(promethazine HCl and phenylephrine HCl) Syrup
Each 5 mL (one teaspoonful), for oral administration contains: Promethazine hydrochloride 6.25 mg; phenylephrine hydrochloride 5 mg, Alcohol 7%.
Inactive Ingredients: Citric acid, FD& C yellow #6, flavor, methyl- paraben, propylene glycol, propyl- paraben, purified water, saccharin sodium, sodium benzoate, sodium citrate, sucrose. Promethazine hydrochloride, a phenothiazine derivative, is chemically designated as (±)-10-[2-(Dimethylamino) propyl] phenothiazine monohydrochloride.
Promethazine hydrochloride occurs as a white to faint yellow, practically odorless, crystalline powder which slowly oxidizes and turns blue on prolonged exposure to air. It is soluble in water and freely soluble in alcohol. It has a molecular weight of 320.89, and a molecular formula of C17H20N2S•HCl.
Phenylephrine hydrochloride is a sympathomimetic amine salt which is chemically designated as (-)- m- Hydroxy-a-[(methylamino) methyl] benzyl alcohol hydrochloride. It occurs as white or nearly white crystals, having a bitter taste. It is freely soluble in water and alcohol. Phenylephrine hydrochloride is subject to oxidation and must be protected from light and air. It has a molecular weight of 203.67, and a molecular formula of C9H13NO2•HCl.
Promethazine hydrochloride and phenylephrine hydrochloride syrup is indicated for the temporary relief of upper respiratory symptoms, including nasal congestion, associated with allergy or the common cold.
DOSAGE AND ADMINISTRATION
The recommended doses are given in the following table:
|Adults and children 12 years and over:|
|1 teaspoonful (5 mL) every 4 to 6 hours, |
not to exceed 6 teaspoonsful (30 mL) in 24 hours.
|Children 6 to under 12 years of age:|
|½ to 1 teaspoonful (2.5 to 5 mL) every 4 to 6 hours, |
not to exceed 6 teaspoonsful (30 mL) in 24 hours.
|Children 2 to under 6 years of age:|
|¼ to ½ teaspoonful (1.25 to 2.5 mL) every 4 to 6 hours.|
Promethazine and phenylephrine is not recommended for children under 2 years of age.
This preparation is a yellow-orange colored, fruit-flavored syrup. Each 5 mL (one teaspoonful) contains Promethazine hydrochloride 6.25 mg, phenylephrine hydrochloride 5 mg, and alcohol 7 percent, and is available in bottles of 4 fluid ounce (118 mL), 8 fluid ounce (237 mL), one pint (473 mL) and one gallon (3785 mL).
Keep tightly closed. Protect from light.
Storage: Store at controlled room temperature 59°- 86° F (15°- 30° C).
Dispense in a tight, light-resistant container as defined in the USP
CAUTION: Federal law prohibits dispensing without prescription.
Nervous System: Sedation, sleepiness, occasional blurred vision, dryness of mouth, dizziness; rarely: confusion, disorientation, and extrapyramidal symptoms such as oculogyric crisis, torticollis, and tongue protrusion (usually in association with parenteral injection or excessive dosage).
Cardiovascular: Increased or decreased blood pressure.
Gastrointestinal: Nausea and vomiting.
Nervous System: Restlessness, anxiety, nervousness, and dizziness.
The sedative action of promethazine is additive to the sedative effects of other central nervous system depressants, including alcohol, narcotic analgesics, sedatives, hypnotics, tricyclic antidepressants, and tranquilizers; therefore, these agents should be avoided or administered in reduced dosage to patients receiving promethazine.
Drug: Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).
Drug: Phenylephrine with tricyclic antidepressants.
Effect: Pressor response increased.
Drug: Phenylephrine with ergot alkaloids.
Effect: Excessive rise in blood pressure.
Drug: Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.
Effect: Tachycardia or other arrhythmias may occur.
Drug: Phenylephrine with atropine sulfate.
Drug: Phenylephrine with prior administration of propranolol or other b- adrenergic blockers.
Effect: Cardiostimulating effects blocked.
Drug: Phenylephrine with prior administration of phentolamine or other a- adrenergic blockers.
Effect: Pressor response decreased.
Drug: Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.
Effect: Synergistic adrenergic response.
Promethazine may cause marked drowsiness. Ambulatory patients should be cautioned against such activities as driving or operating dangerous machinery until it is known that they do not become drowsy or dizzy from promethazine therapy.
The sedative action of promethazine hydrochloride is additive to the sedative effects of central nervous system depressants; therefore, agents such as alcohol, narcotic analgesics, sedatives, hypnotics, and tranquilizers should either be eliminated or given in reduced dosage in the presence of promethazine hydrochloride. When given concomitantly with promethazine hydrochloride, the dose of barbiturates should be reduced by at least one-half, and the dose of analgesic depressants, such as morphine or meperidine, should be reduced by one-quarter to one-half.
