Posted by don (152.163.207.211) on January 26, 2002 at 11:57:04:
In Reply to: Sibelium(Flunarazine) posted by Brian Kennedy on January 26, 2002 at 00:48:53:
Sibelium* CAPSULES
Selective Calcium-Entry Blocker
ACTION AND CLINICAL PHARMACOLOGY
SIBELIUM* (flunarizine hydrochloride) prevents the deleterious effects of cellular calcium overload by reducing excessive transmembrane fluxes of calcium. Flunarizine does not interfere with normal cellular calcium homeostasis. Flunarizine also has antihistaminic properties.
The effects of flunarizine in the prophylaxis of migraine are most pronounced with regards to the reduction of the frequency of attacks. The severity of migraine attacks improves to a lesser extent, while little or no effect is seen on the duration of migraine episodes. The pharmacokinetic parameters of orally administered flunarizine are summarized in Table 1.
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Table 1: Pharmacokinetic parameters of flunarizine in healthy volunteers
No. of
Doses Dose
(mg) Cmax
(ng/mL) Tmax
(h) AUC
(ng/mL o h) t1/2”
(h) Clp
(mL/min) t1/2b
(mean days)
[range]
Single
Dose
Studies 5
10
20
30 30.5
81.5
117.0
81.6
2-4
2-6
133a
615d
1091d
1169c 2.4
2.8
3.6
5.5 443.7 4
[2-8]
Multiple
Dose
Studies 14
14
14
57 5
10
15
10 18.1b
38.8b
68.4b
114.5 1264d
1678d 301.2 [4-19]
19
a Area under curve 0 to 8 hours
b Plasma concentrations at 2 hours
c Area under curve 0 to 168 hours
d Area under curve 0 to 24 hours
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Flunarizine is well absorbed; peak plasma levels are attained 2 to 4 hours after oral administration in healthy volunteers. Plasma concentrations increase gradually during chronic administration of 10 mg daily, reaching a steady state level after 5 to 6 weeks of drug administration. Steady state plasma levels remain constant during prolonged treatment although there is substantial interindividual variation; plasma levels range between 39 and 115 ng/mL.
In 50 elderly patients (mean age 61 years), with intermittent claudication, long term (median 6 months) treatment with flunarizine, 10 mg per day, yielded fairly constant steady-state plasma levels albeit with considerable interindividual differences. While plasma flunarizine levels were between 50 ng/mL and 100 ng/mL in 46% of patients, individual values ranged from less than 20 ng/mL to 580 ng/mL. Flunarizine was devoid of cumulative effects as shown by repeated measure-ments.
As indicated by the large apparent volume of distribu-tion (mean=43.2 L/kg; range=26.7-79.9 L/kg) seen after the oral administration of 30 mg in healthy volunteers, flunarizine is extensively distributed to tissues. Drug concentrations in tissues, particularly adipose tissue and skeletal muscle, were several times higher than plasma levels.
Flunarizine is 99.1 % bound; 90% is bound to plasma proteins and 9% distributed to blood cells, leaving less than 1% present as free drug in the plasma water. Flunarizine is metabolized principally through N-oxida-tion and aromatic hydroxylation. During a 48 hour period after a single 30 mg dose, minimal urinary (<0.2%) and fecal (<6%) excretion of flunarizine and/or its metabolites was found. This indicates that the drug and its metabolites are excreted very slowly over a prolonged period of time. Flunarizine has a long elimination half-life of about 19 days.
INDICATIONS AND CLINICAL USE
SIBELIUM (flunarizine hydrochloride) is indicated in the prophylaxis of migraine with and without aura. The safety of flunarizine in long-term use (i.e., for more than 4 months) has not been systematically evaluated in controlled clinical trials. Flunarizine is not indicated in the treatment of acute migraine attacks.
CONTRAINDICATIONS
SIBELIUM (flunarizine hydrochloride) is contra-indicated in patients with known hypersensitivity to the drug.
Flunarizine is contraindicated in patients with a history of depression or pre-existing extrapyramidal disorders.
WARNINGS
Clinical studies indicate that flunarizine treatment, even at recommended doses, can produce motor disturbances in subjects who did not show previous neurological deficits. The clinical symptoms resemble Parkinson's disease, however, they do not improve with antiparkinson medication. Experience to date suggests that in most instances the extrapyramidal symptoms tend to be reversible following discontinua-tion of flunarizine treatment. It is recommended that patients on flunarizine therapy be followed closely and monitored at regular intervals so that extrapyramidal symptoms may be detected early, and if necessary, treatment discontinued.
Clinical studies indicate that flunarizine can, even at recommended doses, precipitate depression, mostly in younger patients.
PRECAUTIONS
Since sedation and/or drowsiness occur in some patients during treatment with SIBELIUM (flunarizine hydrochloride) (see ADVERSE REACTIONS), patients should be cautioned against activities which require alertness or rapid, precise responses (e.g. operating machinery or a motor vehicle) until the response to the drug has been determined.
