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Promethazine and Phenylephrine Hydrochloride and Codeine Phosphate

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Overview

What is Promethazine VC with Codeine?

Each 5 mL (one teaspoonful), for oral administration contains: Codeine phosphate 10 mg; promethazine hydrochloride 6.25 mg; phenylephrine hydrochloride 5 mg in a flavored syrup base with a pH between 4.4 and 5.2. Alcohol 7%.

Inactive ingredients

Codeine is one of the naturally occurring phenanthrene alkaloids of opium derived from the opium poppy, it is classified pharmacologically as a narcotic analgesic. Codeine phosphate may be chemically designated as 7,8-Didehydro-4, 5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate.

The phosphate salt of codeine occurs as white, needle-shaped crystals or white crystalline powder. Codeine phosphate is freely soluble in water and slightly soluble in alcohol. It has a molecular weight of 406.37, a molecular formula of CHNO • HPO • ½ HO and the following structural formula:

Promethazine hydrochloride occurs as a white to faint yellow, practically odorless, crystalline powder which slowly oxidizes and turns blue on prolonged exposure to air. It is soluble in water and freely soluble in alcohol. It has a molecular weight of 320.88, a molecular formula of CH0NS • HCl, and the following structural formula:

m

Phenylephrine hydrochloride is subject to oxidation and must be protected from light and air. It has a molecular weight of 203.67, a molecular formula of CHNO • HCl and the following structural formula:



What does Promethazine VC with Codeine look like?



What are the available doses of Promethazine VC with Codeine?

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What should I talk to my health care provider before I take Promethazine VC with Codeine?

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How should I use Promethazine VC with Codeine?

Promethazine VC with Codeine Oral Solution is indicated for the temporary relief of coughs and upper respiratory symptoms, including nasal congestion, associated with allergy or the common cold.

It is important that Promethazine VC with Codeine Oral Solution is measured with an accurate measuring device

PRECAUTIONS-Information for Patients

Promethazine VC with Codeine Oral Solution is contraindicated in pediatric patients less than 12 years of age. (See WARNINGS - Ultra- Rapid Metabolism of Codeine and Respiratory Depression).

The average effective dose is given in the following table:


What interacts with Promethazine VC with Codeine?

Promethazine VC with Codeine Oral Solution is contraindicated in all children younger than 12 years of age. (See ).


Promethazine VC with Codeine Oral Solution is contraindicated for postoperative management in children younger than 18 years of age who have undergone tonsillectomy and/or adenoidectomy. (See ).


Codeine is contraindicated in patients with a known hypersensitivity to the drug.


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 and codeine are both contraindicated for use in the treatment of lower respiratory tract symptoms, including asthma.Phenylephrine is contraindicated in patients with hypertension or with peripheral vascular insufficiency (ischemia may result with risk of gangrene or thrombosis of compromised vascular beds). Phenylephrine should not be used in patients known to be hypersensitive to the drug or in those receiving a monoamine oxidase inhibitor (MAOI).



What are the warnings of Promethazine VC with Codeine?

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  • Promethazine VC with Codeine Oral Solution is contraindicated in all children younger than 12 years of age. (See ).
  • Promethazine VC with Codeine Oral Solution is contraindicated for postoperative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.  (See ).
  • Avoid the use of Promethazine VC with Codeine Oral Solution in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression
  • When prescribing codeine for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose. (See OVERDOSAGE)


Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon post-marketing reports, children younger than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the postoperative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine.  Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect.

Because of the risk of life-threatening respiratory depression and death:

Nursing Mothers

At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. Breastfeeding is not recommended during treatment with Promethazine VC with Codeine Oral Solution. (See ).

CYP2D6 Genetic Variability: Ultra-rapid metabolizer

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican).

These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing).  (See ). Therefore, individuals who are ultra-rapid metabolizers should not use Promethazine VC with Codeine Oral Solution.

