DESCRIPTION

Each rectal suppository contains 12.5 mg or 25 mg promethazine hydrochloride. The inactive ingredients present are ascorbyl palmitate, colloidal silicon dioxide, glyceryl monostearate, hard fat, and white wax. Promethazine hydrochloride suppositories, USP are for rectal administration only.
Promethazine hydrochloride is a racemic compound; the empirical formula is C 17H 20N 2S•HCl and its molecular weight is 320.88.
Promethazine hydrochloride, a phenothiazine derivative, is designated chemically as (±)-10-[2-(Dimethylamino)propyl] phenothiazine monohydrochloride with the following structural formula:

 Promethazine hydrochloride USP occurs as a white to faint yellowish, crystalline powder. It is very soluble in water, freely soluble in ethanol and in methanol, practically insoluble in ethyl acetate, diethyl ether and acetone.

CLINICAL PHARMACOLOGY

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 H 1 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 suppositories are useful for:
Perennial and seasonal allergic rhinitis.
Vasomotor rhinitis.
Allergic conjunctivitis due to inhalant allergens and foods.
Mild, uncomplicated allergic skin manifestations of urticaria and angioedema.
Amelioration of allergic reactions to blood or plasma.
Dermographism.
Anaphylactic reactions, as adjunctive therapy to epinephrine and other standard measures, after the acute manifestations have been controlled.
Preoperative, postoperative, or obstetric sedation.
Prevention and control of nausea and vomiting associated with certain types of anesthesia and surgery.
Therapy adjunctive to meperidine or other analgesics for control of post-operative pain.
Sedation in both children and adults, as well as relief of apprehension and production of light sleep from which the patient can be easily aroused.
Active and prophylactic treatment of motion sickness.
Antiemetic therapy in postoperative patients.

CONTRAINDICATIONS

Promethazine hydrochloride suppositories are contraindicated for use in pediatric patients less than two years of age.
Promethazine hydrochloride suppositories are 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

CNS Depression
Promethazine hydrochloride suppositories 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 hydrochloride (see PRECAUTIONS−Information for Patients and Drug Interactions).
Respiratory Depression
Promethazine hydrochloride suppositories may lead to potentially fatal respiratory depression.
Use of Promethazine hydrochloride suppositories in patients with compromised respiratory function (e.g., COPD, sleep apnea) should be avoided.
Lower Seizure Threshold
Promethazine hydrochloride suppositories 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 hydrochloride suppositories should be used with caution in patients with bone-marrow depression. Leukopenia and agranulocytosis have been reported, usually when promethazine hydrochloride 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 hydrochloride 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 hydrochloride, 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 hydrochloride should be carefully considered.
Use in Pediatric Patients
PROMETHAZINE HYDROCHLORIDE SUPPOSITORIES ARE CONTRAINDICATED FOR USE IN PEDIATRIC PATIENTS LESS THAN TWO YEARS OF AGE.
CAUTION SHOULD BE EXERCISED WHEN ADMINISTERING PROMETHAZINE HYDROCHLORIDE SUPPOSITORIES TO PEDIATRIC PATIENTS 2 YEARS OF AGE AND OLDER BECAUSE OF THE POTENTIAL FOR FATAL RESPIRATORY DEPRESSION. RESPIRATORY DEPRESSION AND APNEA, SOMETIMES ASSOCIATED WITH DEATH, ARE STRONGLY ASSOCIATED WITH PROMETHAZINE PRODUCTS AND ARE NOT DIRECTLY RELATED TO INDIVIDUALIZED WEIGHT-BASED DOSING, WHICH MIGHT OTHERWISE PERMIT SAFE ADMINISTRATION. CONCOMITANT ADMINISTRATION OF PROMETHAZINE PRODUCTS WITH OTHER RESPIRATORY DEPRESSANTS HAS AN ASSOCIATION WITH RESPIRATORY DEPRESSION, AND SOMETIMES DEATH, IN PEDIATRIC PATIENTS.
ANTIEMETICS ARE NOT RECOMMENDED FOR TREATMENT OF UNCOMPLICATED VOMITING IN PEDIATRIC PATIENTS, AND THEIR USE SHOULD BE LIMITED TO PROLONGED VOMITING OF KNOWN ETIOLOGY. THE EXTRAPYRAMIDAL SYMPTOMS WHICH CAN OCCUR SECONDARY TO PROMETHAZINE HYDROCHLORIDE SUPPOSITORIES ADMINISTRATION MAY BE CONFUSED WITH THE CNS SIGNS OF UNDIAGNOSED PRIMARY DISEASE, e.g., ENCEPHALOPATHY OR REYE’S SYNDROME. THE USE OF PROMETHAZINE HYDROCHLORIDE SUPPOSITORIES SHOULD BE AVOIDED IN PEDIATRIC PATIENTS WHOSE SIGNS AND SYMPTOMS MAY SUGGEST REYE’S SYNDROME OR OTHER HEPATIC DISEASES.
Excessively large dosages of antihistamines, including promethazine hydrochloride suppositories, in pediatric patients may cause sudden death (see OVERDOSAGE). Hallucinations and convulsions have occurred with therapeutic doses and overdoses of promethazine hydrochloride in pediatric patients. In pediatric patients who are acutely ill associated with dehydration, there is an increased susceptibility to dystonias with the use of promethazine hydrochloride.
Other Considerations
Administration of promethazine hydrochloride has been associated with reported cholestatic jaundice.

