HT1B/1D receptor agonists (e.g., almotriptan, eletriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan).2 7 8

• Precise mechanism of action not established;6 may ameliorate migraine through selective constriction of certain intracranial blood vessels, inhibition of neuropeptide release, and reduced transmission in trigeminal pain pathway.1 2

• Risk of serious cardiovascular or cerebrovascular events (e.g., MI, stroke) or other vasospastic reactions.1 Importance of seeking medical care if symptoms of such reactions (e.g., shortness of breath, weakness, slurring of speech, or tightness, pain, pressure, or heaviness in chest, throat, jaw, or neck) occur and of not taking frovatriptan again until evaluated by clinician.1 8 21

• Importance of taking frovatriptan exactly as prescribed.1

• Importance of providing patient a copy of manufacturer’s patient information.1

• Risk of dizziness or fatigue; importance of exercising caution when driving or operating machinery.1

• Overuse of drugs indicated for the management of acute migraine attacks may exacerbate headaches; importance of recording headache frequency and drug use to monitor effectiveness of treatment.21 31

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease).1

• Importance of informing patients of risk of serotonin syndrome, particularly with concurrent use of frovatriptan and an SSRI or SNRI.1 11 Importance of seeking immediate medical attention if symptoms of serotonin syndrome develop.11

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)