Flunarizine

Clinical data
Trade names	Sibelium, others
Other names	1-[bis(4-fluorophenyl)methyl]-4-cinnamyl-piperazine
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Pregnancy category	C
Routes of administration	By mouth
ATC code	N07CA03 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding	>99%
Metabolism	MainlyCYP2D6
Metabolites	≥15
Eliminationhalf-life	5–15 hrs (single dose) 18–19 days (multiple doses)
Excretion	Feces, <1% urine
Identifiers
IUPAC name 1-[bis(4-fluorophenyl)methyl]-4-[(2E)-3-phenylprop-2-en-1-yl]piperazine
CAS Number	52468-60-7 Y
PubChemCID	941361
DrugBank	DB04841 Y
ChemSpider	819216 Y
UNII	R7PLA2DM0J
KEGG	D07971 Y
ChEMBL	ChEMBL30008 Y
CompTox Dashboard(EPA)	DTXSID6045616
ECHA InfoCard	100.052.652
Chemical and physical data
Formula	C26H26F2N2
Molar mass	404.505 g·mol−1
3D model (JSmol)	Interactive image
Melting point	251.5 °C (484.7 °F) (dihydrochloride)
SMILES Fc1ccc(cc1)C(c2ccc(F)cc2)N3CCN(CC3)C\C=C\c4ccccc4
InChI InChI=1S/C26H26F2N2/c27-24-12-8-22(9-13-24)26(23-10-14-25(28)15-11-23)30-19-17-29(18-20-30)16-4-7-21-5-2-1-3-6-21/h1-15,26H,16-20H2/b7-4+ Y Key:SMANXXCATUTDDT-QPJJXVBHSA-N Y
(verify)

Flunarizine, sold under the brand nameSibelium among others, is a drug classified as acalcium antagonist which is used for various indications.^[1] It is not available by prescription in theUnited States orJapan. The drug was discovered atJanssen Pharmaceutica (R14950) in 1968.

Flunarizine is effective in the prophylaxis ofmigraine,^[2] occlusiveperipheral vascular disease,vertigo of central and peripheral origin,^[3] and as an add-on in the treatment ofepilepsy where its effect is weak and not recommended.^[4] It has been shown to significantly reduce headache frequency and severity in both adults and children.

Flunarizine iscontraindicated in patients with depression, in the acute phase of astroke, and in patients withextrapyramidal symptoms orParkinson's disease.^[5] It is also contraindicated inhypotension, heart failure andarrhythmia.^{[citation needed]}

Common side effects include drowsiness (20% of patients), weight gain (10%), as well as extrapyramidal effects anddepression in elderly patients.^[3]

The effects of othersedating drugs and alcohol, as well asantihypertensives, can be increased. No relevantpharmacokinetic interactions have been described.^[3][5]

Flunarizine is a selective calcium antagonist with moderate other actions includingantihistamine,serotonin receptor blocking anddopamine D₂ blocking activity. Compared to other calcium channel blockers such asdihydropyridine derivatives,verapamil anddiltiazem, flunarizine has low affinity tovoltage-dependent calcium channels. It has been theorised that it may act not by inhibiting calcium entry into cells, but rather by anintracellular mechanism such as antagonisingcalmodulin, a calcium binding protein.^[3]

Flunarizine is well absorbed (>80%) from the gut and reaches maximalblood plasma concentrations after two to four hours, with more than 99% of the substance bound toplasma proteins. It readily passes theblood–brain barrier. When given daily, asteady state is reached after five to eight weeks. Concentrations in the brain are about ten times higher than in the plasma.^[3][5]

It is metabolised in the liver, mainly by the enzymeCYP2D6. At least 15 different metabolites are described, including (in animals)N-desalkyl andhydroxy derivatives andglucuronides. Less than 1% is excreted in unchanged form, and the main excretion path is viabile and faeces.Elimination half life varies widely between individuals and is about 5 to 15 hours after a single dose, and 18 to 19 days on average when given daily.^[3][5]

Flunarizine is adiphenylmethylpiperazinederivative related to the antihistamineshydroxyzine andcinnarizine (an older molecule also discovered by Janssen).

Flunarizine may help to reduce the severity and duration of attacks of paralysis associated with the more serious form ofalternating hemiplegia, as well as being effective in rapid onset dystonia-parkinsonism (RDP). Both these conditions arise from specific mutations in the ATP1A3 gene.^[6][7]

Flunarizine extendedmotor neuron survival inspinal cord, protectedskeletal muscles fromcell death andatrophy and extended survival by 40% in an animal model ofspinal muscular atrophy.^[8] Flunarizine has also shown promise as an anti-prion medication.^{[citation needed]}

• Therapeutic Choices, sixth edition,Canadian Pharmacists Association, 2011.

• Belgian inventions
• Calcium channel blockers
• D2 antagonists
• Bis(4-fluorophenyl)methanes
• H1 receptor antagonists
• Janssen Pharmaceutica
• Piperazines
• Serotonin receptor antagonists
• Depressogens

• CS1 German-language sources (de)
• Articles with short description
• Short description is different from Wikidata
• Drugs with non-standard legal status
• ECHA InfoCard ID from Wikidata
• Drugboxes which contain changes to watched fields
• All articles with unsourced statements
• Articles with unsourced statements from May 2016
• Articles with unsourced statements from July 2023