Flunarin Tablet – Medical Manual

FLUNARIN TABLET
MEDICAL MANUAL
 Flunarin Tablet – Medical Manual

TABLE OF CONTENTS

MIGRAINE..................................................................................................................................... 2

ROLE OF CALCIUM IONS IN MIGRAINE HEADACHES ....................................................... 5

ROLE OF CALCIUM CHANNEL BLOCKERS IN PROPHYLAXIS OF MIGRAINE

HEADACHES ................................................................................................................................ 6

FLUNARIN TABLETS .................................................................................................................. 7

CLINICAL EFFICACY OF FLUNARIZINE IN PROPHYLAXIS OF MIGRAINE

HEADACHES .............................................................................................................................. 10

UNIQUE SELLING POINTS....................................................................................................... 13

REFERENCES ............................................................................................................................. 14

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MIGRAINE
What is migraine?1
Migraine is a complex disorder characterized by recurrent episodes of headache, most
often unilateral.

Signs and symptoms1

Typical symptoms of migraine include the following:
 Throbbing or pulsatile headache, with moderate to severe pain that intensifies with
movement or physical activity
 Unilateral and localized pain in the frontotemporal and ocular area, but the pain
may be felt anywhere around the head or neck
 Pain builds up over a period of 1-2 hours, progressing posteriorly and becoming
diffuse
 Headache lasts 4-72 hours
 Nausea (80%) and vomiting (50%), including anorexia and food intolerance, and
light-headedness
 Sensitivity to light and sound
 Preceded by aura that lasts a few minutes

Aura1
The migraine aura is a complex of neurologic symptoms that may precede or accompany
the headache phase or may occur in isolation. It usually develops over 5-20 minutes and
lasts less than 60 minutes. The aura can be visual, sensory, or motor or any combination of
these.

The most common visual phenomenon is the scintillating scotoma, an arc or band of absent
vision with a shimmering or glittering zigzag border.

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Figure: Examples of visual changes during migraine

Classification of migraine1
 Migraine without aura (common migraine)
 Migraine with aura (classic migraine)

Migraine triggers1
A history of migraine triggers may be elicited. Common triggers include the following:
 Hormonal changes (eg, those resulting from menstruation, ovulation, oral
contraceptives, or hormone replacement)
 Head trauma
 Lack of exercise
 Sleep changes
 Medications (eg, nitroglycerin, histamine, reserpine, hydralazine, ranitidine,
estrogen)
 Stress

Etiology1
 Unknown
 Migraine has a strong genetic component. Approximately 70% of migraine patients
have a first-degree relative with a history of migraine.

Incidence1
 The worldwide prevalence of migraine is 10%.
 Females > males
 Onset often in adolescence / young adulthood
 Onset of migraine after age 50 years is rare.

Pathophysiology1

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The mechanisms of migraine remain incompletely understood. Following two theories

explain the pathophysiology of migraine.

1. Vascular theory:
According to this theory, migraine results from intracranial vasoconstriction followed by
rebound vasodilation.

2. Neurovascular theory
This theory describes migraine as primarily a neurogenic process with secondary changes
in cerebral perfusion associated with a sterile neurogenic inflammation

Treatment options1
Pharmacologic agents used for the treatment of migraine can be classified as abortive (ie,
for alleviating the acute phase) or prophylactic (i.e, preventive).

Abortive medications include the following:

 Selective serotonin receptor (5-HT1) agonists (triptans): e.g. sumatriptan
 Ergot alkaloids: e.g. ergotamine tartrate, dihydroergotamine (DHE)
 Analgesics: e.g. paracetamol
 Nonsteroidal anti-inflammatory drugs (NSAIDs): e.g. ibuprofen, naproxen
 Combination products: e.g. paracetamol plus codeine
 Antiemetics: e.g. droperidol, prochlorperazine
 Antihistamines: e.g. promethazine

Prophylactic medications include the following:

 Antiepileptic drugs: e.g. valproic acid, topiramate
 Beta blockers: e.g. propranolol
 Tricyclic antidepressants: e.g. amitriptyline, nortryptyline, doxepin
 Calcium channel blockers: e.g. flunarizine, verapamil
 Selective serotonin reuptake inhibitors (SSRIs): e.g. paroxetine, fluoxetine,
sertraline
 NSAIDs: e.g. ibuprofen, naproxen
 Botulinum toxin

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ROLE OF CALCIUM IONS IN MIGRAINE HEADACHES

Calcium ions preside over numerous cells, including nerve cell, functions. For executing
these functions the ions are mobilized either from intracellular pools or enter from the
exterior. Calcium enters cells via "slow" or "fast" channels.

