Key points from the evidence

The content of this evidence summary was up-to-date in September 2014. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

Flunarizine is a calcium channel blocker that reduces smooth muscle spasm. Overall, the studies included in this evidence summary suggest that flunarizine is as effective as propranolol or topiramate at reducing the frequency of migraines in adults. In children, flunarizine was more effective than placebo at reducing migraine frequency, and as effective as nimodipine, aspirin, propranolol or dihydroergotamine. However, all of the studies in children were small and of poor quality. The most common adverse effect of flunarizine is weight gain.

Regulatory status: unlicensed. This topic was prioritised because of the potential clinical impact of long-term prescribing in primary care.

Effectiveness

  • In 1 RCT (n=783 adults), flunarizine was as effective as propranolol, each reducing the mean migraine frequency from around 3 at baseline to around 2 per 4 weeks (calculated over the 16-week study duration).

  • In a 16 week study conducted in primary care (n=434 adults), frequency of migraine attacks was reduced in 54.5% of people in the flunarizine group and 53.1% of people in the propranolol group. In an outpatient study (n=87 adults), frequency of migraine attacks was reduced in 67.9% of people in the flunarizine group and 45.8% of people in the propranolol group. No statistical analysis was reported in either study.

  • Another RCT (n=150 adults), compared flunarizine, topiramate, and their combination. At 1 year it found no statistically significant difference in the proportion of people who had at least a 50% reduction in mean monthly migraine frequency compared with baseline.

  • A Cochrane review in children and young people aged 3 to 17 years included 2 RCTs comparing flunarizine with placebo and 4 RCTs comparing flunarizine with an active comparator. Flunarizine reduced migraine frequency more than placebo and to a similar degree to the active comparators, although all of these studies were small and of poor quality.

Safety

  • Flunarizine is contraindicated in people with current depressive illness, a history of recurrent depression, pre-existing symptoms of Parkinson's disease or other extrapyramidal disorders (Sibelium; Irish summary of product characteristics [SPC]).

  • Flunarizine should be used with caution in older people, and people taking flunarizine should be assessed at regular intervals for the development of extrapyramidal symptoms or the symptoms of depression (Sibelium; Irish SPC).

  • Accumulation may occur at higher than recommended doses, with an increased incidence of adverse effects (Sibelium; Irish SPC).

Patient factors

  • Weight gain is a very common (1 in 10 or more) adverse effect (Sibelium; Irish SPC).

  • For maintenance treatment, 2 successive drug-free days every week are recommended and flunarizine should be stopped after 6 months and only re-started if the person's condition relapses (Sibelium; Irish SPC).

Resource implications

  • No price is listed for flunarizine and the cost will differ depending on the source. NHS prescription cost analysis for England 2013 reported that flunarizine hydrochloride 5 mg capsules cost £115.42 per item (with the average quantity per item of 68.92).

  • The cost of alternative treatment options for migraine prophylaxis (not all of which are licensed specifically for this use) varies depending on the treatment used and the dosage. Propranolol tablets 40 mg 3 times a day costs £9.06 for 30 days' treatment. Topiramate tablets 50 mg twice a day cost £3.52 for 30 days' treatment.

Introduction and current guidance

The NICE guideline on the diagnosis and management of headaches in young people and adults makes recommendations on diagnosing and managing the most common primary headache disorders in young people (aged 12 years and older) and adults. It states that headaches are 1 of the most common neurological problems presenting to GPs and neurologists. The most common primary headache disorders are tension-type headache, migraine and cluster headache. For migraine with or without aura, the NICE guideline recommends that the benefits and risks of prophylactic treatment should be discussed with the person taking into account the person's preference, comorbidities, risk of adverse events and the impact of the headache on their quality of life.

NICE recommends that topiramate or propranolol should be offered for the prophylactic treatment of migraine according to the person's preference, comorbidities and risk of adverse events, with other treatments recommended if both of these are unsuitable or ineffective.

Full text of Introduction and current guidance.

Product overview

Flunarizine is a calcium channel blocker that reduces arterial and arteriolar smooth muscle spasm. While flunarizine is unlicensed in the UK, it is licensed in other countries, including Ireland, for the prophylaxis of migraine in adults aged 18 years and older. For adults aged 18 to 64 years the starting dose is 10 mg at night, and for adults aged 65 years and older the starting dose is 5 mg at night (Sibelium summary of product characteristics; Janssen-Cilag).

Full text of Product overview.

Evidence review

  • This evidence summary is based on 4 studies and a Cochrane review. Two of the studies were randomised controlled trials (RCTs): Diener et al. (2002) compared flunarizine with propranolol, and Luo et al. (2012) compared flunarizine, topiramate, and a combination of the two. The other 2 studies were identically designed double blind studies that compared flunarizine with propranolol (Lucking et al. 1988); it is unclear if these 2 studies were randomised. The Cochrane review (Victor et al. 2003) evaluated drug treatment for the prevention of migraine in children and young people. This was last updated in December 2002 and is not planned to be reviewed.

