Israel - English - Ministry of Health
Promethazine is a phenothiazine however it is not used
clinically as a neuroleptic. It is an H 1 -antagonist with
considerable anticholinergic, sedative and antiemetic
effects and some local anesthetic properties.
Promethazine is a versatile drug but is used pre-
dominantly as an antiemetic.
Mechanism of Action
The predominant action of promethazine is antagonism
of H 1 -receptors. Although promethazine is classified as
a phenothiazine, its ability to antagonize dopamine is
approximately one-tenth that of chlorpromazine. For
this reason, promethazine is not used as a neuroleptic.
Like other H 1 -antagonists, promethazine does not
prevent the release of histamine, as do cromolyn and
nedocromil, but competes with free histamine for
binding at H 1 -receptor sites. Histamine receptors in the
GI tract, uterus, large blood vessels and bronchial muscle
are blocked. The relief of motion sickness and
nausea/vomiting appear to be related to central
anticholinergic actions and may implicate activity on
the medullary chemoreceptor trigger zone. Other CNS
receptor sites can also be affected, since promethazine
is believed to indirectly reduce stimuli to the brain stem
reticular system. Sedation is significant at concentrations
achieved from therapeutic dosages. Local anesthetic
activity requires higher concentrations than those
required to antagonize histamine receptors.
Amelioration of allergic reactions to blood or plasma.
In anaphylaxis as an adjunct to adrenaline and other
standard measures after the acute symptoms have been
controlled. For other uncomplicated allergic conditions
of the immediate type when oral therapy is impossible
or contraindicated. Preoperative, postoperative and
obstetric (during labor) sedation. Prevention and control
of nausea and vomiting associated with certain types
of anesthesia and surgery. For sedation and relief of
apprehension and to induce light sleep from which the
patient can be easily aroused. Intravenously in special
surgical situations, such as repeated bronchoscopy,
ophthalmic surgery and poor-risk patients with reduced
amounts of meperidine or other narcotic analgesic as
an adjunct to anesthesia and analgesia.
Promethazine injection is administered intramuscularly,
and intravenously. Onset of action occurs within 20
minutes after intramuscular administration. Following
intravenous administration, onset of action occurs within
3–5 minutes. Antihistaminic and sedative effects are
sustained for 4–6 hours and 2–8 hours, respectively.
Promethazine is highly protein-bound (80–93%). It is
widely distributed in body tissues and fluids, and it
crosses the placenta and is excreted into breast milk.
Metabolism occurs in the liver, producing inactive
metabolites such as promethazine sulfoxide and other
glucuronides. The elimination half-life is 10–14 hours,
with excretion of metabolites in the urine and the feces.
Dosage and Administration
Promethazine should not be given subcutaneously or
Visually inspect parenteral products for particulate
matter and discoloration prior to administration
whenever solution and container permit.
The preferred parenteral route of administration for
promethazine hydrochloride is by deep intramuscular
Inject deeply into a large muscle (i.e., upper outer
quadrant of the gluteus maximus or lateral part of the
thigh). Aspirate prior to injection to avoid injection into
a blood vessel.
The 50 mg/ml solution should not be given IV; for IM
Infuse the appropriate dose into the tubing of a free
flowing IV solution.
Maximum IV concentration is 25 mg/ml. Further dilution
(i.e., to concentrations < 25 mg/ml) may be required
to minimize risk of thrombophlebitis. Maximum infusion
rate is 25 mg/minute.
For the treatment of nausea/vomiting:
Intramuscular or intravenous dosage:
Adults: 12.5–25 mg every 4–6 hours as needed.
Children≥2years: 0.25–0.5 mg/kg (max: 25 mg/dose)
every 4–6 hours as needed. According to the
manufacturer, the average effective dose is 25 mg.
For the treatment of allergic manifestations:
The average adult dose is 25 mg. This dose may be
repeated within 2 hours if necessary; but continued
therapy, if indicated, should be via the oral route as
soon as circumstances permit. After initiation of
treatment, dosage should be adjusted to the smallest
amount adequate to relieve symptoms.
