PROMETHAZINE HYDROCHLORIDE

Promethazine HCl occurs as a white to faint yellow, practically odorless, crystalline powder which slowly oxidizes and turns blue on prolonged exposure to air. It is freely soluble in water and soluble in alcohol.

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 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-desmethylpromethazine are the predominant metabolites appearing in the urine.

PROMETHAZINE HYDROCHLORIDE INDICATIONS AND USAGE

Promethazine HCl Oral Solution is 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 postoperative 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.

PROMETHAZINE HYDROCHLORIDE CONTRAINDICATIONS

Promethazine HCl Oral Solution is contraindicated for use in pediatric patients less than two years of age.

Promethazine HCl Oral Solution 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

PRECAUTIONS

General

Drugs having anticholinergic properties should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, stenosing peptic ulcer, pyloroduodenal obstruction, and bladder-neck obstruction.

Promethazine HCl Oral Solution should be used cautiously in persons with cardiovascular disease or with impairment of liver function.

Information for Patients

Patients should be advised to measure Promethazine HCl Oral Solution with an accurate measuring device. A household teaspoon is not an accurate measuring device and could lead to overdosage, especially when a half a teaspoon is measured. A pharmacist can recommend an appropriate measuring device and can provide instructions for measuring the correct dose.

Promethazine HCl Oral Solution may cause marked drowsiness or 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 therapy. Pediatric patients 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, such as sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers may enhance impairment (see WARNINGS-CNS Depression and PRECAUTIONS–Drug Interactions ).

Patients should be advised to report any involuntary muscle movements.

Avoid prolonged exposure to the sun.

A patient information leaflet is included and summarizes important information about promethazine.

Drug Interactions

CNS Depressants – Promethazine HCl Oral Solution 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 HCl. When given concomitantly with Promethazine HCl 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 HCl 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 HCl Oral Solution to reverse epinephrine’s vasopressor effect, epinephrine should NOT be used to treat hypotension associated with Promethazine HCl Oral Solution overdose.

Anticholinergics– Concomitant use of other agents with anticholinergic properties should be undertaken with caution.

Monoamine Oxidase Inhibitors (MAOI) – Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAOI and phenothiazines are used concomitantly. This possibility should be considered with Promethazine HCl Oral Solution.

Drug/Laboratory Test Interactions

The following laboratory tests may be affected in patients who are receiving therapy with promethazine HCl:

Pregnancy Tests

Diagnostic pregnancy tests based on immunological reactions between HCG and anti-HCG may result in false-negative or false-positive interpretations.

Glucose Tolerance Test

An increase in blood glucose has been reported in patients receiving promethazine HCl.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to assess the carcinogenic potential of promethazine, nor are there other animal or human data concerning carginogenicity, mutagenicity, or impairment of fertility with this drug. Promethazine was nonmutagenic in the Salmonella test system of Ames.

Pregnancy

Teratogenic Effects-Pregnancy Category C

Teratogenic effects have not been demonstrated in rat-feeding studies at doses of 6.25 and 12.5 mg/kg of promethazine HCl. These doses are from approximately 2.1 to 4.2 times the maximum recommended total daily dose of promethazine for a 50-kg subject, depending upon the indication for which the drug is prescribed. Daily doses of 25 mg/kg intraperitoneally have been found to produce fetal mortality in rats.

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 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 HCl Oral Solution in pregnant women.

Promethazine HCl Oral Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Promethazine HCl Oral Solution administered to a pregnant woman within two weeks of delivery may inhibit platelet aggregation in the newborn.

Labor And Delivery

Promethazine HCl Oral Solution may be used alone or as an adjunct to narcotic analgesics during labor (see DOSAGE AND ADMINISTRATION ). Limited data suggest that use of Promethazine HCl Oral Solution during labor and delivery does not have an appreciable effect on the duration of labor or delivery and does not increase the risk of need for intervention in the newborn. The effect on later growth and development of the newborn is unknown. (See also Nonteratogenic Effects ).

