PROTHIAZINE INJECTION

Israel - English - Ministry of Health

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Active ingredient:
PROMETHAZINE AS HYDROCHLORIDE 50.0 MG / 2 ML
Available from:
CTS CHEMICAL INDUSTRIES LTD
ATC code:
R06AD02
Pharmaceutical form:
SOLUTION FOR INJECTION
Administration route:
I.M, I.V
Manufactured by:
RAFA LABORATORIES LTD, JERUSALEM
Therapeutic group:
PROMETHAZINE
Therapeutic indications:
Amelioration of allergic reactions to blood or plasma. In analphylaxis as an adjunct to adrenaline and other standard measures after the acute symptoms have been controlled. For other uncomplicated allergic conditions of the immedite type when oral therapy is impossible or contraindicated. Preoperative, postoperative and obstetric (during lobour) sedation. Prevention and control of nausea and vomiting associated with certain types of anaesthesia 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, opthalmic surgery and poor-risk patients with reduced amounts of meperidine or other narcotic analgesic as an adjunct to anaesthesia and analgesia.
Authorization number:
117352313200
Authorization date:
2010-01-01

Prothiazine Injection

Chemical Structure

Description

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.

Indications

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.

Pharmacokinetics

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

intra-arterially.

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

injection.

Intramuscular injection:

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.

Intravenous injection:

The 50 mg/ml solution should not be given IV; for IM

use only.

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.

Children:

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.

Contraindications

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.

Sulfite sensitivity:

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

nonasthmatic persons.

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

gangrene.

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

injection.

Intramuscular injection must also be performed carefully

to avoid inadvertent subcutaneous injection, which

could lead to local necrosis.

Interactions

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

concurrent use.

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

propylthiouracil.

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

hours afterwards.

Adverse Reactions

-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

have occurred.

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

discontinued.

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.

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

haloperidol.

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.

Overdosage

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

November 2006.

LFL 005 11/07

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