For routine preoperative or postoperative sedation
induction, intramuscular or intravenous dosage:
Adults: 25–50 mg as a single dose.
Children≥2years: 12.5–25 mg as a single dose.
Torelieve apprehension and induce quiet sleep from
which the patient can be easily aroused, intramuscular
or intravenous dosage:
Adults: 25–50 mg at bedtime.
For sedation in obstetrics:
Intramuscular or intravenous dosage:
Adults: 25–50 mg IM or IV during the early stages of
labor and 25–75 mg after labor is established; repeat
every 2–4 hours as needed.
In children under 12 years of age, the dosage should
not exceed half that of the recommended adult dosages.
As an adjunct to premedication, the suggested dose is
0.9 mg/kg body weight in combination with an equal
dose of narcotic or barbiturate and the appropriate
dose of an atropine-like drug. Antiemetics should not
be used in vomiting of unknown etiology in children.
Patients with renal impairment:
Specific guidelines for dosage adjustments in renal
impairment are not available; it appears that no dosage
adjustments are needed.
Phenothiazine derivatives lower the seizure threshold
through their effect on GABA; therefore, promethazine
should be avoided, if possible, in patients with a seizure
disorder or those receiving anticonvulsants.
The anticholinergic activity of H 1 -antagonists may result
in thickened bronchial secretions in the respiratory tract,
thereby aggravating an acute asthmatic attack or COPD.
Although H 1 -antagonists should be avoided during an
acute asthmatic attack, these anticholinergic effects do
not preclude the use of H 1 -antagonists in all asthmatic
or COPD patients, particularly if the above respiratory
symptom is not a primary component of the illness.
Because promethazine exhibits a significant amount of
anticholinergic activity, it should be avoided in those
who have experienced a worsening in respiratory status
due to H 1 -antagonist therapy.
Promethazine is classified as pregnancy category C. H 1 -
antagonists generally are not recommended for use in
pregnancy, especially during the third trimester, because
of a seizure risk to the fetus. Because there are no
adequate studies in pregnant women, promethazine
should be considered during pregnancy only when the
benefits of therapy outweigh the risks to the fetus. H 1 -
antagonists are not recommended for use during breast-
feeding because they can induce a paradoxical CNS
stimulation in neonates or seizures in premature infants.
Inhibition of lactation may also occur. Alternative
methods of feeding should be used if promethazine
therapy is necessary.
Promethazine should be used cautiously in children
since a paradoxical CNS stimulation can occur. There
have been a number of cases of respiratory depression,
sleep apnea and SIDS in children receiving phenothiazine
antihistamines. The mechanism of this reaction is not
yet known; therefore, promethazine should be used
with extreme caution, if at all, in children with a family
history of SIDS or sleep apnea. H 1 -antagonists should
not be used in neonates due to the possibility of
paradoxical CNS stimulation or seizures.
Promethazine should be avoided, if possible, in patients
with open-angle or closed-angle glaucoma and an H 1 -
antagonist with less anticholinergic effects should be
substituted. An increase in intraocular pressure may
occur from the anticholinergic actions of the drug,
precipitating an acute attack of glaucoma. Elderly
patients are moresusceptible to the anticholinergic
effects of promethazine, including possible precipitation
of undiagnosed glaucoma. Other ocular effects resulting
from the anticholinergic effects of promethazine include
dry eyes or blurred vision. This may be of significance
in the elderly and wearers of contact lenses.
Promethazine has substantial anticholinergic effects
and a worsening of symptoms may be seen in patients
with bladder obstruction, GI obstruction or ileus, benign
prostatic hypertrophy or urinary retention. These
precautions are most significant when using
antihistamines from the ethanolamine or phenothiazine
group. The elderly are moresusceptible to the
anticholinergic effects of drugs since there is a decline
in endogenous cholinergic activity that occurs with age.
