PHENERGAN Injection (promethazine hydrochloride injection, USP) is a sterile, pyrogen-free solution for deep intramuscular or intravenous administration. Promethazine hydrochloride (10 H -Phenothiazine-10-ethanamine, N,N,α -trimethyl-, monohydrochloride, (±)-) is a racemic compound and has the following structural formula: C 17 H 21 ClN 2 S MW 320.88 Each mL contains promethazine hydrochloride, either 25 mg or 50 mg, edetate disodium 0.1 mg, calcium chloride 0.04 mg, sodium metabisulfite 0.25 mg and phenol 5 mg in Water for Injection. pH 4.0 to 5.5; buffered with acetic acid-sodium acetate. PHENERGAN Injection is a clear, colorless solution. The product is light sensitive. It should be inspected before use and discarded if either color or particulate is observed. chemical structure

PHENERGAN Injection is indicated for the following conditions: Amelioration of allergic reactions to blood or plasma. In anaphylaxis as an adjunct to epinephrine and other standard measures after the acute symptoms have been controlled. For other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated. For sedation and relief of apprehension and to produce light sleep from which the patient can be easily aroused. Active treatment of motion sickness. Prevention and control of nausea and vomiting associated with certain types of anesthesia and surgery. As an adjunct to analgesics for the control of postoperative pain. Preoperative, postoperative, and obstetric (during labor) sedation. Intravenously in special surgical situations, such as repeated bronchoscopy, ophthalmic surgery, and poor-risk patients, with reduced amounts of meperidine or other narcotic analgesic as an adjunct to anesthesia and analgesia.

Important Administration Information for Adult and Pediatric Patients 2 Years of Age and Older The preferred route of administration of PHENERGAN Injection is by deep intramuscular administration . PHENERGAN Injection may be administered intravenously after dilution as recommended below . If pain occurs at the injection site during intravenous infusion, immediately discontinue the infusion, and evaluate for possible arterial injection or perivascular extravasation. Allergic Conditions The average adult dose is 25 mg. This dose may be repeated within two hours if necessary, but continued therapy, if indicated, should be via the oral route as soon as existing circumstances permit. After initiation of treatment, dosage should be adjusted to the smallest amount adequate to relieve symptoms. The average adult dose for amelioration of allergic reactions to blood or plasma is 25 mg. Sedation In hospitalized adult patients, nighttime sedation may be achieved by a dose of 25 to 50 mg of PHENERGAN Injection. Nausea and Vomiting For control of nausea and vomiting, the usual adult dose is 12.5 to 25 mg, not to be repeated more frequently than every four hours. When used for control of postoperative nausea and vomiting, the dosage of analgesics and barbiturates should be reduced accordingly . Antiemetics should not be used in vomiting of unknown etiology in children and adolescents . Preoperative and Postoperative Use As an adjunct to preoperative or postoperative medication, 25 to 50 mg of PHENERGAN Injection in adults may be combined with appropriately reduced doses of analgesics and atropine-like drugs as desired. Dosage of concomitant analgesic or hypnotic medication should be reduced accordingly . PHENERGAN Injection is contraindicated for use in pediatric patients less than two years of age. Obstetrics PHENERGAN Injection in doses of 50 mg will provide sedation and relieve apprehension in the early stages of labor. When labor is definitely established, 25 to 75 mg (average dose, 50 mg) PHENERGAN Injection may be given with an appropriately reduced dose of any desired narcotic . If necessary, PHENERGAN Injection with a reduced dose of analgesic may be repeated once or twice at four-hour intervals in the course of a normal labor. A maximum total dose of 100 mg of PHENERGAN Injection may be administered during a 24-hour period to patients in labor. Pediatric Patients PHENERGAN Injection is contraindicated for use in pediatric patients less than 2 years of age . Caution should be exercised when administering promethazine hydrochloride to pediatric patients 2 years of age or 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 . In pediatric patients 2 years of age and older, the dosage should not exceed half that of the suggested adult dose. As an adjunct to premedication, the suggested dose is 1.1 mg per kg of body weight in combination with an appropriately reduced dose of narcotic or barbiturate and the appropriate dose of an atropine-like drug . Antiemetics should not be used in vomiting of unknown etiology in pediatric patients. Preparation and Administration Instructions for Diluted Intravenous Infusion in Adults Inspect the solution for particulate matter and discoloration, before dilution, after dilution, and before administration. Discard the vial, ampule, or bag if particulates and/or discoloration are observed. 1. Determine the recommended dose of promethazine hydrochloride injection. 2. Aseptically withdraw the required volume from the vial or ampule and transfer it into an infusion bag. Use a filter needle when withdrawing promethazine hydrochloride injection from the ampule. 3. Dilute with the recommended volume of 0.9% Sodium Chloride Injection, see Table 1. Avoid mixing and/or diluting with any other drugs or solutions other than 0.9% Sodium Chloride Injection. 4. Gently invert the infusion bag. 5. Check patency of the access site before administration. 6. Administer the diluted solution through an intravenous catheter, inserted in a large vein (preferably through a central venous catheter), over 20 to 40 minutes; for maximum infusion rates, see Table 1. Do NOT administer via an intravenous catheter in the hand or wrist. 7. If pain occurs at the injection site during intravenous infusion, immediately discontinue the infusion and evaluate for possible arterial injection or perivascular extravasation. Table 1. Preparation and Infusion Information by Adult Dose of PHENERGAN Injection Dose of PHENERGAN Injection Volume of 0.9% Sodium Chloride Injection for Dilution Maximum Concentration of the Diluted PHENERGAN Injection Solution Maximum Rate of Infusion 12.5 mg 50 mL 1 mg/mL 2.5 mL/minute 25 mg 50 mL 2.5 mL/minute 50 mg 50 mL 2.5 mL/minute 75 mg 100 mL 5 mL/minute Preparation and Administration Instructions for Diluted Intravenous Infusion to Pediatric Patients 2 Years of Age and Older Inspect the solution for particulate matter and discoloration, before dilution, after dilution, and before administration. Discard the vial, ampule, syringe or bag if particulates and/or discoloration are observed. 1. Determine the recommended dose of promethazine hydrochloride injection for pediatric patients 2 years of age and older. 2. Aseptically withdraw the required volume from the vial or ampule and transfer it into an appropriately sized syringe or bag for use with an infusion pump. Use a filter needle when withdrawing promethazine hydrochloride injection from the ampule. 3. Dilute with the recommended volume of 0.9% Sodium Chloride Injection, see Table 2. Avoid mixing and/or diluting with any other drugs or solutions other than 0.9% Sodium Chloride Injection. 4. Gently invert the syringe or bag. 5. Check patency of the access site before administration. 6. Administer the diluted solution through an intravenous catheter, inserted in a large vein (preferably through a central venous catheter) with a maximum infusion rate of 1.25 mL/minute. Do NOT administer via an intravenous catheter in the hand or wrist. 7. If pain occurs at the injection site during intravenous infusion, immediately discontinue the infusion and evaluate for possible arterial injection or perivascular extravasation. Table 2. Preparation and Infusion Information by Pediatric Dose of PHENERGAN Injection Avoid mixing and/or diluting with any other drugs or solutions besides 0.9% Sodium Chloride Injection Dose of PHENERGAN Injection Volume of 0.9% Sodium Chloride Injection for Dilution Maximum Concentration of the Diluted PHENERGAN Injection Solution Maximum Rate of Infusion Up to 25 mg 25 mL 1 mg/mL 1.25 mL/minute 25 mg to 50 mg 50 mL Storage of Diluted PHENERGAN Injection Diluted solution may be stored up to 4 hours at room temperature, 20°C to 25°C (68°F to 77°F), or refrigerated at 2°C to 8°C (36° to 46°F), up to 24 hours.