Promethazine and Respiratory Depression

Children

  • Children


Concomitant Conditions and Other Risk Factors

  • Concomitant Conditions and Other Risk Factors


Postmarketing cases of respiratory depression, including fatalities have been reported with use of promethazine in pediatric patients.  Concomitant administration with other respiratory depressants may increase the risk of respiratory depression. Children may be particularly sensitive to the additive respiratory depressant effects when promethazine is combined with other respiratory depressants, including codeine. See for limitations on the use of Promethazine VC with Codeine Oral Solution in children.

Excessively large dosages of antihistamines, including promethazine hydrochloride, in pediatric patients may cause sudden death (see ).

Avoid use of promethazine in patients at risk for respiratory depression. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression. (See )

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use of opioids, including Promethazine VC with Codeine Oral Solution, with benzodiazepines, or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Because of these risks, avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol. (See teractions).

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. Because of similar pharmacologic properties, it is reasonable to expect similar risk with concomitant use of opioid cough medications and benzodiazepines, other CNS depressants, or alcohol.

Advise both patients and caregivers about the risks of respiratory depression and sedation if Promethazine VC with Codeine Oral Solution is used with benzodiazepines, alcohol, or other CNS depressants. (See ).

CNS Depression and Other CNS Effects

CNS Depression

  • CNS Depression


Convulsions

  • Convulsions


Dystonias

  • Dystonias


Head Injury and Increased Intracranial Pressure

  • Head Injury and Increased Intracranial Pressure


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 avoid use of Promethazine VC with Codeine Oral Solution in patients on these medications.  (See PRECAUTIONS – Information for Patients and Drug Interactions).

Convulsions have occurred with therapeutic doses and overdoses of promethazine hydrochloride in pediatric patients.  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.

Promethazine is a phenothiazine.  Phenothiazines are associated with dystonic reactions.  In pediatric patients who are acutely ill associated with dehydration, there is an increased susceptibility to dystonias with the use of promethazine HCl.

The respiratory-depressant effects of narcotic analgesics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, intracranial lesions, or a pre-existing increase in intracranial pressure. Narcotics may produce adverse reactions which may obscure the clinical course of patients with head injuries.

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.

Pulmonary Considerations

Asthma and Other Pulmonary Disease

  • Asthma and Other Pulmonary Disease


Unresponsive Cough

  • Unresponsive Cough


Narcotic analgesics or cough suppressants, including codeine, should not be used in patients with severe asthma or those with frequent asthma attacks (see ). Nor should they be used in acute febrile illness associated with productive cough or in chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient’s respiratory function.

Dosage of codeineif cough fails to respond; an unresponsive cough should be re-evaluated in 5 days or sooner for possible underlying pathology, such as a foreign body or lower respiratory tract disease.

Cardiovascular Effects

Concomitant Conditions

  • Concomitant Conditions


Hypotension

  • Hypotension


Phenylephrine can cause a decrease in cardiac output, and extreme caution should be used when administering the drug parenterally or orally to patients with arteriosclerosis, to elderly individuals, and/or to patients with initially poor cerebral or coronary circulationPhenylephrine should be used with caution in patients taking diet preparations, such as amphetamines or phenylpropanolamine, because synergistic adrenergic effects could result in serious hypertensive response and possible stroke.  Because phenylephrine is an adrenergic agent, it should be given with caution to patients with thyroid diseases, diabetes mellitus and heart diseases or those receiving tricyclic antidepressants.

Codeine may produce orthostatic hypotension in ambulatory patients.

Bone-Marrow Depression

Promethazine 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

Constipation

Codeine may cause or aggravate constipation.

Other Considerations

Administration of promethazine has been associated with reported cholestatic jaundice.

Administration of codeine may be accomplished by histamine release and should be used with caution in atopic children.

Men with symptomatic, benign prostatic hypertrophy can experience urinary retention when given oral nasal decongestants.


What are the precautions of Promethazine VC with Codeine?