The mechanism by which calcium ions produce migraine headaches is shown below.

Calcium ion entry in cerebral vascular smooth muscles through

calcium channels

Leads to cerebral vasoconstriction

Leads to rebound cerebral vasodilation

Pain

Migraine headaches

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ROLE OF CALCIUM CHANNEL BLOCKERS IN PROPHYLAXIS OF

MIGRAINE HEADACHES

Calcium antagonists are in fact a heterogeneous group of compounds and as noted above
are employed in numerous clinical conditions.

These drugs block the entry of calcium ions in cells by blocking the calcium channels.
Therefore, there will be a low level of intracellular calcium available for action.

The mechanism by which calcium channel blockers prevent migraine headaches is shown
below.

Calcium channel blockers blocks the entry of calcium ions in cerebral

vascular smooth muscles through calcium channels

Stops cerebral vasoconstriction

Prevent rebound cerebral vasodilation

Prevent pain

Prevent migraine headaches

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FLUNARIN TABLETS

Composition of Flunarin
Flunarin 5 mg:
Each uncoated tablet contains
Flunarizine.......................5 mg
(As Flunarizine Dihydrochloride)

Flunarin 10 mg:
Each uncoated tablet contains
Flunarizine.......................10 mg
(As Flunarizine Dihydrochloride)

What is Flunarizine?2
 Flunarizine is a calcium antagonist.
 It distributes preferentially in the adipose tissue and passes the blood brain barrier.
 Numerous controlled clinical studies have established that flunarizine is efficacious
in migraine prophylaxis, including double-blind studies in which the drug was
compared with placebo or other antimigraine drugs.

Indications:3
Migraine prophylaxis

Dosage:3
Adults
 Initial dose, 10 milligrams once daily in the evening (at bedtime).
 Usual dose, 5 to 10 milligrams once daily.
 Lower doses are recommended for patients intolerant of 10-mg doses.

Children
 Initial dose, 5 milligrams once daily (children weighing less than 40 kilograms)
 Usual dose, 5 to 10 milligrams once daily
 Safety and efficacy in children under 18-years-old not established

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Mechanism of action

Flunarizine when taken for the prophylaxis of migraine headache

Flunarizine blocks the entry of calcium ions in cerebral vascular

smooth muscles through calcium channels

Stops cerebral vasoconstriction

Prevent rebound cerebral vasodilation

Prevent pain

Prevent migraine headaches

Pharmacokinetics4
Bioavailability: > 95%
Cmax: 50-100 mcg/L
Tmax: 2-4 hours
Protein-binding: 90%
Half-life: approx 18 days
Elimination: Almost entirely by hepatic biotransformation, with less than 0.01% excreted
unchanged in the urine over 24 h and less than 5% unchanged in feces.

Contraindications4
The preparation is contraindicated in patients with hypersensitivity to Flunarizine or
Cinnarizine, depressive illness, Parkinson’s disease and extrapyramidal disorders, hepatic
insufficiency.

Precautions & Warning4

Treatment with Flunarizine may give rise to extrapyramidal and depressive symptoms and
reveal Parkinsonism, especially in predisposed patients such as the elderly. Therefore, it

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should be used with caution. Since Flunarizine is primarily metabolized in the liver, dosage
adjustments are required in hepatic insufficiency.

Hypnotics and tranquilizers – Excessive sedation can occur when alcohol, hypnotics or
tranquilizers are taken simultaneously with Flunarizine.

Adverse effects4
The most commonly observed adverse reactions of Flunarizine have been drowsiness,
which occurred in 7% of patients, headache, insomnia, asthenia, and depression.
Heartburn, nausea, drug mouth and gastralgia occur in less than 1% of patients treated
with Flunarizine and isolated cases of constipation and diarrhea have also been reported.
Weight gain (11%) has been reported during Flunarizine therapy (2-3 kg), particularly in
migrainous patients.

Drug interactions4
Excessive sedation can occur when alcohol, hypnotics or tranquilizers are taken
simultaneously with Flunarizine.

With adenosine prolonged bradycardia may occurs, and calcium channel blocking agents
may enhance the neuromuscular blockade induced by non-depolarizing agents such as
tubocurarine, but Flunarizine is not contraindicated in patients who use beta blocking
agents

Pregnancy and Lactation5

Use during pregnancy
There are no data from the use of flunarizine in pregnant women. Animal studies do not
indicate direct or indirect harmful effects with respect to pregnancy, embryonal/ foetal
development, parturition or postnatal development. As a precautionary measure, it is
preferable to avoid the use of flunarizine during pregnancy.

