Promethazine Hydrochloride and Dextromethorphan Hydrobromide

INDICATIONS AND USAGE Promethazine hydrochloride and dextromethorphan hydrobromide oral solution is indicated for the temporary relief of coughs and upper respiratory symptoms associated with allergy or the common cold.

DOSAGE AND ADMINISTRATION It is important that Promethazine Hydrochloride and Dextromethorphan Hydrobromide Oral Solution is measured with an accurate measuring device (see PRECAUTIONS – Information for Patients ). A household teaspoon is not an accurate measuring device and could lead to overdosage, especially when half a teaspoon is to be measured. It is strongly recommended that an accurate measuring device be used. A pharmacist can provide an appropriate device and can provide instructions for measuring the correct dose. Promethazine Hydrochloride and Dextromethorphan Hydrobromide Oral Solution is CONTRAINDICATED for children under 2 years of age (see WARNINGS – Boxed Warning and Use in Pediatric Patients ). The average effective dose for adults is 5 mL (one teaspoon) every 4 to 6 hours, not to exceed 30.0 mL in 24 hours. For children 6 years to under 12 years of age, the dose is 2.5 to 5.0 mL (one-half to one teaspoon) every 4 to 6 hours, not to exceed 20.0 mL in 24 hours. For children 2 years to under 6 years of age, the dose is 1.25 to 2.5 mL (one-quarter to one-half teaspoon) every 4 to 6 hours, not to exceed 10.0 mL in 24 hours.

CONTRAINDICATIONS Promethazine hydrochloride and dextromethorphan hydrobromide oral solution is contraindicated for use in pediatric patients less than two years of age. Promethazine is contraindicated in comatose states, and 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. Dextromethorphan should not be used in patients receiving a monoamine oxidase inhibitor (MAOI) (see PRECAUTIONS – Drug Interactions).

ADVERSE REACTIONS PROMETHAZINE Central Nervous System – Drowsiness is the most prominent CNS effect of this drug. Sedation, somnolence, blurred vision, dizziness; confusion, disorientation and extrapyramidal symptoms such as oculogyric crisis, torticollis, and tongue protrusion; lassitude, tinnitus, incoordination, fatigue, euphoria, nervousness, diplopia, insomnia, tremors, convulsive seizures, excitation, catatonic-like states, hysteria. Hallucinations have also been reported. Cardiovascular – Increased or decreased blood pressure, tachycardia, bradycardia, faintness. Dermatologic – Dermatitis, photosensitivity, urticaria. Hematologic – Leukopenia, thrombocytopenia, thrombocytopenic purpura, agranulocytosis. Gastrointestinal – Dry mouth, nausea, vomiting, jaundice. Respiratory – Asthma, nasal stuffiness, respiratory depression (potentially fatal) and apnea (potentially fatal) (see WARNINGS –Respiratory Depression.) Other – Angioneurotic edema. Neuroleptic malignant syndrome (potentially fatal) has also been reported (see WARNINGS –Neuroleptic Malignant Syndrome.) Paradoxical Reactions Hyperexcitability and abnormal movements have been reported in patients following a single administration of promethazine hydrochloride and dextromethorphan hydrobromide oral solution. Consideration should be given to the discontinuation of promethazine hydrochloride and to the use of other drugs if these reactions occur. Respiratory depression, nightmares, delirium, and agitated behavior have also been reported in some of these patients. DEXTROMETHORPHAN Dextromethorphan hydrobromide occasionally causes slight drowsiness, dizziness, and gastrointestinal disturbances. To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions Monoamine Oxidase (MAO) Inhibitors – Hyperpyrexia, hypotension, and death have been reported coincident with the co-administration of monoamine oxidase (MAO) inhibitors and products containing dextromethorphan. Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAO inhibitors and phenothiazines are used concomitantly. Thus, concomitant administration of Promethazine Hydrochloride and Dextromethorphan Hydrobromide Oral Solution and MAO inhibitors should be avoided (see CONTRAINDICATIONS ). CNS Depressants – Promethazine may increase, prolong, or intensify the sedative action of other central-nervous-system depressants, such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore, such agents should be avoided or administered in reduced dosage to patients receiving promethazine. When given concomitantly with Promethazine Hydrochloride and Dextromethorphan Hydrobromide Oral Solution, 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. Epinephrine – Because of the potential for promethazine to reverse epinephrine’s vasopressor effect, epinephrine should NOT be used to treat hypotension associated with Promethazine Hydrochloride and Dextromethorphan Hydrobromide Oral Solution overdose. Anticholinergics – Concomitant use of other agents with anticholinergic properties should be undertaken with caution.

