Promethazine and Dextromethorphan

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.

• Tell all of your health care providers that you take promethazine and dextromethorphan. This includes your doctors, nurses, pharmacists, and dentists.
• Do not take more than what your doctor told you to take. Taking more than you are told may raise your chance of very bad side effects.
• Do not take this medicine for longer than you were told by your doctor.
• Avoid driving and doing other tasks or actions that call for you to be alert or have clear eyesight until you see how promethazine and dextromethorphan affects you.
• This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take this medicine.
• If you have high blood sugar (diabetes), you will need to watch your blood sugar closely.
• This medicine may cause the results of some pregnancy tests to be wrong. Talk with the doctor.
• Talk with your doctor before you drink alcohol or use other drugs and natural products that slow your actions.
• You may get sunburned more easily. Avoid sun, sunlamps, and tanning beds. Use sunscreen and wear clothing and eyewear that protects you from the sun.
• This medicine may raise the chance of seizures in some people, including people who have had seizures in the past. Talk to your doctor to see if you have a greater chance of seizures while taking promethazine and dextromethorphan.
• If you are 65 or older, use this medicine with care. You could have more side effects.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using promethazine and dextromethorphan while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food. Take with food if it causes an upset stomach.
• Measure liquid doses carefully. Use the measuring device that comes with promethazine and dextromethorphan. If there is none, ask the pharmacist for a device to measure this medicine.

What do I do if I miss a dose?

• If you take promethazine and dextromethorphan on a regular basis, take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.
• Many times this medicine is taken on an as needed basis. Do not take more often than told by the doctor.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Dextromethorphan should not be used in patients receiving a monoamine oxidase inhibitor (MAOI) (see PRECAUTIONS, Drug Interactions).

Promethazine 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.

Animal reproduction studies have not been conducted with the drug combination–Promethazine 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 and Dextromethorphan should be given to a pregnant woman only if clearly needed.

General

Dextromethorphan should be used with caution in sedated patients, in the debilitated, and in patients confined to the supine position.

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 should be used cautiously in persons with cardiovascular disease or with impairment of liver function.

Information For Patients

Promethazine and Dextromethorphan 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. Children 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, including narcotic analgesics, sedatives, hypnotics, and tranquilizers, may have an additive effect and should be avoided or their dosage reduced.

Patients should be advised to report any involuntary muscle movements.

Avoid prolonged exposure to the sun.

Drug Interactions

Hyperpyrexia, hypotension, and death have been reported coincident with the coadministration of monoamine oxidase (MAO) inhibitors and products containing dextromethorphan. Thus, concomitant administration of promethazine with dextromethorphan 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 HCl. When given concomitantly with promethazine, 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 to reverse epinephrine's vasopressor effect, epinephrine should NOT be used to treat hypotension associated with promethazine 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.

Drug/Laboratory Test Interactions

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

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

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

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 the carcinogenicity, mutagenicity, or impairment of fertility with these drugs. Promethazine was nonmutagenic in the Salmonella test system of Ames.

Pregnancy

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 in pregnant women.

Promethazine and Dextromethorphan should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

Promethazine 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 or dextromethorphan is excreted in human milk.

Caution should be exercised when Promethazine and Dextromethorphan is administered to a nursing woman.

Pediatric Use

PROMETHAZINE HYDROCHLORIDE AND DEXTROMETHORPHAN HYDROBROMIDE SYRUP IS CONTRAINDICATED FOR USE IN PEDIATRIC PATIENTS LESS THAN TWO YEARS OF AGE (see WARNINGS – Black Box Warning and Use in Pediatric Patients).

Promethazine hydrochloride and dextromethorphan hydrobromide 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 hydrochloride and dextromethorphan hydrobromide syrup 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 Hydrochloride and Dextromethorphan Hydrobromide Syrup and observed closely.

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Syrup: Promethazine hydrochloride 6.25 mg and dextromethorphan hydrobromide 15 mg per 5 mL (120 mL, 480 mL)

There are no dosage adjustments provided in the manufacturer’s labeling.

See individual agents.

Do not use in patients younger than 2 years of age because of potential for fatal respiratory depression. Administer with caution to children older than 2 years of age.