General

Narcotic analgesics, including codeine, should be administered with caution and the initial dose reduced in patients with acute abdominal conditions, convulsive disorders, significant hepatic or renal impairment, fever, hypothyroidism, Addison’s disease, ulcerative colitis, prostatic hypertrophy, in patients with recent gastrointestinal or urinary tract surgery and in the very young or elderly or debilitated patients

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

Anticholinergic Effects

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.

Information for Patients

Advise patients of the risks of respiratory depression and death with Promethazine VC with Codeine Oral Solution in children younger than 18 years of age. Advise patients that Promethazine VC with Codeine Oral Solution should not be used in children younger than 12 years of age or in a child younger than 18 years of age for treatment after tonsillectomy and/or adenoidectomy. Advise caregivers of children ages 12 to 18 receiving Promethazine VC with Codeine Oral Solution to monitor for signs of respiratory depression. (See ).

Advise women that breastfeeding is not recommended during treatment with Promethazine VC with Codeine Oral Solution. (See ).

Promethazine, phenylephrine and codeine may cause marked drowsiness or may 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, phenylephrine and codeine therapy. Pediatric patients should be supervised to avoid potential harm in bike riding or in other hazardous activities.

Inform patients and caregivers that potentially fatal additive effects may occur if Promethazine VC with Codeine Oral Solution is used with benzodiazepines or other CNS depressants, including alcohol. Because of this risk, patients should avoid concomitant use of Promethazine VC with Codeine Oral Solution with benzodiazepines or other CNS depressants, including alcohol. (See ).

Advise patients to measure Promethazine VC with Codeine 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.

Patients should be advised to report any involuntary muscle movements.

Avoid prolonged exposure to the sun.

Codeine, like other narcotic analgesics, may produce orthostatic hypotension in some ambulatory patients. Patients should be cautioned accordingly.

Drug Interactions

Codeine

In patients receiving MAO inhibitors, an initial small test dose is advisable to allow observation of any excessive narcotic effects or MAOI interaction.

The use of benzodiazepines, opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants (including alcohol) concomitantly with Promethazine VC with Codeine Oral Solution may cause an additive CNS depressant effect, profound sedation, respiratory depression, coma, and death and should be avoided. (See ).

Promethazine

Epinephrine

Anticholinergics

Monoamine Oxidase Inhibitors (MAOI)

DrugEffect
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).Cardiac pressor response potentiated. May cause acute hypertensive crisis.
Phenylephrine with tricyclic antidepressants.Pressor response increased.
Phenylephrine with ergot alkaloids.Excessive rise in blood pressure.
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.Tachycardia or other arrhythmias may occur.
Phenylephrine with prior administration of propranolol or other β-adrenergic blockers.Cardiostimulating effects blocked.
Phenylephrine with atropine sulfate.Reflex bradycardia blocked; pressor response enhanced.
Phenylephrine with prior administration of phentolamine or other a-adrenergic blockers.Pressor response decreased.
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.Synergistic adrenergic response.


Drug/Laboratory Test Interactions

Because narcotic analgesics may increase biliary tract pressure, with resultant increase in plasma amylase or lipase levels, determination of these enzyme levels may be unreliable for 24 hours after a narcotic analgesic has been given.

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

Pregnancy Tests

Glucose Tolerance Test

Carcinogenesis, Mutagenesis, Impairment of Fertility

Codeine and Promethazine: Long-term animal studies have not been performed to assess the carcinogenic potential of codeine or of promethazine, nor are there other animal or human data concerning carcinogenicity, mutagenicity, or impairment of fertility with these agents. Codeine has been reported to show no evidence of carcinogenicity or mutagenicity in a variety of test systems, including the micronucleus and sperm abnormality assays and the assay. Promethazine was nonmutagenic in the test system of Ames.

Phenylephrine: A study which followed the development of cancer in 143,574 patients over a four-year period indicated that in 11,981 patients who received phenylephrine (systemic or topical), there was no statistically significant association between the drug and cancer at any or all sites.