Promethazine is extensively metabolized in the liver.
The metabolism of promethazine may be reduced in
the presence of hepatic impairment. Those with
significant hepatic disease receiving H 1 -antagonists
should be monitored for liver function and side effects.
Dosage adjustment may be required in these patients.
The quinidine-like local anesthetic and anticholinergic
effects of antihistamines are responsible for the adverse
cardiac effects which have been observed including
tachycardia, ECG changes, hypotension and arrhythmias.
Although these cardiovascular effects are uncommon,
-antagonists should be used conservatively in patients
with cardiac disease.
This product contains sodium sulfite and sodium
matabisulfite which may cause allergic-type reactions
(e.g. hives, itching, wheezing, anaphylaxis) in certain
susceptible persons. Although the overall prevalence
of sulfite sensitivity in the general population is probably
low, it is seen more frequently in asthmatics or in atopic
Special Warnings and Precautions for use
Intravenous injection should be performed with extreme
care to avoid extravasation or inadvertent intra-arterial
injection, which could lead to necrosis and peripheral
If a patient complains of pain during intravenous
injection, stop the injection immediately, as this may
be a sign of extravasation or inadvertent intra-arterial
Intramuscular injection must also be performed carefully
to avoid inadvertent subcutaneous injection, which
could lead to local necrosis.
Phenothiazines have been reported to inhibit and reverse
the vasopressor effect of epinephrine; therefore, if
treatment with a vasopressor agent is necessary in a
S HCl S HCl N CH 2 CH(CH 3 )N(CH 3 ) 2
norepinephrine should be used.
The anticholinergic activity of MAOIs is minimal; however,
anticholinergic effects sometimes occur. It is
recommended that the concurrent use of MAOIs with
drugs possessing anticholinergic activity be avoided,
especially atropine and scopolamine, since their effects
and those of other anticholinergic drugs are potentiated
and may become severe. Most manufacturers
recommend that antihistamines not be used within two
weeks of therapy with an MAOI.
Depending on the specific agent, additive anticholinergic
effects may be seen when drugs with antimuscarinic
properties are used concomitantly with other
antimuscarinics. The following drugs are known to
possess antimuscarinic properties and should be used
together cautiously: atropine and other similar
antimuscarinics; some H 1 -blockers (e.g., carbinoxamine,
clemastine, diphenhydramine, methdilazine,
promethazine, trimeprazine); some phenothiazines (e.g.,
mesoridazine, promazine, thioridazine, triflupromazine);
some tricyclic antidepressants (e.g., amitriptyline,
amoxapine, clomipramine, protriptyline); and other
drugs with substantial antimuscarinic properties such
as clozapine, cyclobenzaprine and disopyramide. Drugs
with minor degrees of anticholinergic effects include
amantadine, bupropion, chlorpromazine, doxepin,
imipramine, maprotiline, nortriptyline, procainamide
and trimipramine. Clinicians should note that
antimuscarinic effects may be seen not only on GI
smooth muscle, but also on bladder function, the eye,
and temperature regulation.
Because promethazine causes pronounced sedation,
an enhanced CNS depressant effect may occur when
it is combined with other CNS depressants including
ethanol, barbiturates, anxiolytics, sedatives and hypnotics,
phenothiazines, opiate agonists or other H 1 -blockers.
A reduction in dosage is recommended during
An increased incidence of extrapyramidal symptoms
may occur if promethazine is used concurrently with
other agents capable of causing these reactions. Drugs
which antagonize dopamine thereby causing EPS
reactions include antipsychotics, metoclopramide and
amoxapine. Conversely,the effectiveness of dopamine
agonists, such as levodopa, amantadine or
bromocriptine, may be diminished when given with
promethazine due to its blockade of dopamine receptors.
Chlorpromazine has been reported to affect control of
blood glucose in diabetic patients. It is unclear if
phenothiazines directly interact with antidiabetic agents.
Since promethazine is a phenothiazine, it should be
used cautiously in patients receiving antidiabetic agents.