Nursing Mothers

It is not known whether promethazine HCl is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Promethazine HCl Oral Solution, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Promethazine HCl Oral Solution is contraindicated for use in pediatric patients less than two years of age (see WARNINGS – Boxed Warning and Use in Pediatric Patients ).

Promethazine HCl Oral Solution should be used with caution in pediatric patients 2 years of age and older (see WARNINGS-Use in Pediatric Patients ).

Geriatric Use

Clinical studies of promethazine formulations did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of Promethazine HCl Oral Solution and observed closely.

PROMETHAZINE HYDROCHLORIDE 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 HCl. Consideration should be given to the discontinuation of promethazine HCl 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 HCl 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 HCl 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 antiparkinson agents, diphenhydramine, or barbiturates. Oxygen may also be administered.

Limited experience with dialysis indicates that it is not helpful.

PROMETHAZINE HYDROCHLORIDE DOSAGE AND ADMINISTRATION

It is important that Promethazine HCl 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 HCl Oral Solution is contraindicated for children under 2 years of age (see WARNINGS – Boxed Warning and Use in Pediatric Patients).

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 HCl 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 taken on arising and again before the evening meal. For children, 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 HCl Oral Solution for the active therapy of nausea and vomiting in children or adults is 25 mg. When oral medication cannot be tolerated, the dose should be given parenterally (cf. Promethazine Hydrochloride Injection) or by rectal suppository. 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 HCl Oral Solution by the oral route 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 HCl Oral Solution 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 HCl Oral Solution 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 HCl Oral Solution is contraindicated for children under 2 years of age.

HOW SUPPLIED

Promethazine Hydrochloride Oral Solution, USP, 6.25 mg/5 mL, is a clear, green oral solution supplied as follows:

4oz Bottle - 68788-9543-1

Keep bottles tightly closed.

Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature.]

Protect from light.

Dispense in a tight, light-resistant container (USP/NF) with a child-resistant closure.

Distributed by:
Caraco Pharmaceutical Laboratories, Ltd.
Detroit, Michigan 48202

Manufactured by:
SUN Pharmaceutical Industries, Inc.
Bryan, Ohio 43506

Relabeled by Preferred Pharmaceuticals, Inc.

PATIENT INFORMATION LEAFLET PROMETHAZINE HYDROCHLORIDE ORAL SOLUTION, USP 6.25 mg/5 mL(Promethazine Hydrochloride Syrup, 6.25 mg per 5 mL)Rx Only

What Is Promethazine HCl Oral Solution?

Promethazine is an antihistamine which can be taken by mouth as an Oral Solution or tablet, rectally as a suppository, or by injection. It can be used for:

• •“hay fever,” or, a stuffy runny nose from allergy
• •watery, itchy eyes due to inhaled allergies and foods
• •mild allergic skin reactions with itching and swelling
• •allergic reactions to blood or plasma
• •dermographism, a form of hives known as “skin writing”
• •serious allergic reactions along with epinephrine and other treatments
• •sedation before or after surgery, or during childbirth
• •prevention and control of nausea and vomiting after surgery
• •along with meperidine (demerol) or other pain medicines
• •sedation, relief of anxiety, and production of light sleep from which the patient can be easily aroused
• •treatment and prevention of motion sickness

Who Should Not Use Promethazine HCl Oral Solution?

Promethazine should not be given to:

• •children under two years of age
• •patients who are unconscious
• •patients who are allergic to promethazine, any of the ingredients in promethazine, or to other phenothiazines
• •patients with lung symptoms including asthma
• •children who are vomiting unless the vomiting is prolonged and there is a known cause 

What Are The Risks?

The following are the major potential risks and side effects of promethazine HCl Oral Solution therapy. However, this list is not complete.