Long-term animal studies have not been performed to assess the carcinogenic potential of phenylephrine, nor are there other animal or human data concerning mutagenicity.

A study of the effects of adrenergic drugs on ovum transport in rabbits indicated that treatment with phenylephrine did not alter incidence of pregnancy; the number of implantations was significantly reduced when high doses of the drug were used.

Pregnancy

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Pregnancy Category C:

Codeine

There are no studies in humans, and the significance of these findings to humans, if any, is not known.

Promethazine

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.

Phenylephrine

Another study showed that phenylephrine was associated with anomalies of aortic arch and with ventricular septal defect in the chick embryo.

Animal reproduction studies have not been conducted with the drug combination – promethazine, phenylephrine and codeine. It is not known whether this drug combination can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Promethazine VC with Codeine Oral Solution should be given to a pregnant woman only if clearly needed.

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

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Dependence has been reported in newborns whose mothers took opiates regularly during pregnancy. Withdrawal signs include irritability, excessive crying, tremors, hyperreflexia, fever, vomiting and diarrhea. Signs usually appear during the first few days of life.

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

Labor and Delivery

Narcotic analgesics cross the placental barrier. The closer to delivery and the larger the dose used, the greater the possibility of respiratory depression in the newborn. Narcotic analgesics should be avoided during labor if delivery of a premature infant is anticipated. If the mother has received narcotic analgesics during labor, newborn infants should be observed closely for signs of respiratory depression. Resuscitation may be required (see ).

Limited data suggest that use of promethazine hydrochloride 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 of promethazine and/or codeine on later growth and development of the newborn is unknown.

Administration of phenylephrine to patients in late pregnancy or labor may cause fetal anoxia or bradycardia by increasing contractility of the uterus and decreasing uterine blood flow.

See also

Nursing Mothers

Codeine and its active metabolite, morphine, are present in human milk. There are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to codeine via breast milk. Women who are ultra-rapid metabolizers of codeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent.

There is no information on the effects of the codeine on milk production. Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Promethazine VC with Codeine Oral Solution. (See ).

If infants are exposed to Promethazine VC with Codeine Oral Solution through breast milk, they should be monitored for excess sedation and respiratory depression.  Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

It is not known whether phenylephrine or promethazine are excreted in human milk.

Pediatric Use

  • Promethazine VC with Codeine Oral Solution is contraindicated in all children younger than 12 years of age.  (See ).
  • Promethazine VC with Codeine Oral Solution is contraindicated in pediatric patients younger than 18 years of age following tonsillectomy and/ or adenoidectomy.  (See ).
  • Avoid the use of Promethazine VC with Codeine Oral Solution in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression. (See ).
  • When prescribing codeine for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose. (See ).


Life threatening respiratory depression and death have occurred in children who received codeine.  (See ).  Postmarketing cases of respiratory depression, including fatalities have been reported with use of promethazine in pediatric patients. (See).   Because of the risk of life-threatening respiratory depression and death:

Geriatric Use

Clinical studies of Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution 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 VC with Codeine Oral Solution and observed closely.


What are the side effects of Promethazine VC with Codeine?

Codeine

Central Nervous System

Cardiovascular

Gastrointestinal

Genitourinary

Allergic

Other

Promethazine

Central Nervous System

Cardiovascular

Dermatologic

Hematologic

Gastrointestinal

Respiratory

WARNINGS – Promethazine; Respiratory Depression

Other

WARNINGS – Promethazine; Neuroleptic Malignant Syndrome

Paradoxical Reactions

Respiratory depression, nightmares, delirium and agitated behavior have also been reported in some of these patients.

Phenylephrine

Central Nervous System

Cardiovascular

WARNINGS

Other


What should I look out for while using Promethazine VC with Codeine?

Promethazine VC with Codeine Oral Solution is contraindicated in all children younger than 12 years of age. (See ).

