Cyclizine
Cyclizine Hydrochloride
A white, odourless or almost odourless, crystalline powder, or
small colourless crystals. Soluble I in 115 of water and of
alcohol and I in 75 of chloroform; practically insoluble in
ether. A 2% solution in alcohol 2 vol. and water 3 vol. has a
pH of 4.5 to 5.5. Store in airtight containers. Protect from
light.
Adverse Effects, Precautions & Interactions as for the sedating antihistamines in general, like promethazine.
PROMETHAZINE
CONTRAINDICATIONS:
Promethazine is contraindicated in comatose states, in patients who have
received large amounts of central-nervous-system depressants (alcohol, sedative-
hypnotics, including barbiturates, general anesthetics, narcotics, narcotic
analgesics, tranquilizers, etc.), and in patients who have demonstrated an
idiosyncrasy or hypersensitivity to promethazine.
Under no circumstances should promethazine be given by intra-arterial injection
due to the likelihood of severe arteriospasm and the possibility of resultant
gangrene (see "WARNINGS").
Phenergan Injection should not be given by the subcutaneous route; evidence of
chemical irritation has been noted, and necrotic lesions have resulted on rare
occasions following subcutaneous injection. The preferred parenteral route of
administration is by deep intramuscular injection.
WARNINGS:
Promethazine HCl Injection (ampuls only) contains sodium metabisulfite, a
sulfite that may cause allergic-type reactions, including anaphylactic symptoms
and life-threatening or less severe asthmatic episodes, in certain susceptible
people. The overall prevalence of sulfite sensitivity in the general population
is unknown and probably low. Sulfite sensitivity is seen more frequently in
asthmatic than in nonasthmatic people.
Promethazine may impair the mental and/or physical abilities required for the
performance of potentially hazardous tasks, such as driving a vehicle or
operating machinery. The concomitant use of alcohol, sedative hypnotics
(including barbiturates), general anesthetics, narcotics, narcotic analgesics,
tranquilizers or other central-nervous-system depressants may have an additive
sedative effect. Patients should be warned accordingly.
USAGE IN PREGNANCY
The safe use of promethazine has not been established with respect to the
possible adverse effects upon fetal development. Therefore, the need for the use
of this drug during pregnancy should be weighed against the possible but unknown
hazards to the developing fetus.
USE IN CHILDREN
Excessively large dosages of antihistamines, including promethazine, in children
may cause hallucinations, convulsions, and sudden death. In children who are
acutely ill associated with dehydration, there is an increased susceptibility to
dystonias with the use of promethazine hydrochloride injection.
CAUTION SHOULD BE EXERCISED WHEN ADMINISTERING PHENERGAN TO CHILDREN.
ANTIEMETICS ARE NOT RECOMMENDED FOR TREATMENT OF UNCOMPLICATED VOMITING IN
CHILDREN, AND THEIR USE SHOULD BE LIMITED TO PROLONGED VOMITING OF KNOWN
ETIOLOGY. THE EXTRAPYRAMIDAL SYMPTOMS WHICH CAN OCCUR SECONDARY TO PHENERGAN
ADMINISTRATION MAY BE CONFUSED WITH THE CNS SIGNS OF UNDIAGNOSED PRIMARY
DISEASE, e.g., ENCEPHALOPATHY OR REYE'S SYNDROME. THE USE OF PHENERGAN SHOULD BE
AVOIDED IN CHILDREN WHOSE SIGNS AND SYMPTOMS MAY SUGGEST REYE'S SYNDROME OR
OTHER HEPATIC DISEASES.
USE IN THE ELDERLY (APPROXIMATELY 60 YEARS OR OLDER)
Since therapeutic requirements for sedative drugs tend to be less in elderly
patients, the dosage of Phenergan should be reduced for these patients.
OTHER CONSIDERATIONS
Drugs having anticholinergic properties should be used with caution in patients
with asthmatic attack, narrow-angle glaucoma, prostatic hypertrophy, stenosing
peptic ulcer, pyloroduodenal obstruction, and bladder-neck obstruction.
Promethazine should be used with caution in patients with bone-marrow
depression. Leukopenia and agranulocytosis have been reported, usually when
Phenergan has been used in association with other known toxic agents.
INADVERTENT INTRA-ARTERIAL INJECTION
Due to the close proximity of arteries and veins in the areas most commonly used
for intravenous injection, extreme care should be exercised to avoid
perivascular extravasation or inadvertent intra-arterial injection. Reports
compatible with inadvertent intra-arterial injection of promethazine, usually in
conjunction with other drugs intended for intravenous use, suggest that pain,
severe chemical irritation, severe spasm of distal vessels, and resultant
gangrene requiring amputation are likely under such circumstances. Intravenous
injection was intended in all the cases reported, but perivascular extravasation
or arterial placement of the needle is now suspect. There is no proven
successful management of this condition after it occurs, although sympathetic
block and heparinization are commonly employed during the acute management
because of the results of animal experiments with other known arteriolar
irritants. Aspiration of dark blood does not preclude intra-arterial needle
placement, because blood is discolored upon contact with promethazine. Use of
syringes with rigid plungers or of small bore needles might obscure typical
arterial backflow if this is relied upon alone.