Concomitant use of antithyroid agents and
phenothiazines can increase the risk of developing
agranulocytosis. Promethazine should not be used with
Concurrent use of intrathecal metrizamide with
promethazine can lower the seizure threshold.
Promethazine should be discontinued at least 48 hours
before myelography and not resumed until at least 24
-antagonists sometimes cause CNS stimulation. This
reaction is more likely to occur in children, particularly
with a phenothiazine. Symptoms include restlessness,
insomnia, palpitations or seizures. Extrapyramidal effects
are morelikely to be dose-related and may disappear
with a reduction in dosage.
Extrapyramidal symptoms (EPS) occur frequently during
treatment with phenothiazines and appear to be the
result of D 2 -receptor blockade. These symptoms occur
with greater severity and frequency during high-dose
therapy. Extrapyramidal symptoms are categorized as
dystonic reaction, akathisia (subjective and objective
motor restlessness) and parkinsonism. Parkinsonian
symptoms are morecommon in the elderly, whereas
children most often develop dystonic reactions, which
can be worsened by acute infections or severe
dehydration. Dystonic reactions are typically seen during
the first week of treatment. Akathisia and parkinsonian
symptoms usually develop several days to weeks into
therapy. Dystonia and pseudoparkinsonism usually are
easily treated with concomitant benztropine,
diphenhydramine, lorazepam or amantadine. Akathisia
may respond to dosage reduction or concomitant
administration of a benzodiazepine (usually lorazepam)
or propranolol. In rare patients, an alternate antipsychotic
may be necessary.
Neuroleptic malignant syndrome (NMS) can occur in
patients receiving phenothiazines. NMS is characterized
by hyperthermia, severe extrapyramidal dysfunction,
alterations in consciousness, altered mental status, and
autonomic instability (sinus tachycardia, low blood
pressure or hypertension, diaphoresis). Increased serum
creatine phosphokinase (CPK), acute renal failure, and
leukocytosis also have occurred. NMS does not appear
to be dose-related. Severe cases have resulted in death
3–30 days after the onset of the syndrome. Several
predisposing factors may contribute to the development
of NMS including heat stress, physical exhaustion,
dehydration and organic brain disease. NMS occurs
more frequently in young men. The phenothiazine
should be immediately discontinued and appropriate
supportive therapy initiated as soon as symptoms of
NMS are discovered. Hypothermia and hyperthermia
have been reported with phenothiazines independent
of the neuroleptic malignant syndrome and may be
caused by the effect of the phenothiazine on the
hypothalamic control of temperature regulation.
Hyperpyrexia and heat stroke unrelated to NMS also
Tardive dyskinesia (TD) is characterized by involuntary
movements of the perioral region (tongue, mouth, jaw,
eyelids or face) or choreoathetoid movements in the
extremities. It can develop during long-term therapy or
following discontinuation of phenothiazine therapy and
it is observed more frequently in elderly women. The
incidence of TD may be higher in patients with bipolar
irreversible. While contradictory evidence exists, it has
been suggested that the likelihood of developing TD
increases with prolonged treatment and cumulative
doses. Although this complication often occurs following
prolonged treatment or with administration of high
dosages, it also has been reported to occur after short
periods of time and with low dosages. Routine
monitoring (at 3- to 6-month intervals) of movement
disorders is considered the standard practice when using
phenothiazines. If signs or symptoms of TD develop,
the neuroleptic should be reevaluated and possibly
Phenothiazines can cause a variety of CNS effects.
Drowsiness occurs occasionally during initial treatment
with some phenothiazines. Tolerance usually develops
with continued therapy. Dizziness may occur as a result
of orthostatic hypotension. Other CNS effects reported
less frequently include restlessness, insomnia, depression,
headache and cerebral edema. Seizures can occur and
are of special significance in patients with preexisting
seizure disorders or EEG abnormalities.
