FrovaŽ
Summary
Frova® (frovatriptan succinate) 2.5 mg tablets is a selective 5-HT1B/1D receptor agonist approved as an acute oral treatment for migraine headache and its associated symptoms. Frova® belongs to the triptan class of drugs and is distinguished from other triptans by its exceptionally long half-life. Frova® is also being developed for the short term prevention of menstrual migraine (MM) (see www.vernalis.com/ver/rdc2/pain/mm)
Vernalis co-promotes Frova® in North America with Endo Pharmaceuticals. Endo re-launched the product during 2005 with an expanded sales force and a new marketing strategy focused on the benefits of Frova®’s long duration of action. Under the co-promote agreement Endo is funding the direct costs of 25 of Vernalis' 34 strong specialty neurology sales force that was launched in January 2006. For full prescribing information, please visit: www.frova.com.
Frovatriptan is approved in the 25 EU countries as well as in Switzerland, Turkey and Central America. Menarini markets frovatriptan under various trade names in 15 EU countries including the major markets: UK, Italy, Germany, France and Spain and also in Switzerland. The most recent EU launch was in France in April 2007 and Menarini also recently launched frovatriptan in Turkey in March 2007. Menarini also markets frovatriptan in 7 Central American countries including Panama and Costa Rica.
In September 2004, Frova® was granted approval in Canada
for the treatment of acute migraine. The approval follows a
successful dialogue with the Canadian Health Authorities regarding
the product label, a necessary step prior to initiation of the
national pricing approval.
Frova® is approved for the treatment of migraines in adults. The most common adverse events include dizziness, fatigue, paresthesia, flushing, and headache.
Background
The American Migraine Society has estimated that more than 20 million people over the age of 12 suffer from severe migraine headaches. For such a widespread disorder, the social and economic effects are staggering: it is estimated that more than $15 billion is lost in annual productivity. Migraine occurs in about 10% of the population in the United Kingdom and the United States. Incidence is 16-18% among women and 6% among men. Migraine is characterised by headache attacks lasting for 4 to 72 hours and the headache is usually severe, one-sided, pulsating and aggravated by physical activity. It is often accompanied by nausea, vomiting and, increased sensitivity to light and sound. Over 50% of migraine headaches last over 24 hours if not treated. Some patients experience warning symptoms or "aura", so the headache is preceded by symptoms and neurological disturbances, such as visual, sensory, speech and movement effects. The exact cause of a migraine attack is unclear, however, it is generally agreed that a migraine trigger disturbs the blood circulation in the brain resulting in cerebral vasodilatation and perivascular inflammation. This causes activation of sensory nerve fibres and ultimately headache. Drugs that block the neurotransmitter serotonin have been used for a number of years to treat migraine. The triptan drugs, including Frova®, act selectively on 5-HT1B/1D receptors. Annual sales of prescription medicines to treat migraine were approaching $3.4bn in 2005 (Pharmaceutical Business Insights).
Current Migraine Therapies
Sumatriptan (IMIGRAN or IMITREX, GlaxoSmithKline), a 5-HT1B/1D receptor agonist, has been marketed for the acute treatment of migraine since 1991 (UK). It was the first new acute therapy for migraine for over 20 years. The main antimigraine action of sumatriptan is thought to be due to constriction of intracranial vasculature action on 5-HT1B/1D receptors, although a secondary effect on pain transmission is possible. Other triptans available in the UK include zolmitriptan (ZOMIG, AstraZeneca), naratriptan (NARAMIG, GlaxoSmithKline), rizatriptan (MAXALT, Merck), eletriptan (RELPAX, Pfizer) and almotriptan (ALMOGRAN, Lundbeck).
Pre-clinical Studies
The pharmacological profile of frovatriptan has been studied in vitro and in vivo. Frovatriptan exhibits marked selectivity for 5-HT1B/1D receptors and is believed to act selectively on extracerebral, intracranial arteries to inhibit excessive dilatation of these vessels in migraine. At clinically relevant concentrations, frovatriptan produced constriction of human isolated cerebral arteries with little or no effect on human isolated coronary arteries.
Clinical Studies
Studies with Frova® in healthy subjects indicate that, at the recommended clinical dose of 2.5 mg, the half-life is considerably longer than that reported for other triptans (about 26 hours as against 6 hours for naratriptan). This may explain why Frova® appears to maintain effectiveness over a long period, demonstrated in clinical trials where there was a low incidence of recurrence of the headache in the 24 hours following dosing with Frova®. The oral bioavailability of Frova® in man is 20% - 30% and the peak blood levels (Tmax) occur at 2-4 hours. Three Phase II clinical studies, including over 1,600 patients have evaluated the efficacy and safety of Frova® for the acute treatment of migraine at doses between 0.5 mg and 40 mg versus placebo. The results revealed 2.5 mg to be the optimum single dose for the acute treatment of migraine. The headache response (change in severity from severe to moderate or moderate to mild or none) after 2 hours, at doses of 2.5 mg and above, was two-fold greater than for placebo. After 4 hours about 64% of patients had responded to a dose of 2.5 mg (placebo 33%). Nearly 3,200 patients have been studied in four Phase III trials, three of which were placebo controlled. The results confirmed the findings of the Phase II studies. These trials also highlighted a distinguishing feature of Frova®, its low recurrence rate. In only 7%-25% of patients did the headache recur after initially improving.
Regulatory Status
Frova® has been approved for the acute treatment of migraine attacks with or without aura in adults in the US by the Food & Drug Administration (FDA). It was originally launched in the US in June 2002 and was marketed by Elan until May 2004. When that licensing agreement was terminated, Vernalis re-acquired the product. In July 2004, Frova® was licensed to Endo Pharmaceuticals and has been marketed in the US by Endo since September 2004.
Frovatriptan is approved in the 25 EU countries as well as in Switzerland, Turkey and Central America. Menarini markets frovatriptan under various trade names in 15 EU countries including the major markets: UK, Italy, Germany, France and Spain and also in Switzerland. The most recent EU launch was in France in April 2007 and Menarini also recently launched frovatriptan in Turkey in March 2007. Menarini also markets frovatriptan in 7 Central American countries including Panama and Costa Rica.
In September 2004, Frova® was granted approval in Canada for the treatment of acute migraine. The approval follows a successful dialogue with the Canadian Health Authorities regarding the product label, a necessary step prior to initiation of the national pricing approval.
Also in September 2004, Vernalis signed an agreement with SK Chemicals Co.Ltd of Korea, granting SK exclusive distribution rights for Frova® in the Korean market.