  • Diener et al. (2002) was an RCT conducted in 8 European countries. It compared the safety and efficacy of flunarizine at 2 different doses with propranolol over a 16-week period. The study included 810 adults aged 18 to 65 years with a history of migraine for at least 1 year. For the intention-to-treat (ITT) population, flunarizine 10 mg daily (with 2 consecutive 'drug-free' days from week 9 onwards) and flunarizine 5 mg daily were reported to be at least as effective as propranolol 160 mg daily for the efficacy outcome of mean migraine frequency per 4 weeks (p<0.001 in one-sided equivalence test; each group reduced the mean migraine frequency from around 3 at baseline to around 2 per 4 weeks). For the percentage of responders per 4 weeks for the ITT population, flunarizine 10 mg daily was reported to be at least as effective as propranolol (p=0.01 in one-sided equivalence test) but flunarizine 5 mg daily was not (p=0.344 in one-sided equivalence test). It is unclear if Diener et al. (2002) was a non-inferiority study or an equivalence study, and results from both the ITT population and the per protocol population would be needed to support this finding. The per protocol analysis was not presented.

  • Lucking et al. (1988) compared flunarizine 10 mg daily with propranolol 40 mg 3 times a day over a 16-week period in 2 identically designed double-blind studies in Germany in adults with a history of migraine. The first study included 87 people recruited from 12 hospital outpatient departments and the second study included 434 people recruited from 99 medical practices in primary care. In the primary care study, the frequency of migraine attacks was reduced in 54.5% of people in the flunarizine group and 53.1% of people in the propranolol group after 4 months of treatment. In the outpatient department study, the frequency of migraine attacks was reduced in 67.9% of people in the flunarizine group and 45.8% of people in the propranolol group after 4 months of treatment. No statistical analysis was presented.

  • Luo et al. (2012), an RCT conducted in China, compared flunarizine 5 mg daily alone with topiramate 25 mg to 100 mg daily alone and topiramate and flunarizine combined over a 12-month period in 150 adults aged 18 to 65 years with a history of migraine for at least a year. The proportion of people who had at least a 50% reduction in their mean monthly migraine frequency compared with baseline (the primary outcome) was 66.7% (26/39) in the flunarizine group, 72.7% (32/44) in the topiramate group and 76.7% (33/43) in the combined group. There was no statistically significant difference between the 3 groups (p=0.593).

  • Diener et al. (2002) and Luo et al. (2012) only included people aged 18 to 65 years. There is limited evidence available for people outside of this age range. The majority of people in the studies were female, however this reflects the higher prevalence rate of migraine in women. None of the studies was conducted in the UK and therefore may not be applicable to UK practice. The results of these studies may also not be applicable to people whose migraine has not responded to a number of different prophylactic treatments already.

  • A Cochrane review (Victor et al. 2003) included 2 RCTs that compared flunarizine with placebo and 4 RCTs that compared it with an active comparator. All of the studies were conducted in children and young people aged 3 to 17 years, but were small and of poor quality. There was a statistically significant reduction in migraine frequency with flunarizine compared with placebo in the 2 RCTs that compared flunarizine with placebo. In the 4 RCTs that compared flunarizine with an active comparator (propranolol, aspirin, nimodipine or dihydroergotamine), there was no statistically significant difference between flunarizine and the other treatments for reduction in migraine frequency.

  • The Irish summary of product characteristics for flunarizine dihydrochloride 5 mg tablets (Sibelium; Janssen-Cilag) states that flunarizine is contraindicated in people with a current depressive illness or with a history of recurrent depression and in people with pre-existing symptoms of Parkinson's disease or other extrapyramidal disorders. Weight gain is reported as a very common (1 in 10 or more) adverse effect; common (1 in 100 or more to less than 1 in 10) adverse effects include rhinitis, increased appetite, depression, insomnia, somnolence, constipation, stomach discomfort, nausea, myalgia, menstruation irregularities, breast pain and fatigue.

Full text of Evidence review.

Context and estimated impact for the NHS

No estimate of the current use of flunarizine for migraine was identified. No price is listed for flunarizine and the cost will differ depending on the source. NHS prescription cost analysis for England 2013 reported that flunarizine hydrochloride 5 mg capsules cost £115.42 per item (with the average quantity per item of 68.92), and that in 2013, 700 items of flunarizine hydrochloride 5 mg capsules were dispensed at a net cost of £77,600. It is not known for which indications these items were prescribed.

Full text of Context and estimated impact for the NHS.

Information for the public

A plain English summary is available on the NICE website. This sets out the main points from the evidence summary in non-technical language and may be especially helpful for people with migraine who are thinking about trying flunarizine.

About this evidence summary

'Evidence summaries: unlicensed or off-label medicines' summarise the published evidence for selected unlicensed or off-label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision-making and support the construction and updating of local formularies.

The summaries support decision-making on the use of an unlicensed or off-label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual.

The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance.