Flunarizine Hydrochloride
Flunarizine dihydrochloride 11.8 mg is approximately equiv-
alent to 10 mg of Flunarizine.
Adverse Effects and Precautions as for the sedating antihistamines like promethazine whose details are given below
PROMETHAZINE
PRECAUTIONS:
Promethazine may significantly affect the actions of other drugs. It may
increase, prolong, or intensify the sedative action of central-nervous- system
depressants, such as alcohol, sedative hypnotics (including barbiturates),
general anesthetics, narcotics, narcotic analgesics, tranquilizers, etc. When
given concomitantly with promethazine hydrochloride, the dose of barbiturates
should be reduced by at least one- half, and the dose of narcotics should be
reduced by one-quarter to one-half. Dosage must be individualized. Excessive
amounts of promethazine relative to a narcotic may lead to restlessness and
motor hyperactivity in the patient with pain; these symptoms usually disappear
with adequate control of the pain. Promethazine should be used cautiously in
persons with cardiovascular disease or impairment of liver function.
Although reversal of the vasopressor effect of epinephrine has not been reported
with promethazine, the possibility should be considered in case of promethazine
overdose.
ADVERSE REACTIONS:
CNS EFFECTS
Drowsiness is the most prominent CNS effect of this drug. Extrapyramidal
reactions may occur with high doses; this is almost always responsive to a
reduction in dosage. Other reported reactions include dizziness, lassitude,
tinnitus, incoordination, fatigue, blurred vision, euphoria, diplopia,
nervousness, insomnia, tremors, convulsive seizures, oculogyric crises,
excitation, catatonic-like states, and hysteria.
CARDIOVASCULAR EFFECTS
Tachycardia, bradycardia, faintness, dizziness, and increases and decreases in
blood pressure have been reported following the use of promethazine
hydrochloride injection. Venous thrombosis at the injection site has been
reported. INTRA-ARTERIAL INJECTION MAY RESULT IN GANGRENE OF THE AFFECTED
EXTREMITY ("see WARNINGS").
GASTROINTESTINAL
Nausea and vomiting have been reported, usually in association with surgical
procedures and combination drug therapy.
ALLERGIC REACTIONS
These include urticaria, dermatitis, asthma, and photosensitivity. Angioneurotic
edema has been reported.
OTHER REPORTED REACTIONS
Leukopenia and agranulocytosis, usually when Phenergan has been used in
association with other known toxic agents, have been reported. Thrombocytopenic
purpura and jaundice of the obstructive type have been associated with the use
of promethazine. The jaundice is usually reversible on discontinuation of the
drug. Subcutaneous injection has resulted in tissue necrosis. Nasal stuffiness
may occur. Dry mouth has been reported.
LABORATORY TESTS
The following laboratory tests may be affected in patients who are receiving
therapy with promethazine hydrochloride:
Pregnancy Tests--Diagnostic pregnancy tests based on immunological reactions
between HCG and anti- HCG may result in false-negative or false- positive
interpretations.
Glucose Tolerance Test--An increase in glucose tolerance has been reported in
patients receiving promethazine hydrochloride.
PARADOXICAL REACTIONS (OVERDOSAGE)
Hyperexcitability and abnormal movements, which have been reported in children
following a single administration of promethazine, may be manifestations of
relative overdosage, in which case, consideration should be given to the
discontinuation of the promethazine and to the use of other drugs. Respiratory
depression, nightmares, delirium, and agitated behavior have also been reported
in some of these patients.
Adverse effects observed after administration of flu-
narizine also 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. Partial or complete improvement of
symptoms occurred after withdrawal of flunarizine. There
have been other reports of similar effects , but the associa-
tion with flunarizine has not always been certain. Some work-
ers have commented that flunarizine is often used in patients
at increased risk of depression (migraine and geriatric pa-
tients) or extrapyramidal symptoms (geriatric patients)~ or
that flunarizine may unmask subclinical idiopathic Parkin-
son's diseased .
Extrapyramidal signs, including parkinsonism, have also
been associated with the related drug, cinnarizine. 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.