Respiratory Depression Pediatrics PHENERGAN Injection 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 in pediatric patients less than 2 years of age. A wide range of weight-based doses of PHENERGAN Injection have resulted in respiratory depression in these patients. Caution should be exercised when administering PHENERGAN Injection to pediatric patients 2 years of age and older. It is recommended that the lowest effective dose of PHENERGAN Injection be used in pediatric patients 2 years of age and older. Avoid concomitant administration of other drugs with respiratory depressant effects because of an association with respiratory depression, and sometimes death, in pediatric patients. Other Because of the risk of potentially fatal respiratory depression, use of PHENERGAN Injection in patients with compromised respiratory function or patients at risk for respiratory failure (e.g. COPD, sleep apnea) should be avoided. Severe Tissue Injury, Including Gangrene PHENERGAN Injection has been reported to cause severe chemical irritation and damage to tissues, including gangrene, regardless of the route of parenteral administration. Intra-arterial and subcutaneous administration have resulted in more significant complications. The use of PHENERGAN Injection by intravenous injection at concentrations greater than 1 mg/mL, intra- arterial injection, or subcutaneous injection is contraindicated . Irritation and damage can result from perivascular extravasation, intra- arterial injection, and intraneuronal or perineuronal infiltration. Inadvertent intra-arterial injection can cause severe arteriospasm. Other reported adverse reactions included burning, pain, erythema, swelling, sensory loss, palsies, paralysis, severe spasm of distal vessels, thrombophlebitis, venous thrombosis, phlebitis, abscesses, tissue necrosis, and gangrene. In some cases, surgical intervention, including fasciotomy, skin graft, and/or amputation have been required. The preferred route of administration of PHENERGAN Injection is by deep intramuscular administration. PHENERGAN Injection may be administered intravenously after dilution through an intravenous catheter inserted in a large vein. Preferably through a central venous catheter . If pain occurs at the injection site during intravenous infusion, immediately discontinue the infusion, evaluate for possible arterial injection or perivascular extravasation, and initiate appropriate medical management. CNS Depression PHENERGAN Injection 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, sedative/hypnotics (including barbiturates), general anesthetics, narcotics, narcotic analgesics, tricyclic antidepressants, and tranquilizers; therefore such agents should either be eliminated or given in reduced dosage in the presence of promethazine hydrochloride . Lower Seizure Threshold PHENERGAN Injection may lower seizure threshold and 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 PHENERGAN Injection 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. Sulfite Sensitivity PHENERGAN Injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthma episodes, in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. Visual Inspection This product is light sensitive and should be inspected before use and discarded if either color or particulate is observed. Cholestatic Jaundice Administration of promethazine has been associated with reported cholestatic jaundice.

Drug Interactions CNS Depressants PHENERGAN Injection may increase, prolong, or intensify the sedative action of central-nervous-system depressants, such as alcohol, sedative/hypnotics (including barbiturates), general anesthetics, narcotics, narcotic analgesics, tricyclic antidepressants, and tranquilizers; therefore, such agents should be avoided or administered in reduced dosage to patients receiving promethazine hydrochloride. When given concomitantly with PHENERGAN Injection, 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 PHENERGAN Injection 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 hydrochloride to reverse epinephrine’s vasopressor effect, epinephrine should NOT be used to treat hypotension associated with PHENERGAN Injection overdose. Anticholinergics Concomitant use of other agents with anticholinergic properties should be undertaken with caution. Monoamine Oxidase (MAO) Inhibitors Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAO Inhibitors and phenothiazines are used concomitantly. This possibility should be considered with PHENERGAN Injection.