PRECAUTIONS

ADVERSE REACTIONS

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. 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.

OVERDOSAGE

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.
Treatment
Treatment of overdosage 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 hydrochloride 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 patients with partial adrenergic blockade may further lower the blood pressure. Extrapyramidal reactions may be treated with 
anticholinergic antiparkinsonian agents, diphenhydramine, or barbiturates. Oxygen may also be administered.
Limited experience with dialysis indicates that it is not helpful.

DOSAGE AND ADMINISTRATION

Promethazine hydrochloride suppositories are contraindicated for children under 2 years of age (see WARNINGS–Black Box Warningand Use in Pediatric Patients).
Promethazine hydrochloride suppositories are for rectal administration only.
Allergy
The average oral dose is 25 mg taken before retiring; however, 12.5 mg may be taken before meals and on retiring, if necessary. Single 25-mg doses at bedtime or 6.25 to 12.5 mg taken three times daily will usually suffice. After initiation of treatment in children or adults, dosage should be adjusted to the smallest amount adequate to relieve symptoms. The administration of promethazine hydrochloride in 25-mg doses will control minor transfusion reactions of an allergic nature.
Motion Sickness
The average adult dose is 25 mg taken twice daily. The initial dose should be taken one-half to one hour before anticipated travel and be repeated 8 to 12 hours later, if necessary. On succeeding days of travel, it is recommended that 25 mg be given on arising and again before the evening meal. For children, promethazine hydrochloride rectal suppositories, 12.5 to 25 mg, twice daily, may be administered.
Nausea and Vomiting
Antiemetics should not be used in vomiting of unknown etiology in children and adolescents (see WARNINGS-Use in Pediatric Patients ).
The average effective dose of promethazine hydrochloride for the active therapy of nausea and vomiting in children or adults is 25 mg. 12.5- to 25-mg doses may be repeated, as necessary, at 4- to 6-hour intervals.
For nausea and vomiting in children, the usual dose is 0.5 mg per pound of body weight, and the dose should be adjusted to the age and weight of the patient and the severity of the condition being treated.
For prophylaxis of nausea and vomiting, as during surgery and the postoperative period, the average dose is 25 mg repeated at 4- to 6-hour intervals, as necessary.
Sedation
This product relieves apprehension and induces a quiet sleep from which the patient can be easily aroused. Administration of 12.5 to 25 mg promethazine hydrochloride by rectal 
suppository at bedtime will provide sedation in children. Adults usually require 25 to 50 mg for nighttime, presurgical, or obstetrical sedation.
Pre- and Postoperative Use
Promethazine hydrochloride in 12.5- to 25-mg doses for children and 50-mg doses for adults the night before surgery relieves apprehension and produces a quiet sleep.
For preoperative medication, children require doses of 0.5 mg per pound of body weight in combination with an appropriately reduced dose of narcotic or barbiturate and the appropriate dose of an atropine-like drug. Usual adult dosage is 50 mg promethazine hydrochloride with an appropriately reduced dose of narcotic or barbiturate and the required amount of a belladonna alkaloid.
Postoperative sedation and adjunctive use with analgesics may be obtained by the administration of 12.5 to 25 mg in children and 25- to 50-mg doses in adults.
Promethazine Hydrochloride Rectal Suppositories are contraindicated for children under 2 years of age.

HOW SUPPLIED

Promethazine Hydrochloride Rectal Suppositories USP are available in boxes of 12 as follows:
12.5 mg, white to off-white colored bullet shaped suppository wrapped in an Alu/PE shell.
NDC    31722-040-31
25 mg, white to off-white colored bullet shaped suppository wrapped in an Alu/PE shell.
NDC    31722-041-31
Store refrigerated between 2º to 8ºC (36º to 46ºF).
Dispense in well-closed container.
For more information, call Annora Pharma Private Limited at 1-866-495-1995.

Manufactured for:
Camber Pharmaceuticals, Inc.
Piscataway, NJ 08854
By: Annora Pharma Pvt. Ltd.
Sangareddy - 502313, Telangana, India. 

Revised: 07/2022

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Promethazine Hydrochloride Suppositories, USP 12.5 mg Carton Label

Promethazine Hydrochloride Suppositories, USP 25 mg Carton Label