Promethazine VC with Codeine Oral Solution is contraindicated for postoperative management in children younger than 18 years of age who have undergone tonsillectomy and/or adenoidectomy. (See ).

Codeine is contraindicated in patients with a known hypersensitivity to the drug.

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 and codeine are both contraindicated for use in the treatment of lower respiratory tract symptoms, including asthma.Phenylephrine is contraindicated in patients with hypertension or with peripheral vascular insufficiency (ischemia may result with risk of gangrene or thrombosis of compromised vascular beds). Phenylephrine should not be used in patients known to be hypersensitive to the drug or in those receiving a monoamine oxidase inhibitor (MAOI).

(see )


What might happen if I take too much Promethazine VC with Codeine?

Codeine

Serious overdose with codeine is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin and sometimes bradycardia and hypotension. The triad of coma, pinpoint pupils and respiratory depression is strongly suggestive of opiate poisoning. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. Promethazine is additive to the depressant effects of codeine.

It is difficult to determine what constitutes a standard toxic or lethal dose. However, the lethal oral dose of codeine in an adult is reported to be in the range of 0.5 to 1.0 gram. Infants and children are believed to be relatively more sensitive to opiates on a body-weight basis. Elderly patients are also comparatively intolerant to opiates.

Promethazine

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 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.

Phenylephrine

Signs and symptoms of overdosage with phenylephrine include hypertension, headache, convulsions, cerebral hemorrhage, and vomiting. Ventricular premature beats and short paroxysms of ventricular tachycardia may also occur. Headache may be a symptom of hypertension. Bradycardia may also be seen early in phenylephrine overdosage through stimulation of baroreceptors.

Treatment

The treatment of overdosage with promethazine, phenylephrine and codeine 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 re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. The narcotic antagonist, naloxone hydrochloride, may be administered when significant respiratory depression occurs with promethazine, phenylephrine and codeine; any depressant effects of promethazine are not reversed by naloxone. Diazepam may be used to control convulsions. Avoid analeptics, which may cause convulsions. Acidosis and electrolyte losses should be corrected. A rise in temperature or pulmonary complications may signal the need for institution of antibiotic therapy.

Severe hypotension usually responds to the administration of norepinephrine or phenylephrine. EPINEPHRINE SHOULD NOT BE USED, since its use in a patient with partial adrenergic blockade may further lower the blood pressure.

Limited experience with dialysis indicates that it is not helpful.


How should I store and handle Promethazine VC with Codeine?

Store between 2°C and 25°C (36°F and 77°F). Retain in the original package to protect from light. Freezing does not adversely affect the product. Each 5 mL of reddish-clear solution with odor of strawberry menthol contains promethazine hydrochloride 6.25 mg, phenylephrine hydrochloride 5 mg, codeine phosphate 10 mg; and alcohol 7% and is available as follows:NDC 0603-1588-54               4 fluid ounce (118 mL) NDC 0603-1588-58                1 pint (473 mL).Each 5 mL of reddish-clear solution with odor of strawberry menthol contains promethazine hydrochloride 6.25 mg, phenylephrine hydrochloride 5 mg, codeine phosphate 10 mg; and alcohol 7% and is available as follows:NDC 0603-1588-54               4 fluid ounce (118 mL) NDC 0603-1588-58                1 pint (473 mL).


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Clinical Information

Chemical Structure

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Clinical Pharmacology

Narcotic analgesics, including codeine, exert their primary effects on the central nervous system and gastrointestinal tract. The analgesic effects of codeine are due to its central action; however, the precise sites of action have not been determined, and the mechanisms involved appear to be quite complex. Codeine resembles morphine both structurally and pharmacologically, but its actions at the doses of codeine used therapeutically are milder, with less sedation, respiratory depression and gastrointestinal, urinary, and pupillary effects. Codeine produces an increase in biliary tract pressure, but less than morphine or meperidine. Codeine is less constipating than morphine.

