Prescription Drugs

CLINICAL PHARMACOLOGY 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. 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- methylmorphinan, (+)-3-hydroxymorphinan, and traces of unmetabolized drug were found in urine after oral administration.

Promethazine HCl and Dextromethorphan Hydrobromide (promethazine HCl and dextromethorphan hydrobromide (promethazine and dextromethorphan) ) Syrup DESCRIPTION Each teaspoon (5 mL) of Promethazine HCl and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup contains 6.25 mg promethazine HCl and 15 mg dextromethorphan hydrobromide in a flavored syrup base with a pH between 4.7 and 5.2. Alcohol 7%. The inactive ingredients present are artificial and natural flavors, citric acid, D&C Yellow 10, FD&C Yellow 6, glycerin, saccharin sodium, sodium benzoate, sodium citrate, sodium propionate, water, and other ingredients. Promethazine HCl is a racemic compound; the empirical formula is C17H20N2S•HCl and its molecular weight is 320.88. Promethazine HCl, a phenothiazine derivative, is chemically designated as 10H-Phenothiazine-10- ethanamine, N,N, α-trimethyl-, monohydrochloride, (±)- with the following structural formula: 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. 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 with the following structural formula: Dextromethorphan hydrobromide monohydrate occurs as white crystals, is sparingly soluble in water, and is freely soluble in alcohol. The empirical formula is C18H25NO•HBr•H2O, and the molecular weight of the monohydrate is 370.33. Dextromethorphan HBr monohydrate is dextrorotatory with a specific rotation of +27.6 degrees in water (20 degrees C, sodium D-line).

INDICATIONS Promethazine HCl and Dextromethorphan Hydrobromide Syrup 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 HCl and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup 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 and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup 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. HOW SUPPLIED Promethazine HCl and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup is a clear, yellow solution supplied as follows: NDC 62559-7581-4 - bottle of 4 fl. oz. (118 mL) NDC 62559-7581-6 - bottle of 16 fl. oz. (473 mL) Keep bottles tightly closed. Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Protect from light. Dispense in tight, light-resistant container (USP/NF) with a child-resistant closure. Manufactured by: ANI Pharmaceuticals, Inc. Baltimore, MD 21244. Rev 03/08. FDA Rev date: 4/2/2008

PATIENT INFORMATION Patients should be advised to measure Promethazine HCl and Dextromethorphan Hydrobromide Syrup 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 and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup 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 and dextromethorphan 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.

OVERDOSE Promethazine HCL 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. 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 HCl and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup 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 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 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. CONTRAINDICATIONS Promethazine HCl and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup is contraindicated for use in pediatric patients less than two years of age. Promethazine HCl 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).

SIDE EFFECTS 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 HCl and Dextromethorphan Hydrobromide Syrup. 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. Dextromethorphan Dextromethorphan hydrobromide occasionally causes slight drowsiness, dizziness, and gastrointestinal disturbances. Drug Abuse And Dependence According to the WHO Expert Committee on Drug Dependence, dextromethorphan could produce very slight psychic dependence but no physical dependence. DRUG INTERACTIONS Hyperpyrexia, hypotension, and death have been reported coincident with the co-administration of monoamine oxidase (MAO) inhibitors and products containing dextromethorphan. Thus, concomitant administration of Promethazine HCl and Dextromethorphan Hydrobromide Syrup and MAO inhibitors should be avoided (see CONTRAINDICATIONS). CNS Depressants - Promethazine HCl 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 and Dextromethorphan Hydrobromide Syrup, 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 to reverse epinephrine's vasopressor effect, epinephrine should NOT be used to treat hypotension associated with Promethazine HCl and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup 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 and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup. 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.

WARNINGS Promethazine HCl and Dextromethorphan Hydrobromide Syrup 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 promethazine have resulted in respiratory depression in these patients. Caution should be exercised when administering promethazine to pediatric patients 2 years of age and older. It is recommended that the lowest effective dose of promethazine be used in pediatric patients 2 years of age and older and concomitant administration of other drugs with respiratory depressant effects be avoided. CNS Depression Promethazine HCl 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 HCl may lead to potentially fatal respiratory depression. Use of Promethazine HCl and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup in patients with compromised respiratory function (e.g. COPD, sleep apnea syndrome) should be avoided. Lower Seizure Threshold Promethazine HCl 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 HCl and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup 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. Use in Pediatric Patients Promethazine HCl and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup is contraindicated for use in pediatric patients less than two years of age. Caution should be exercised when administering Promethazine HCl and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup 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 HCl and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup administration may be confused with the CNS signs of undiagnosed primary disease, e.g., encephalopathy or Reye's syndrome. The use of Promethazine HCl and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup 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 HCl, in pediatric patients may cause sudden death (see OVERDOSAGE). Hallucinations and convulsions have occurred with therapeutic doses and overdoses of Promethazine HCl 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 HCl. Other Considerations Administration of promethazine HCl has been associated with reported cholestatic jaundice. DEXTROMETHORPHAN Administration of dextromethorphan may be accompanied by histamine release and should be used with caution in atopic children. 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 and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup should be used cautiously in persons with cardiovascular disease or with impairment of liver function. Dextromethorphan should be used with caution in sedated patients, in the debilitated, and in patients confined to the supine position. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to assess the carcinogenic potential of promethazine or of dextromethorphan. There are no animal or human data concerning carginogenicity, mutagenicity, or impairment of fertility with these drugs. 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 8.3 and 16.7 times the maximum recommended total daily dose for a 50-kg subject. 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 and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup in pregnant women. Animal reproduction studies have not been conducted with the drug combination - promethazine HCl and dextromethorphan. It is not known whether this drug combination can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Promethazine HCl and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup should be given to a pregnant woman only if clearly needed. Promethazine HCl and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Promethazine HCl and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup administered to a pregnant woman within two weeks of delivery may inhibit platelet aggregation in the newborn. Labor and Delivery Limited data suggest that use of promethazine HCl 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 or dextromethorphan 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 and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup, 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 and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup is contraindicated for use in pediatric patients less than two years of age (see WARNINGS - Boxed Warning and Use in Pediatric Patients). Promethazine HCl and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup 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 HCl 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 and Dextromethorphan Hydrobromide (promethazine and dextromethorphan) Syrup and observed closely.