Promethazine may lower seizure threshold. This should be taken into consideration when administering to persons with known seizure disorders or when giving in combination with narcotics or local anesthetics which may also affect seizure threshold. Sedative drugs or CNS depressants should be avoided in patients with a history of sleep apnea. Antihistamines should be used with caution in patients with narrow-angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, and urinary bladder obstruction due to symptomatic prostatic hypertrophy and narrowing of the bladder neck.
Administration of promethazine has been associated with reported cholestatic jaundice.
Because phenylephrine is an acirenergic agent, it should be given with caution to patients with thyroid diseases, diabetes mellitus, and heart disease or those receiving tricyclic antidepressants. Men with symptomatic, benign prostatic hypertrophy can experience urinary retention when given oral or nasal decongestants.
Phenylephrine can cause a decrease in cardiac output, and extreme caution should be used when administering the drug parenterally or orally to patients with arteriosclerosis, to elderly individuals, and/ or to patients with initially poor cerebral or coronary circulation.
Phenylephrine should be used with caution in patients taking diet preparations, such as amphetamines or phenylpropanolamine, because synergistic adrenergic effects could result in serious hypertensive response and possible stroke.
Animal reproduction studies have not been conducted with the drug combination - promethazine and phenylephrine. It is not known whether this drug combination can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Promethazine and phenylephrine should be given to a pregnant woman only if clearly needed.
Promethazine should be used cautiously in persons with cardiovascular disease or impairment of liver function. Phenylephrine should be used with caution in patients with cardiovascular disease, particularly hypertension.
Drug/ Laboratory Test Interactions
The following laboratory tests may be affected in patients who are receiving therapy with promethazine hydrochloride.
Glucose Tolerance Test: An increase in blood glucose has been reported in patients receiving promethazine.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Promethazine: Long-term animal studies have not been performed to assess the carcinogenic potential of promethazine, nor are there other animal or human data concerning carcinogenicity, mutagenicity, or impairment of fertility with this drug. Promethazine was nonmutagenic in the Salmonella test system of Ames.
Phenylephrine: A study which followed the development of cancer in 143,574 patients over a four-year period indicated that in 11,981 patients who received phenylephrine (systemic or topical), there was no statistically significant association between the drug and cancer at any or all sites. Long- term animal studies have not been performed to assess the carcinogenic potential of phenylephrine, nor are there other animal or human data concerning mutagenicity.
A study of the effects of adrenergic drugs on ovum transport in rabbits indicated that treatment with phenylephrine did not alter incidence of pregnancy; the number of implantations was significantly reduced when high doses of the drug were used.
Pregnancy Category C:
Promethazine: Teratogenic effects have not been demonstrated in rat- feeding studies at doses of 6.25 and 12.5 mg/ kg of promethazine. These doses are 8.3 and 16.7 times the maximum recommended total daily dose of promethazine for a 50-kg subject. Specific studies to test the action of the drug on parturition, lactation, and development of the animal neonate were not done, but a general preliminary study in rats indicated no effect on these parameters. Although antihistamines, including promethazine, have been found to produce fetal mortality in rodents, the pharmacological effects of histamine in the rodent do not parallel those in man. There are no adequate and well-controlled studies of promethazine in pregnant women.
Phenylephrine: A study in rabbits indicated that continued moderate overexposure to phenylephrine (3 mg/ day) during the second half of pregnancy (22nd day of gestation to delivery) may contribute to perinatal wastage, prematurity, premature labor, and possibly fetal anomalies; when phenylephrine (3 mg/ day) was given to rabbits during the first half of pregnancy (3rd day after mating for seven days), a significant number gave birth to litters of low birth weight. Another study showed that phenylephrine was associated with anomalies of aortic arch and with ventricular septal defect in the chick embryo.
Promethazine and phenylephrine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Promethazine taken within two weeks of delivery may inhibit platelet aggregation in the newborn.
Labor and Delivery
Administration of phenylephrine to patients in late pregnancy or labor may cause fetal anoxia or bradycardia by increasing contractility of the uterus and decreasing uterine blood flow. (See also Pregnancy: Nonteratogenic Effects above).
It is not known whether promethazine or phenylephrine are excreted in human milk. Caution should be exercised when promethazine and phenylephrine is administered to a nursing woman.
This product should not be used in pediatric patients under 2 years of age because safety for such use has not been established.
Signs and Symptoms
Signs and symptoms of overdosage with promethazine range from mild depression of the central nervous system and cardiovascular system to profound hypotension, respiratory depression, and unconsciousness. Stimulation may be evident, especially in children and geriatric patients. Convulsions may rarely occur. A paradoxical reaction has been reported in children receiving single doses of 75 mg to 125 mg orally, characterized by hyperexcitability and nightmares. Atropine-like signs and symptoms, dry mouth, fixed dilated pupils, flushing, as well as gastrointestinal symptoms, may occur.