Interactions
As for the sedating antihistamines in general,
Hepatic enzyme inducers such as carbamazepine,
phenytoin, and valproate may interact with flunar-
izine by increasing its metabolism: an increase in
dosage of flunarizine may be required.
Pharmacokinetics
Flunarizine hydrochloride is well absorbed from the
gastro-intestinal tract, peak plasma concentrations
occurring 2 to 4 hours after oral administration.
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 hydro-
chloride has an elimination half-life of about 18
days.
Uses and Administration
Flunarizine is the difluorinated derivative of cinnar-
izine. It has antihistamine, sedative, and calcium-
channel blocking activity. Flunarizine hydrochlo-
ride is used for migraine prophylaxis, for vertigo
and vestibular disorders, and for peripheral and cer-
ebral vascular disorders. It has also been tried as ad-
junctive antiepileptic therapy in patients refractory
to standard regimens.
Flunarizine hydrochloride is given by mouth; doses
are expressed in terms of the equivalent amount of
flunarizine. The usual dose is 5 to 10 mg daily, usu-
ally given at night to minimise the effects of drowsi-
ness.
Epilepsy. Flunarizine has demonstrated antiepileptic activity
in animal models, but the mechanism of action is unclear: cal-
cium entry blockade or an effect on sodium channels has been
postulated. Most clinical studies have evaluated its use as ad-
junctive therapy in epileptic patients with partial seizures re-
sistant to conventional treatment (see p.335). Doses of
fiunarizine of 15 to 20 mg daily by mouth appeared to provide
the best response when given as part of multiple-drug antiep-
ileptic regimens. However, studies using fixed doses of flu-
narizinc have been considered unsatisfactory because of
flunarizine's variable clearance and long elimination half-life.
Pledger et all overcame this by using a parallel group design
and adjusting doses to achieve a constant plasma concentra-
tion of 60 ng per ml. They found flunarizine to have modest
antiepileptic efficacy as adjunctive therapy for partial sei-
zures. Even so, others have concluded that the pharmacoki-
netic profile of flunarizine is too complex for its clinical use
as an antiepileptic.
Migraine. Flunarizine is used for the prophylaxis of mi-
graine in some countries. As noted in reviews placebo-con-
trolled studies have confirmed the efficacy of flunarizine in
reducing the frequency of migraine attacks in both adult and
paediatric patients. Also, comparative studies suggested it to
be at least as effective as several other prophylactic antimi-
graine drugs including those generally preferred, pizotifen
and propranolol , subsequent studies appeared to
confirm this opinion. However, flunarizine is more likely to
be reserved for use when first-line drugs have proved to be
ineffective or unsuitable. Doses of flunarizine reported to be
used for migraine prophylaxis are 10 mg daily for adults and
5 mg daily for children. Its mode of action in migraine is un-
clear; possible mechanisms are inhibition of vasospasm in-
duced by mediators such as serotonin and prostaglandins,
inhibition of cellular hypoxia and improved blood viscosity
and erythrocyte deformability. Calcium-channel blocking ac-
tivity might have a role. but evidence for the efficacy of other
calcium-channel blockers in migraine prophylaxis, is less convincing than for flunarizine.
Case reports have indicated benefit with flunarizine in the
prophylaxis of the rare disorder of alternating hemiplegia in
childhood. While subsequent studies in 12 children did not
produce conclusive findings, further investigation with fluna-
rizine was considered to be warranted.
Touretteβs syndrome. Tourette's syndrome is a disorder
characterised by motor and vocal tics and behavioural distur-
bances . When symptoms are severe enough to
cause discomfort or embarrassment treatment is usually with
dopamine blockers such as haloperidol or pimozide but fluna-
rizine is one of several drugs that have also been tried. A small
unblinded study' involving 7 patients has suggested that flu-
narizine is more effective than placebo.
Vertigo. Antihistamines are the mainstay of the treatment of
vertigo . However, their antimuscarinic side-ef-
fects may prove troublesome, particularly in the elderly, and
they produce central sedation. Flunarizine is a calcium-chan-
nel blocker and an antihistamine that is devoid of antimus-
carinic properties, although it may produce central sedation.