Flunarizine Hydrochloride

Flunarizine Hydrochloride

Drug Nomenclature

Date of monograph revision: 10-Dec-1997; 19-May-1998; 12-Aug-1999; 14-Nov-2001; 08-Apr-2004; 27-Jun-2006; 27-Jun-2006
Synonyms: Flunaritsiinidihydrokloridi; Flunarizin-dihydrochlorid; Flunarizina, hidrocloruro de; Flunarizindihydroklorid; Flunarizini Dihydrochloridum; Flunarizino dihidrochloridas; R-14950
BAN: Flunarizine Hydrochloride [BANM]
USAN: Flunarizine Hydrochloride
INN: Flunarizine Hydrochloride [rINNM (en)]
INN: Hidrocloruro de flunarizina [rINNM (es)]
INN: Flunarizine, Chlorhydrate de [rINNM (fr)]
INN: Flunarizini Hydrochloridum [rINNM (la)]
INN: Флунаризина Гидрохлорид [rINNM (ru)]
Chemical name: trans-1-Cinnamyl-4-(4,4´-difluorobenzhydryl)piperazine dihydrochloride
Molecular formula: C26H26F2N2,2HCl =477.4
CAS: 52468-60-7 (flunarizine); 30484-77-6 (flunarizine hydrochloride)
ATC code: N07CA03
Chemical Structure of Flunarizine

Chemical Structure of Flunarizine

Pharmacopoeias:

In Chin. and Eur. (see Go to European Pharmacopoeia Convention Signatories).

Ph. Eur. 5.5 (Flunarizine Dihydrochloride). A white or almost white hygroscopic powder. Slightly soluble in water, in alcohol, and in dichloromethane; sparingly soluble in methyl alcohol. Store in airtight containers. Protect from light.

Adverse Effects and Precautions

As for the sedating antihistamines in general, Go to Adverse Effects of Antihistamines. Adverse effects also seen with flunarizine include weight gain, extrapyramidal symptoms (sometimes associated with depression), and, rarely, galactorrhoea.

Extrapyramidal disorders.

Extrapyramidal motor signs (including parkinsonism, orofacial tardive dyskinesia, and akathisia) have been reported in 12 patients given flunarizine 10 to 40 mg daily for between 3 weeks and 15 months; 11 also had mental depression.1 Partial or complete improvement of symptoms occurred after withdrawal of flunarizine. There have been other reports of similar effects,2-5 but the association with flunarizine has not always been certain. Some workers have commented that flunarizine is often used in patients at increased risk of depression (migraine and geriatric patients) or extrapyramidal symptoms (geriatric patients)2,6 or that flunarizine may unmask subclinical idiopathic Parkinson's disease.6,7

Extrapyramidal signs, including parkinsonism, have also been associated with the related drug, cinnarizine.3-5 It has been suggested that such effects may be less likely to occur with cinnarizine than with flunarizine because of its shorter half-life and lower lipophilicity.3

  1. 1. Chouza C, et al. Parkinsonism, tardive dyskinesia, akathisia, and depression induced by flunarizine. Lancet 1986; i: 1303–4. PubMed
  2. 2. Meyboom RHB, et al. Parkinsonism, tardive dyskinesia, akathisia, and depression induced by flunarizine. Lancet 1986; ii: 292. PubMed
  3. 3. Laporte J-R, Capella D. Useless drugs are not placebos: lessons from flunarizine and cinnarizine. Lancet 1986; ii: 853–4. PubMed
  4. 4. Laporte J-R, Capella D. Useless drugs are not placebos. Lancet 1987; i: 1324. PubMed
  5. 5. Teive HAG, et al. Flunarizine and cinnarizine-induced parkinsonism: a historical and clinical analysis. Parkinsonism Relat Disord 2004; 10: 243–5. PubMed
  6. 6. Amery W. Side-effects of flunarizine. Lancet 1986; i: 1497. PubMed
  7. 7. Benvenuti F, et al. Side-effects of flunarizine. Lancet 1986; ii: 464.

Porphyria.

Flunarizine hydrochloride is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in in-vitro systems.

Interactions

As for the sedating antihistamines in general, Go to Interactions of Antihistamines.

Hepatic enzyme inducers such as carbamazepine, phenytoin, and valproate may interact with flunarizine by increasing its metabolism; an increase in dosage of flunarizine may be required.

Pharmacokinetics

Flunarizine hydrochloride is well absorbed from the gastrointestinal tract, peak plasma concentrations occurring 2 to 4 hours after oral doses. Flunarizine hydrochloride is very lipophilic and is more than 90% bound to plasma proteins. It appears to undergo extensive metabolism; metabolites are excreted principally in the bile. Flunarizine hydrochloride has an elimination half-life of about 18 days.

Uses and Administration

Flunarizine is the difluorinated derivative of cinnarizine. It has antihistamine, sedative, and calcium-channel blocking activity. Flunarizine hydrochloride is used for migraine prophylaxis, for vertigo and vestibular disorders, and for peripheral and cerebral vascular disorders. It has also been used as adjunctive antiepileptic therapy in patients refractory to standard regimens.

Flunarizine is given orally as the hydrochloride although doses are expressed in terms of the base. Flunarizine hydrochloride 11.8 mg is equivalent to about 10 mg of flunarizine. The usual dose is 5 to 10 mg daily, usually given at night to minimise the effects of drowsiness.

Epilepsy.