Use in Pregnancy
To date, there are no data to support the use of flunarizine during pregnancy. It should therefore not be administered to pregnant women unless the anti-cipated benefits outweigh the potential risks.
Use During Lactation
Studies in lactating dogs have shown that flunarizine is excreted in milk. The concentration of flunarizine in milk is much greater than that in plasma. Breast feeding should therefore be discouraged in women taking flunarizine.
Use in the Elderly
The efficacy of flunarizine in the prophylaxis of migraine has not been established in elderly subjects.
Endocrine Effects
Galactorrhea has been reported in a few female patients, some of whom were also on oral contraceptives, within the first two months of flunarizine treatment. Discontinuation of flunarizine therapy resolved the galactorrhea in most cases. Flunarizine therapy caused a mild but significant elevation of serum prolactin levels while GH, LH, FSH and TSH levels did not show significant variation. Two cases of menstrual irregularities have been reported.
Drug Interactions
Evidence from therapeutic trials in epileptic patients indicates that whereas flunarizine does not affect the kinetics of phenytoin, carbamazepine and valproic acid, it does decrease the plasma levels of mephenytoin. Furthermore, steady state levels of flunarizine are reduced by coadministration of two or more anticonvulsants. This is considered to be a result of enhanced first pass metabolism of flunarizine as a consequence of liver enzyme induction by the anticonvulsant medications.
In other studies, flunarizine was shown not to affect the anticoagulant effect of warfarin sodium or the hypoglycemic effect of glibenclamide and insulin.
Excessive sedation can occur when alcohol, hypnotics or tranquilizers are taken simultaneously with SIBELIUM capsules.
Use in Patients with Impaired Hepatic Function
Flunarizine is metabolised by the liver, therefore care should be exercised when flunarizine is given to patients with compromised liver function.
ADVERSE REACTIONS
In clinical trials with SIBELIUM (flunarizine hydro-chloride) in migraine patients, drowsiness (also described as sedation or fatigue) as well as weight gain (and/or increased appetite) occurred fairly frequently, in the order of 20 and 15%, respectively. Of 840 migraine patients, 23 (2.7%) and 9 (1.1 %) required withdrawal from flunarizine therapy due to drowsiness and weight gain, respectively.
The most serious side effect encountered in migraineurs during clinical trials was depression. Of 840 migraine patients, 11 (1.3%) were withdrawn due to depression. International post-marketing experience suggests that patients between 20 and 54 years of age with a personal or familial history of depression are particularly at risk (see CONTRAINDICATIONS and WARNINGS).
Clinical experience in other indications and epidemiologic surveys suggest that extrapyramidal symptoms may develop during flunarizine therapy. Elderly patients are particularly at risk (see CONTRAINDICATIONS and WARNINGS).
Other side effects encountered in clinical trials for migraine prophylaxis included the following:
Gastrointestinal: Heartburn, nausea, emesis, gastral-gia;
Central Nervous System: Insomnia and sleep change, anxiety, dizziness/vertigo;
Miscellaneous: Dry mouth, asthenia, muscle aches, skin rash
SYMPTOMS AND TREATMENT OF OVERDOSE
On the basis of the pharmacological properties of the drug, sedation and asthenia may be expected to occur. A few cases of acute overdosage (up to 600 mg in one intake) have been reported and the observed symp-toms included central nervous system effects (e.g. sedation, confusion and agitation) and cardiovascular effects (e.g. tachycardia). Treatment of acute over-dosage consists of charcoal administration, induction of emesis or gastric lavage, and supportive measures. No specific antidote is known.
DOSAGE AND ADMINISTRATION
The usual adult dosage of SIBELIUM (flunarizine hydrochloride) is 10 mg per day administered in the evening. Patients who experience side effects may be maintained on 5 mg HS.
Duration of Therapy
Clinical experience indicates that the onset of effect of flunarizine is gradual and maximum benefits may not be seen before the patient has completed several weeks of continuous treatment. Therapy therefore should not be discontinued for lack of response before an adequate time period has elapsed, e g. 6-8 weeks.
PHARMACEUTICAL INFORMATION
Drug Substance
Trade Name: SIBELIUM capsules
Proper Name: flunarizine hydrochloride
Chemical Name: (E)-1-[bis(4-fluorophenyl)-Methyl]-4-(3-phenyl-2-propenyl) piperazine dihydrochloride.
Chemical Structure: F-()-CH - N()N - CH2 -CH = CH -()
F (E).2HCl
Molecular Formula: C26H26F2N2-2HCI
Molecular Weight: 477.41
Description: Flunarizine is a white to pale cream coloured powder soluble in dimethylsulfoxide, PEG 400, propylene glycol, N,N-dimethyl formamide or methanol. Flunarizine is poorly soluble in water or ethanol (0.1-1%).
Composition: Each red and grey capsule contains 5 mg flunarizine (as hydrochloride).
Stability and Storage Recommendations: SIBELIUM capsules 5 mg should be stored at room temperature (15-30ĄC), protected from light and moisture.