Signs and symptoms of overdosage with phenylephrine include hypertension, headache, convulsions, cerebral hemorrhage, and vomiting. Ventricular premature beats and short paroxysms of ventricular tachycardia may also occur. Headache may be a symptom of hypertension. Bradycardia may also be seen early in phenylephrine overdosage through stimulation of baroreceptors.
The treatment of overdosage with promethazine and phenylephrine is essentially symptomatic and supportive. Only in cases of extreme overdosage or individual sensitivity do vital signs including respiration, pulse, blood pressure, temperature, and EKG need to be monitored. Activated charcoal orally or by lavage may be given, or sodium or magnesium sulfate orally as a cathartic. Attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Diazepam may be used to control convulsions. Acidosis and electrolyte losses should be corrected. Note that any depressant effects of promethazine are not reversed by naloxone. Avoid analeptics which may cause convulsions.
Severe hypotension usually responds to the administration of norepinephrine or phenylephrine. EPINEPHRINE SHOULD NOT BE USED, since its use in a patient with partial adrenergic blockade may further lower the blood pressure.
Limited experience with dialysis indicates that it is not helpful.
Promethazine is contraindicated in individuals known to be hypersensitive or to have had an idiosyncratic reaction to promethazine or to other phenothiazines. Antihistamines are contraindicated for use in the treatment of lower respiratory tract symptoms, including asthma. Phenylephrine is contraindicated in patients with hypertension or with peripheral vascular insufficiency (ischemia may result with risk of gangrene or thrombosis of compromised vascular beds). Phenylephrine should not be used in patients known to be hypersensitive to the drug or in those receiving a monoamine oxidase inhibitor (MAOI).
Promethazine is a phenothiazine derivative which differs structurally from the antipsychotic phenothiazines by the presence of a branched side chain and no ring substitution. It is thought that this configuration is responsible for its relative lack (1/ 10 that of chlorpromazine) of dopaminergic (CNS) action. Promethazine is an H1 receptor blocking agent. In addition to its antihistaminic action, it provides clinically useful sedative and antiemetic effects. In therapeutic dosages, promethazine produces no significant effects on the cardiovascular system. Promethazine is well absorbed from the gastrointestinal tract. Clinical effects are apparent within 20 minutes after oral administration and generally last four to six hours, although they may persist as long as 12 hours. Promethazine is metabolized by the liver to a variety of compounds; the sulfoxides of promethazine and N-demethylpromethazine are the predominant metabolites appearing in the urine.
Phenylephrine is a potent post- synaptic a- receptor agonist with little effect on b- receptors of the heart. Phenylephrine has no effect on b-adrenergic receptors of the bronchi or peripheral blood vessels. A direct action at recep- tors accounts for the greater part of its effects, only a small part being due to its ability to release norepinephrine. Therapeutic doses of phenylephrine mainly cause vasoconstriction. Phenylephrine increases resistance and, to a lesser extent, decreases capacitance of blood vessels. Total peripheral resistance is increased, resulting in increased systolic and diastolic blood pressure. Pulmonary arterial pressure is usually increased, and renal blood flow is usually decreased. Local vasoconstriction and hemostasis occur following topical application or infiltration of phenylephrine into tissues. The main effect of phenylephrine on the heart is bradycardia; it produces a positive inotropic effect on the myocardium in doses greater than those usually used therapeutically. Rarely, the drug may increase the irritability of the heart, causing arrhythmias. Cardiac output is decreased slightly. Phenylephrine increases the work of the heart by increasing peripheral arterial resistance. Phenylephrine has a mild central stimulant effect.
Following oral administration or topical application of phenylephrine to the mucosa, constriction of blood vessels in the nasal mucosa relieves nasal congestion associated with allergy or head colds. Following oral administration, nasal decongestion may occur within 15 or 20 minutes and may persist for up to 4 hours. Phenylephrine is irregularly absorbed from and readily metabolized in the gastrointestinal tract. Phenylephrine is metabolized in the liver and intestine by monoamine oxidase. The metabolites and their route and rate of excretion have not been identified. The pharmacologic action of phenylephrine is terminated at least partially by uptake of the drug into tissues.
Promethazine and phenylephrine may cause marked drowsiness or may impair the mental and/ or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. Ambulatory patients should be told to avoid engaging in such activities until it is known that they do not become drowsy or dizzy from promethazine and phenylephrine therapy. Children should be supervised to avoid potential harm in bike riding or in other hazardous activities.
The concomitant use of alcohol or other central nervous system depressants, including narcotic analgesics, sedatives, hypnotics, and tranquilizers, may have an additive effect and should be avoided or their dosage reduced.
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