When used intravenously, promethazine hydrochloride should be given in a
concentration no greater than 25 mg per mL and at a rate not to exceed 25 mg per
minute. When administering any irritant drug intravenously, it is usually
preferable to inject it through the tubing of an intravenous infusion set that
is known to be functioning satisfactorily. In the event that a patient complains
of pain during intended intravenous injection of promethazine, the injection
should immediately be stopped to provide for evaluation of possible arterial
placement or perivascular extravasation.
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.
DRUG INTERACTIONS:
NARCOTICS AND BARBITURATES
The CNS-depressant effects of narcotics and barbiturates are additive with
promethazine hydrochloride.
MONOAMINE OXIDASE INHIBITORS (MAOI)
Drug interactions, including an increased incidence of extrapyramidal effects,
have been reported when some MAOI and phenothiazines are used concomitantly.
Although such a reaction has not been reported with promethazine, the
possibility should be considered.
(See Also PRECAUTIONS)
Cydizine may aggravate severe heart failure. Hypo-
tension may occur on injection.
Abuse. Cyclizine tablets have been abused either alone or in
conjunction with opioids for their euphoric effects. They
have been taken by mouth or used to make injections. It has
been suggested that cyclizine dependence may occur when it
is used with opioids in the treatment of chronic pain.
Effects on the blood. A report of agranulocytosis occur-
ring in one patient after six weeks of treatment with cyclizine
50 mg three times daily. The blood count returned to normal
once cyclizine was withdrawn.
Effects on the heart. In a study of 11 patients with severe
heart failure, cyclizine produced detrimental haemodynamic
effects including increased systemic and pulmonary artery
pressures and ventricular filling pressures, and negated the
vasodilator effects of diamorphine. It was suggested that the
use of cyclizine should be avoided in patients with acute my-
ocardial infarction or severe heart failure.
Effects on the liver. An 8-year-old girl developed jaundice
on 2 occasions after taking cyclizine hydrochloride 25 mg
daily by mouth , 'Hypersensitivity hepatitis' was considered
responsible.
Pregnancy. For discussion of the use of antihistamines in
pregnancy, including studies involving cyclizine see
promethazine.
Cyclizine may counteract the haemodynamic bene-
fits of opioids and this should be considered before
using preparations that contain a combination of cy-
clizine and an opioid analgesic.
General anaesthetics. For a possible interaction between
cyclizine premedication and barbiturate anaesthetics sec un-
der Thiopentone.
Pharmacokinetics
Cyclizine is absorbed from the gastro-intestinal tract
and has an onset of action within two hours. The du-
ration of action is reported to be approximately 4
hours. Cyclizine is metabolised in the liver to the relatively
inactive metabolite, norcyclizine. Both
cyclizine and norcyclizine have plasma elimination
half-lives of 20 hours. Less than 1% of the total oral
dose is eliminated in the urine.
Uses and Administration
Cyclizine. a piperazine derivative, is a sedating anti-
histamine with antimuscarinic activity, although the
sedative effects are not marked.
It is used as an antiemetic in the management of nau-
sea and vomiting including in motion sick-
ness, irradiation sickness, postoperative nausea and
vomiting, and drug-induced nausea and vomiting. It
is included as an antiemetic in combination prepara-
tions for the treatment of migraine attacks .
Cyclizine is also used for the symptomatic treatment
of vertigo caused by Meniere's disease and
other vestibular disturbances.
In the management of nausea and vomiting, cy-
clizine hydrochloride is given by mouth in a usual
dose of 50 mg up to three times daily, although up to
200 mg may be given in 24 hours if necessary. For
the prevention of motion sickness, the first dose
should be given about 30 minutes before travelling.
Children aged 6 to 12 years may be given 25 mg up
to three times daily.
Cyclizine is given intramuscularly or intravenously
as the lactate. Doses of cyclizine lactate are similar
to those of cyclizine hydrochloride given by mouth.
For the prevention of postoperative nausea and vom-
iting the first dose of cyclizine lactate should be giv-
en about 20 minutes before the anticipated end of
surgery.
Cyclizine tartrate is administered parenterally in
combination with morphine tartrate in doses similar
to those of cyclizine hydrochloride. Cyclizine is also
administered as the hydrochloride by mouth in com-
bination with dipipanone hydrochloride; the use of
such fixed-combination opioid preparations is con-
sidered to be unsuitable for prolonged treatment as
is required in palliative care. See also under Interac-
tions, above.