Codeine has good antitussive activity, although less than that of morphine at equal doses. It is used in preference to morphine, because side effects are infrequent at the usual antitussive dose of codeine.

Codeine in oral therapeutic dosage does not usually exert major effects on the cardiovascular system. Narcotic analgesics may cause nausea and vomiting by stimulating the chemoreceptor trigger zone (CTZ); however, they also depress the vomiting center, so that subsequent doses are unlikely to produce vomiting. Nausea is minimal after usual oral doses of codeine.

Narcotic analgesics cause histamine release, which appears to be responsible for wheals or urticaria sometimes seen at the site of injection on parenteral administration. Histamine release may also produce dilation of cutaneous blood vessels, with resultant flushing of the face and neck, pruritus, and sweating.

Codeine and its salts are well absorbed following both oral and parenteral administration. Codeine is about 2/3 as effective orally as parenterally. Codeine is metabolized primarily in the liver by enzymes of the endoplasmic reticulum, where it undergoes O-demethylation, N­ demethylation, and partial conjugation with glucuronic acid. The drug is excreted primarily in the urine, largely as inactive metabolites and small amounts of free and conjugated morphine. Negligible amounts of codeine and its metabolites are found in the feces.

Following oral or subcutaneous administration of codeine, the onset of analgesia occurs within 15 to 30 minutes and lasts for four to six hours.

The cough-depressing action, in animal studies, was observed to occur 15 minutes after oral administration of codeine, peak action at 45 to 60 minutes after ingestion. The duration of action, which is dose-dependent, usually did not exceed 3 hours.

Non-Clinical Toxicology
Promethazine VC with Codeine Oral Solution is contraindicated in all children younger than 12 years of age. (See ).

Promethazine VC with Codeine Oral Solution is contraindicated for postoperative management in children younger than 18 years of age who have undergone tonsillectomy and/or adenoidectomy. (See ).

Codeine is contraindicated in patients with a known hypersensitivity to the drug.

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 and codeine are both contraindicated for use in the treatment of lower respiratory tract symptoms, including asthma.Phenylephrine is contraindicated in patients with hypertension or with peripheral vascular insufficiency (ischemia may result with risk of gangrene or thrombosis of compromised vascular beds). Phenylephrine should not be used in patients known to be hypersensitive to the drug or in those receiving a monoamine oxidase inhibitor (MAOI).

(see )

Codeine

In patients receiving MAO inhibitors, an initial small test dose is advisable to allow observation of any excessive narcotic effects or MAOI interaction.

The use of benzodiazepines, opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants (including alcohol) concomitantly with Promethazine VC with Codeine Oral Solution may cause an additive CNS depressant effect, profound sedation, respiratory depression, coma, and death and should be avoided. (See ).

Promethazine

Epinephrine

Anticholinergics

Monoamine Oxidase Inhibitors (MAOI)

Narcotic analgesics, including codeine, should be administered with caution and the initial dose reduced in patients with acute abdominal conditions, convulsive disorders, significant hepatic or renal impairment, fever, hypothyroidism, Addison’s disease, ulcerative colitis, prostatic hypertrophy, in patients with recent gastrointestinal or urinary tract surgery and in the very young or elderly or debilitated patients

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

Codeine

Central Nervous System

Cardiovascular

Gastrointestinal

Genitourinary

Allergic

Other

Promethazine

Central Nervous System

Cardiovascular

Dermatologic

Hematologic

Gastrointestinal

Respiratory

WARNINGS – Promethazine; Respiratory Depression

Other

WARNINGS – Promethazine; Neuroleptic Malignant Syndrome

Paradoxical Reactions

Respiratory depression, nightmares, delirium and agitated behavior have also been reported in some of these patients.

Phenylephrine

Central Nervous System

Cardiovascular

WARNINGS

Other

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Professional

Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72
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Tips

Tips

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Interactions

Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).