Dextromethorphan Hydrobromide and Promethazine Hydrochloride

DEXTROMETHORPHAN HYDROBROMIDE AND PROMETHAZINE HYDROCHLORIDE- dextromethorphan hydrobromide and promethazine hydrochloride syrup
Proficient Rx LP

(Promethazine Hydrochloride 6.25 mg/5 mL & Dextromethorphan Hydrobromide 15 mg/5 mL)

Rx only

DESCRIPTION

Each 5 mL (one teaspoonful), for oral administration contains: Dextromethorphan hydrobromide 15 mg; promethazine hydrochloride 6.25 mg. Alcohol 7.0%.

Inactive Ingredients: artificial pineapple flavor, artificial raspberry flavor, ascorbic acid, citric acid anhydrous, dehydrated alcohol, D&C Yellow No. 10, edetate disodium, FD&C Yellow No. 6, glycerin, liquid sugar, methylparaben, purified water, saccharin sodium, sodium benzoate, sodium citrate dihydrate and sodium propionate.

Dextromethorphan hydrobromide 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. Dextromethorphan hydrobromide occurs as white crystals sparingly soluble in water and freely soluble in alcohol. It has a molecular weight of 370.32, a molecular formula of C18 H25 NO•HBr•H2 O, and the following structural formula:

Chemical Structure
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Promethazine is a racemic compound. Promethazine hydrochloride, a phenothiazine derivative, is chemically designated as 10H -Phenothiazine-10-ethanamine, N ,N , α-trimethyl-, 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 320.88, a molecular formula of C17 H20 N2 S•HCl, and the following structural formula:

Chemical Structure
(click image for full-size original)

CLINICAL PHARMACOLOGY

Dextromethorphan

Dextromethorphan is an antitussive agent and, unlike the isomeric levorphanol, it has no analgesic or addictive properties.

The drug acts centrally and elevates the threshold for coughing. It is about equal to codeine in depressing the cough reflex. In therapeutic dosage dextromethorphan does not inhibit ciliary activity.

Dextromethorphan is rapidly absorbed from the gastrointestinal tract and exerts its effect in 15 to 30 minutes. The duration of action after oral administration is approximately three to six hours. Dextromethorphan is metabolized primarily by liver enzymes undergoing O-demethylation, N-demethylation, and partial conjugation with glucuronic acid and sulfate. In humans, (+)-3-hydroxy-N-methyl-morphinan, (+)-3-hydroxymorphinan, and traces of unmetabolized drug were found in urine after oral administration.

Promethazine

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 dopamine antagonist properties.

Promethazine is an H1 receptor blocking agent. In addition to its antihistaminic action, it provides clinically useful sedative and antiemetic effects.

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.

INDICATIONS AND USAGE

Promethazine hydrochloride and dextromethorphan hydrobromide syrup is indicated for the temporary relief of coughs and upper respiratory symptoms associated with allergy or the common cold.

CONTRAINDICATIONS

Dextromethorphan should not be used in patients receiving a monoamine oxidase inhibitor (MAOI) (see PRECAUTIONS, Drug Interactions).

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.

WARNINGS

WARNING

PROMETHAZINE HYDROCHLORIDE SHOULD NOT BE USED IN PEDIATRIC PATIENTS LESS THAN 2 YEARS OF AGE BECAUSE OF THE POTENTIAL FOR FATAL RESPIRATORY DEPRESSION.

POSTMARKETING CASES OF RESPIRATORY DEPRESSION, INCLUDING FATALITIES, HAVE BEEN REPORTED WITH USE OF PROMETHAZINE HYDROCHLORIDE IN PEDIATRIC PATIENTS LESS THAN 2 YEARS OF AGE. A WIDE RANGE OF WEIGHT-BASED DOSES OF PROMETHAZINE HYDROCHLORIDE HAVE RESULTED IN RESPIRATORY DEPRESSION IN THESE PATIENTS.

CAUTION SHOULD BE EXERCISED WHEN ADMINISTERING PROMETHAZINE HYDROCHLORIDE TO PEDIATRIC PATIENTS 2 YEARS OF AGE AND OLDER. IT IS RECOMMENDED THAT THE LOWEST EFFECTIVE DOSE OF PROMETHAZINE HYDROCHLORIDE BE USED IN PEDIATRIC PATIENTS 2 YEARS OF AGE AND OLDER AND CONCOMITANT ADMINISTRATION OF OTHER DRUGS WITH RESPIRATORY DEPRESSANT EFFECTS BE AVOIDED.

Dextromethorphan

Administration of dextromethorphan may be accompanied by histamine release and should be used with caution in atopic children.

Promethazine

CNS Depression

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 impairment may be amplified by concomitant use 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 either be eliminated or given in reduced dosage in the presence of promethazine HCl (see PRECAUTIONS-Information for Patients and Drug Interactions).

Respiratory Depression

Promethazine may lead to potentially fatal respiratory depression.

Use of Promethazine in patients with compromised respiratory function (e.g., COPD, sleep apnea) should be avoided.

Lower Seizure Threshold

Promethazine may lower seizure threshold. It should be used with caution in persons with seizure disorders or in persons who are using concomitant medications, such as narcotics or local anesthetics, which may also affect seizure threshold.

Bone-Marrow Depression

Promethazine should be used with caution in patients with bone-marrow depression. Leukopenia and agranulocytosis have been reported, usually when promethazine HCl has been used in association with other known marrow-toxic agents.

Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with promethazine HCl alone or in combination with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias).

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g. pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include 1) immediate discontinuation of promethazine HCl, antipsychotic drugs, if any, and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

Since recurrences of NMS have been reported with phenothiazines, the reintroduction of promethazine HCl should be carefully considered.

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