• • Severe drowsiness and reduced mental alertness. Promethazine HCl Oral Solution may cause drowsiness which may impair your ability to ride a bike, drive a car, or operate machinery. This may be worsened if taken with alcohol or other drugs that also cause central nervous system (CNS) slowing such as sedatives, pain medicines, tranquilizers or certain drugs for depression.
• • Serious breathing problems. Promethazine HCl Oral Solution should not be used in patients with poor lung function such as chronic obstructive lung disease or breathing problems while sleeping (sleep apnea).
• • Increased risk of seizures. Promethazine HCl Oral Solution should be used with caution in patients with seizures or who are on other medicines which may also increase the risk of seizures.
• • Bone-marrow problems and blood cell production. Promethazine HCl Oral Solution should not be used in patients with bone-marrow problems or used with other drugs that affect the bone marrow's production of blood cells.
• • Neuroleptic malignant syndrome. This potentially deadly syndrome includes symptoms such as fever, muscle rigidity, mental changes, changes in pulse or blood pressure, fast heartbeat, increased sweating or irregular heart rhythm.
• • The most common side effects are drowsiness, changes in blood pressure, skin reactions, blood cell changes and breathing problems. Increased excitability or abnormal movements may occur after one dose of promethazine. If they do, consult your doctor about using another medicine. 

What Should I Tell My Healthcare Professional?

Before you start taking promethazine HCl Oral Solution, tell your healthcare professional if you:

• •have narrow-angle glaucoma
• •have an enlarged prostate
• •have a stomach ulcer
• •have an intestinal blockage
• •have a bladder blockage
• •have heart problems
• •have liver problems
• •have breathing or lung problems
• •have sleep apnea (breathing problems when sleeping)
• •have seizures
• •drink alcohol
• •are trying to become pregnant, are already pregnant, or are breast-feeding 

Can Other Medicines Or Food Affect Promethazine?

Promethazine HCl Oral Solution and certain other medicines can interact with each other. Tell your healthcare professional about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may affect how promethazine works or promethazine may affect how your other medicines work. Know the medicines you take. Keep a list of them with you to show your healthcare professional.

Especially tell your healthcare professional if you take:

• •medicines that affect your brain such as anti-anxiety medicine, sleeping pills, pain medicines, sedatives, narcotics, antidepressants or tranquilizers
• •epinephrine
• •a monoamine oxidase inhibitor (MAOI) which is used to treat depression or other mental disorders
• •medicines called anticholinergics

Storage

Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature.]
Dispense in a tight, light-resistant container (USP/NF) with a child-resistant closure.

Distributed by:
Caraco Pharmaceutical Laboratories, Ltd.
Detroit, Michigan 48202

Manufactured by:
SUN Pharmaceutical Industries, Inc.
Bryan, Ohio 43506

Relabeled by Preferred Pharmaceuticals, Inc.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Promethazine Hydrochloride Oral Solution, USP6.25 mg/5 mL

(Promethazine Hydrochloride Syrup, 6.25 mg per 5 mL)

Alcohol 7% v/v

Rx Only

DO NOT USE IF INNER FOIL SEAL PRINTED “SEALED FOR YOUR
PROTECTION” IS BROKEN OR MISSING.
Each teaspoonful (5mL) contains 6.25 mg of Promethazine Hydrochloride, USP. Alcohol 7% v/v.
Usual Dosage: See accompanying package insert.
WARNINGS: KEEP THIS AND ALL DRUGS OUT OF THE REACH OF
CHILDREN.
In case of accidential overdose, seek professional assistance or contact a Poison Control Center
immediately.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature.]
KEEP TIGHTLY CLOSED. PROTECT FROM LIGHT.
Dispense in a tight, light-resistant container (USP/NF) with a child-resistant closure.
Dist. By: Caraco Pharmaceutical Laboratories, Ltd., Detroit, Michigan 48202
Mfg. by: SUN Pharmaceutical Industries, Inc., Bryan, Ohio 43506
5975L01                                                                                                Iss. 05/09