Anticholinergic effects of phenothiazines include blurred
vision, xerostomia, mydriasis, nausea, adynamic ileus,
urinary retention, impotence and constipation. These
effects can be enhanced by the concomitant
administration of anticholinergic antiparkinsonian drugs,
antidepressants or other anticholinergic agents.
Leukopenia including agranulocytosis is the most
common hematologic disturbance that has been
reported during phenothiazine administration.
Agranulocytosis has occurred rarely and has been
associated with combination treatment with other
agents. Other hematologic abnormalities that have
been associated with phenothiazine therapy include
leukocytosis (usually in association with the neuroleptic
malignant syndrome), eosinophilia, thrombocytopenia,
pancytopenia, aplastic anemia and anemia.
Prolonged therapy with phenothiazines can lead to skin
hyperpigmentation. Hyperpigmentation generally is
restricted to areas of the body exposed to sunlight.
Photosensitivity can result and patients should be warned
either to keep out of the sun or to use effective
sunscreens (SPF 15+) on exposed areas of the body.
Withdrawal of the drug can reverse the effects. Contact
dermatitis is also possible in predisposed individuals if
they come in contact with liquid dosage forms of
Phenothiazines can cause ocular changes. Pigmentary
retinopathy can occur with or without pigmentary
changes in the skin during therapy with phenothiazines.
Symptoms of blurred vision, difficulty with nighttime
vision, or defective color vision should be investigated
promptly.Wearing protective dark glasses can reduce
the possibility of this reaction. Phenothiazines have
been associated with deposition of fine particles in the
lens and cornea, which can lead to corneal opacification
and visual impairment.
Liver impairment in the form of cholestasis has been
reported rarely with administration of phenothiazines.
Jaundice is also possible and may even occur in neonates
of mothers who received phenothiazines during
pregnancy. Cholestatic jaundice from phenothiazines
is generally considered a hypersensitivity reaction.
Adverse cardiovascular reactions that have occurred
during antipsychotic therapy include hypotension,
hypertension, ventricular tachycardia, ECG changes
such as QT prolongation and other cardiac arrhythmias
such as torsades de pointes. Cardiac arrhythmias such
as torsades de pointes secondary to antipsychotic therapy
have mainly been associated with thioridazine and
Dopamine blockade can lead to hyperprolactinemia. As
a result, neuroleptics can cause galactorrhea. Other
endocrine changes that can occur during therapy with
neuroleptics include amenorrhea or other menstrual
irregularity, breast enlargement or mastalgia, libido
decrease, impotence, ejaculation dysfunction (no
ejaculation) and priapism. Weight gain may also occur
during therapy with phenothiazines.
Promethazine can cause an injection site reaction.
Inadvertant intra-arterial injection can result in
arteriospasm, with a possible impairment in circulation
and development of gangrene.
Manifestations: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 replacement of
promethazine by other drugs. General signs and
symptoms of overdosage range from mild depression
of the central nervous and cardiovascular systems, to
profound hypotension, respiratory depression and
unconsciousness. Stimulation may be evident, especially
in children and geriatric patients. Atropine-like signs
and symptoms; dry mouth, fixed dilated pupils, flushing,
etc. as well as gastrointestinal symptoms may occur.
Treatment:The treatment of overdosage is essentially
symptomatic and supportive. Avoid analeptics, which
may cause convulsions. Severe hypotension usually
responds to the administration of noradrenaline or
phenylephrine. Adrenaline should not be used, since
its use in a patient with partial adrenergic blockage may
further lower the blood pressure. Extrapyramidal
reactions may be treated with anticholinergic
antiparkinsonism agents, diphenhydramine or
barbiturates. Additional measures include oxygen and
intravenous fluids. Limited experience with dialysis
indicates that it is not helpful.
Manufacturer:TaroPharmaceutical Industries Ltd.,
14 Hakitor St., Haifa Bay 26110
for CTS Chemical Industries Ltd., Kiryat Malachi
The format of this leaflet was determined by the Ministry
of Health and its content was checked and approved in
LFL 005 11/07