A number of drugs with calcium-channel blocking activity have been investigated as adjuncts in epilepsy (Go to Epilepsy), including flunarizine. Some individual studies have reported benefit, but a systematic review1 concluded that although flunarizine might have a weak effect on seizure frequency the evidence was not convincing, and the withdrawal rate was significant, probably because of poor tolerability; it should therefore not be recommended as adjunctive antiepileptic therapy. The pharmacokinetic profile of flunarizine may in any case be too complex for clinical use as an antiepileptic.2

  1. 1. Chaisewikul R, et al. Calcium antagonists as an add-on therapy for drug-resistant epilepsy. Available in The Cochrane Database of Systematic Reviews; Issue 4. Chichester: John Wiley; 2001 (accessed 13/06/05). PubMed
  2. 2. Hoppu K, et al. Flunarizine of limited value in children with intractable epilepsy. Pediatr Neurol 1995; 13: 143–7. PubMed

Migraine.

Flunarizine reduces the frequency of migraine attacks in both adult and paediatric patients and is used for the prophylaxis of migraine (Go to Migraine) in some countries. Its effects are comparable with several other prophylactic antimigraine drugs, including the generally preferred propranolol,1-4 but it is more likely to be reserved for use when first-line drugs have proved to be ineffective or unsuitable. Its mode of action in migraine is unclear; possible mechanisms are inhibition of vasospasm induced by mediators such as serotonin and prostaglandins, inhibition of cellular hypoxia, and improved blood viscosity and erythrocyte deformability. Calcium-channel blocking activity might have a role, but evidence for the efficacy of other calcium-channel blockers in migraine prophylaxis (see Nifedipine, Go to Migraine and cluster headache.) is less convincing than for flunarizine.

Case reports have indicated benefit with flunarizine in the prophylaxis of the rare disorder of alternating hemiplegia in childhood5,6 but a subsequent study7 in 12 children did not produce conclusive findings. A later long-term study8 reported that 7 of 9 children given flunarizine for up to 5 years for hemiplegia showed a reduction in the duration of attacks, and 3 had a reduction in frequency, but only 1 of these obtained a complete cessation of episodes.

The role of antihistamines in general in the management of migraine is discussed briefly on Go to Migraine.

  1. 1. Todd PA, Benfield P. Flunarizine: a reappraisal of its pharmacological properties and therapeutic use in neurological disorders. Drugs 1989; 38: 481–99. PubMed
  2. 2. Andersson K-E, Vinge E. β-Adrenoceptor blockers and calcium antagonists in the prophylaxis and treatment of migraine. Drugs 1990; 3: 355–73. PubMed
  3. 3. Soelberg Sørensen P, et al. Flunarizine versus metoprolol in migraine prophylaxis: a double-blind, randomized parallel group study of efficacy and tolerability. Headache 1991; 31: 650–7. PubMed
  4. 4. Gawel MJ, et al. Comparison of the efficacy and safety of flunarizine to propranolol in the prophylaxis of migraine. Can J Neurol Sci 1992; 19: 340–5. PubMed
  5. 5. Casaer P, Azou M. Flunarizine in alternating hemiplegia in childhood. Lancet 1984; ii: 579. PubMed
  6. 6. Curatolo P, Cusmai R. Drugs for alternating hemiplegic migraine. Lancet 1984; ii: 980. PubMed
  7. 7. Casaer P. Flunarizine in alternating hemiplegia in childhood. An international study in 12 children. Neuropediatrics 1987; 18: 191–5. PubMed
  8. 8. Silver K, Andermann F. Alternating hemiplegia of childhood: a study of 10 patients and results of flunarizine treatment. Neurology 1993; 43: 36–41. PubMed

Tourette's syndrome.

A small unblinded study1 involving 7 patients has suggested that flunarizine is more effective than placebo in the treatment of Tourette's syndrome (see Tics, Go to Tics.).

  1. 1. Micheli F, et al. Treatment of Tourette's syndrome with calcium antagonists. Clin Neuropharmacol 1990; 13: 77–83. PubMed

Vertigo.

Antihistamines are the mainstay of the treatment of vertigo (Go to Vertigo). However, their antimuscarinic adverse effects may prove troublesome, particularly in the elderly, and they produce central sedation. Flunarizine is devoid of antimuscarinic properties, although it may produce central sedation.

Preparations

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Bercetina; Coromert; Flufenal; Mondus; Niflucan; Sibelium; Vasculoflex¤; Austria: Amalium; Flunarium; Sibelium; Belgium: Sibelium; Brazil: Flunarin; Fluvert; Fluzix; Sibelium; Vertix; Canada: Sibelium; Chile: Flerox; Fluxus; Irrigor; Sibelium; Zentralin; Czech Republic: Sibelium; Denmark: Sibelium; France: Sibelium; Germany: Flunavert; Sibelium; Greece: Sibelium; Hong Kong: Fludan; Sibelium¤; Hungary: Sibelium; India: Migarid; Nomigrain; Ireland: Sibelium; Italy: Flugeral; Flunagen; Fluxarten; Gradient; Issium; Sibelium; Vasculene; Malaysia: Fludan; Forknow; Sibelium; Mexico: Axilin; Fasolan; Nafluryl; Sibelium; Netherlands: Sibelium; Portugal: Sibelium; Vasilium; Zinasen; South Africa: Sibelium; Singapore: Forknow¤; Narizine; Sibelium¤; Spain: Flerudin; Flurpax; Sibelium; Switzerland: Sibelium; Thailand: Cedelate; Finelium¤; Floxin; Fludan; Flulium; Flunarium; Flunaza; Flunazine; Fluricin; FNZ¤; Hexilium; Liberal; Medilium; Poli-Flunarin; Seabell¤; Sibelium; Simoyiam; Sobelin; Vertilium; Zelium; Venezuela: Fludil; Sibelium;

Multi-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Angiolit¤; CCK Flunarizina¤; Sibelium Plus; Brazil: Vertizine D;



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