Use during lactation

It is unknown whether flunarizine is excreted in human milk. Animal studies have shown
excretion of flunarizine in breast milk. A decision on whether to discontinue breast-feeding
or to continue/discontinue therapy with flunarizine should be made taking into account
the benefit of breast-feeding to the child and the benefit of therapy to the woman.

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CLINICAL EFFICACY OF FLUNARIZINE IN PROPHYLAXIS OF

MIGRAINE HEADACHES

1. Reduction in migraine attack frequency6

The occurrence of attacks steadily declined as the flunarizine treatment progressed. A
reduction in attack frequency was observed in 61.9% of the patients after 1 month, in
74.8% after 2 months and in 83.2% after 3 months.

% of patients with reduction in migraine

attack frequency
90.0% 83.2%
80.0% 74.8%
70.0% 61.9%
% of patients

60.0%
50.0%
40.0%
30.0%
20.0%
10.0%
0.0%
1 Month 2 Month 3 Month

2. Reduction in attack frequency as related to duration of disease.6

The decrease in attack frequency during the 3-month treatment was inversely correlated to
the duration of disease. When the patients were grouped in 2 strata (< 20 years and 20
years), a significant difference in response was evident; in particular, patients with a
shorter history stood out by an earlier response.

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70% % reduction in monthly number of attacks as related to

61% duration of disease
60%
% Reduction in attack frequency

51%
50% 46%

40% 38%
Month 1
Month 2
30% 27%
Month 3

20%

10%
3%
0%
< 20 yrs migraine history 20 yrs and above migraine history

3. Reduction in attack frequency as related to the age6

The reduction in attacks tended to be significantly correlated with the age. Younger
patients had more reduction in attack frequency than older patients after 3 months of
treatment with flunarizine.

% reduction in monthly number

of attacks as related to age
60% 55%
52% 51%
50%
41%
40% 37% 38%
33%
30% 27%

20%

10%

0%
13-19 yrs 20-24 yrs 25-29 yrs 30-34 yrs 35-39 yrs 40-44 yrs 45-49 yrs 50-65 yrs

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4. Comparison with propranolol7

4a. Flunarizine provides better clinical response than propranolol in prophylaxis of
migraine. In a comparative clinical trial, the positive clinical response was observed in
67% of flunarizine-treated patients as compared to 51% of the propranolol-treated
patients.7

% of patients with positive clinical response

Flunarizine vs Propranolol
80%
% of patients with positive

70% 67%

60%
clinical response

51%
50%
40%
30%
20%
10%
0%
Flunarizine 10 mg daily for 4 months Propranolol 80 mg twice daily for 4
months

4b. Safety profile7

In a clinical trial, propranolol significantly reduced blood pressure and heart rate;
flunarizine had no effect on cardiovascular function. Therefore, flunarizine has a better
safety profile.

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UNIQUE SELLING POINTS

1. Flunarizine dosed at 10 mg/day is an effective prophylactic therapy for both classical

and common migraine. A practical advantage is that it can be given in a single daily
dose.8
2. Its onset of action is gradual over the first 3 months of treatment.8
3. During prolonged treatment its efficacy is fully maintained.8
4. Flunarizine is a truly prophylactic drug: it prevents the attacks from occurring. Reduced
severity of the attacks has also been observed in some studies.8
5. Flunarizine provides better clinical response than propranolol in prophylaxis of
migraine.7
6. Flunarizine has a better safety profile than propranolol.7

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REFERENCES

1. http://emedicine.medscape.com/article/1142556-overview#aw2aab6b2b1aa
2. Massimo Leone, Licia Grazzi, Loredana La Mantia and Gennaro Bussone. Flunarizine
in Migraine: A Minireview. Headache 31:388-391, 1991.
3. Micromedex 2009 monograph on Flunarizine.
4. Therapeutic Drugs, 2nd Edn., Colin Dollery, Churchill Livingstone, Vol. 1 Pg. F83-88.
5. http://www.medicines.ie/medicine/14498/SPC/Sibelium+5+mg+tablets/#PREGN
ANCY
6. W.K. Amery, L.I. Caers and T.J.L. Aerts. Flunarizine, a Calcium Entry Blocker in
Migraine Prophylaxis. Headache 25:249-254, 1985.
7. Gawel MJ, Kreeft J, Nelson RF, Simard D, Arnott WS. Comparison of the efficacy and
safety of flunarizine to propranolol in the prophylaxis of migraine. Can J Neurol Sci.
1992 Aug;19(3):340-5.
8. W.K. Amery. Flunarizine, a Calcium Channel Blocker: a New Prophylactic Drug in
Migraine. Headache 23:70-74, 1983.

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