DESCRIPTION Each teaspoon (5 mL) of promethazine hydrochloride and dextromethorphan hydrobromide oral solution contains 6.25 mg promethazine hydrochloride, USP and 15 mg dextromethorphan hydrobromide, USP in a flavored oral solution base with a pH between 4.7 and 5.2. Alcohol 7%. The inactive ingredients present are ascorbic acid, citric acid, D&C yellow #10, FD&C yellow #6, menthol, methylparaben, orange flavor (contains ethyl alcohol, nature-identical flavouring substances, flavoring preparations, propylene glycol and water), pineapple flavor (contains artificial flavouring substances, flavoring preparations, nature-identical flavouring substances and propylene glycol), propylene glycol, propylparaben, purified water, saccharin sodium, sodium benzoate, sucrose and trisodium citrate dihydrate. Promethazine, USP is a racemic compound; The molecular formula is C 17 H 20 N 2 S•HCI, and its molecular weight is 320.88. Promethazine hydrochloride, USP a phenothiazine derivative, is chemically designated as (±)-10-[2-(Dimethylamino)propyl] phenothiazine monohydrochloride with the following structural formula: Promethazine hydrochloride, USP occurs as a white or faintly yellowish crystalline powder which slowly oxidizes and turns blue on prolonged exposure to air. It is very soluble in water, freely soluble in ethanol and in methanol, practically insoluble in ethyl acetate, diethyl ether and acetone. Dextromethorphan hydrobromide, USP is a salt of the methyl ether of the dextrorotatory isomer of levorphanol, a narcotic analgesic. It is chemically designated as 3-methoxy-17-methyl-9α, 13α, 14α-morphinan hydrobromide monohydrate with the following structural formula: Dextromethorphan hydrobromide, USP occurs as practically white crystals or crystalline powder having faint odour, freely soluble in alcohol and chloroform, sparingly soluble in water, insoluble in ether. The molecular formula is C 18 H 25 NO•HBr•H 2 O, and the molecular weight of 370.32. promethazinestructure promethazinestructure2

OVERDOSAGE PROMETHAZINE Signs and symptoms of overdosage with promethazine hydrochloride range from mild depression of the central nervous system and cardiovascular system to profound hypotension, respiratory depression, unconsciousness, and sudden death. Other reported reactions include hyperreflexia, hypertonia, ataxia, athetosis and extensor-plantar reflexes (Babinski reflex). Stimulation may be evident, especially in children and geriatric patients. Convulsions may rarely occur. A paradoxical-type 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. DEXTROMETHORPHAN Dextromethorphan may produce central excitement and mental confusion. Very high doses may produce respiratory depression. One case of toxic psychosis (hyperactivity, marked visual and auditory hallucinations) after ingestion of a single dose of 20 tablets (300 mg) of dextromethorphan has been reported. Treatment Treatment of overdosage with promethazine hydrochloride and dextromethorphan hydrobromide oral solution 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. The antidotal efficacy of narcotic antagonists to dextromethorphan has not been established; note that any of the depressant effects of promethazine are not reversed by naloxone. Avoid analeptics, which may cause convulsions. The treatment of choice for resulting hypotension is administration of intravenous fluids, accompanied by repositioning if indicated. In the event that vasopressors are considered for the management of severe hypotension which does not respond to intravenous fluids and repositioning, the administration of norepinephrine or phenylephrine should be considered. EPINEPHRINE SHOULD NOT BE USED, since its use in a patient with partial adrenergic blockade may further lower the blood pressure. Extrapyramidal reactions may be treated with anticholinergic antiparkinson agents, diphenhydramine, or barbiturates. Oxygen may also be administered. Limited experience with dialysis indicates that it is not helpful.

HOW SUPPLIED Promethazine hydrochloride and dextromethorphan hydrobromide oral solution is available as a clear, yellow to orange colored, berry-flavored oral solution containing 6.25 mg promethazine hydrochloride, USP, 15 mg dextromethorphan hydrobromide, USP and 7 percent alcohol in each teaspoonful (5 mL). It is supplied as follows: 4 fl. oz (118 mL) NDC 65162-680-86 16 fl. oz (473 mL) NDC 65162-680-90 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in tight, light-resistant container as defined in the USP. KEEP THIS AND ALL DRUGS OUT OF THE REACH OF CHILDREN. Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 12-2022-01