Promethazine Hydrochloride and Dextromethorphan Hydrobromide 6.25 mg/5mL; 15 mg/5mL Solution, 473 mL — NDC 62559-758-16 (Billing 62559-0758-16)

WARNINGS Promethazine Hydrochloride and Dextromethorphan Hydrobromide Oral Solution 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. 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 (see PRECAUTIONS – Information for Patients and Drug Interactions ). Respiratory Depression Promethazine may lead to potentially fatal respiratory depression.

Use of Promethazine Hydrochloride and Dextromethorphan Hydrobromide Oral Solution in patients with compromised respiratory function (e.g. COPD, sleep apnea syndrome) 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 Hydrochloride and Dextromethorphan Hydrobromide Oral Solution should be used with caution in patients with bone-marrow depression. Leukopenia and agranulocytosis have been reported, usually when promethazine 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 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, 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 should be carefully considered. Use in Pediatric Patients Promethazine Hydrochloride and Dextromethorphan Hydrobromide Oral Solution is contraindicated for use in pediatric patients less than two years of age.

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ADVERSE REACTIONS 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 Hydrochloride and Dextromethorphan Hydrobromide Oral Solution.

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. DEXTROMETHORPHAN Dextromethorphan occasionally causes slight drowsiness, dizziness, and gastrointestinal disturbances.

To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions Monoamine Oxidase (MAO) Inhibitors – Hyperpyrexia, hypotension, and death have been reported coincident with the co-administration of monoamine oxidase (MAO) inhibitors and products containing dextromethorphan. Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAO inhibitors and phenothiazines are used concomitantly. Thus, concomitant administration of Promethazine Hydrochloride and Dextromethorphan Hydrobromide Oral Solution and MAO inhibitors should be avoided (see CONTRAINDICATIONS ).

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

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

Drug/Laboratory Test Interactions The following laboratory tests may be affected in patients who are receiving therapy with promethazine: 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.

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 Hydrochloride and Dextromethorphan Hydrobromide Oral Solution 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.

Information for Patients Patients should be advised to measure Promethazine Hydrochloride and Dextromethorphan Hydrobromide 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 Hydrochloride and Dextromethorphan Hydrobromide 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 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.

Drug Interactions Monoamine Oxidase (MAO) Inhibitors – Hyperpyrexia, hypotension, and death have been reported coincident with the co-administration of monoamine oxidase (MAO) inhibitors and products containing dextromethorphan. Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAO inhibitors and phenothiazines are used concomitantly. Thus, concomitant administration of Promethazine Hydrochloride and Dextromethorphan Hydrobromide Oral Solution and MAO inhibitors should be avoided (see CONTRAINDICATIONS ).

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

Anticholinergics – Concomitant use of other agents with anticholinergic properties should be undertaken with caution. Drug/Laboratory Test Interactions The following laboratory tests may be affected in patients who are receiving therapy with promethazine: Pregnancy Tests Diagnostic pregnancy tests based on immunological reactions between HCG… [Excerpted — this section continues on DailyMed.]

DRUG ABUSE AND DEPENDENCE According to the WHO Expert Committee on Drug Dependence, dextromethorphan could produce very slight psychic dependence but no physical dependence.