Promethazine Vc With Codeine Oral Solution

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 in patients 18 years of age and older.

Oral solution: Each 5 mL contains codeine phosphate, 10 mg; promethazine hydrochloride 6.25 mg; and phenylephrine hydrochloride, 5 mg, in a flavored syrup base [

see Description (

11 DESCRIPTION

Promethazine VC with Codeine Oral Solution (promethazine hydrochloride, phenylephrine hydrochloride, and codeine phosphate) oral solution contains codeine an opioid agonist; promethazine, a phenothiazine; and phenylephrine, an alpha-1 adrenergic receptor agonist.

Each 5 mL of Promethazine VC with Codeine Oral Solution contains 10 mg of codeine phosphate, 6.25 mg of promethazine hydrochloride, and 5 mg of phenylephrine hydrochloride for oral administration.

Promethazine VC with Codeine Oral Solution has a pH between 4.4 and 5.2 and contains alcohol 7%.

Promethazine VC with Codeine Oral Solution also contains the following inactive ingredients: Ascorbic acid, citric acid, D&C Red #33, FD&C Yellow #6, menthol, methylparaben, propylene glycol, propylparaben, purified water, saccharin sodium, sodium benzoate, sodium citrate, strawberry flavor and sucrose.

Codeine Phosphate

The chemical name for codeine phosphate is 7,8-Didehydro-4, 5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate.  Codeine is one of the naturally occurring phenanthrene alkaloids of opium derived from the opium poppy, it is classified pharmacologically as a narcotic analgesic.  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.  The molecular weight is 406.37.  Its molecular formula is C₁₈H₂₁NO₃•H₃PO₄• ½ H₂O, and it has the following chemical structure.

Promethazine Hydrochloride

The chemical name for promethazine hydrochloride, a phenothiazine derivative, is (±)-10-[2-(Dimethylamino)propyl] phenothiazine monohydrochloride.  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.  The molecular weight is 320.88.  Its molecular formula is C₁₇H₂₀N₂S•HCl, and it has the following chemical structure.

Phenylephrine Hydrochloride

The chemical name for phenylephrine hydrochloride, a sympathomimetic amine salt, is (-)-

m

-hydroxy-α-[(methyl-amino)methyl] benzyl alcohol hydrochloride.  It occurs as white or nearly white crystals, having a bitter taste.  It is freely soluble in water and alcohol.  Phenylephrine hydrochloride is subject to oxidation and must be protected from light and air.  The molecular weight is 203.67.  Its molecular formula is C₉H₁₃NO₂• HCl, and it has the following chemical structure.

)

The following serious adverse reactions are described, or described in greater detail, in other sections:

• Addiction, abuse, and misuse [see
  
  Warnings and Precautions (
  

  5.1 Addiction, Abuse, and Misuse

  Promethazine VC with Codeine Oral Solution contains codeine, a Schedule V controlled substance. As an opioid, Promethazine VC with Codeine Oral Solution exposes users to the risks of addiction, abuse, and misuse [

  see Drug Abuse and Dependence

  ], which can lead to overdose and death [

  see Overdosage and Warnings and Precautions

  ].

  Physical dependence, the condition in which continued administration of the drug is required to prevent the appearance of a withdrawal syndrome, assumes clinically significant proportions only after several weeks of continued oral opioid use, although some mild degree of physical dependence may develop after a few days of opioid therapy.

  If Promethazine VC with Codeine Oral Solution is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (eg, naloxone, nalmefene), mixed agonist/antagonist analgesics (eg, pentazocine, butorphanol, nalbuphine), or partial agonists (eg, buprenorphine). Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

  Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see

  Use in Specific Populations

  ].

  )
  
  ]
  
• Life-threatening respiratory depression [see
  
  Warnings and Precautions (
  

  5.2 Life-Threatening Respiratory Depression

  Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, including codeine, one of the active ingredients in Promethazine VC with Codeine Oral Solution. Codeine produces dose-related respiratory depression by directly acting on the brain stem respiratory center that controls respiratory rhythm and may produce irregular and periodic breathing. Codeine is subject to variability in metabolism based upon CYP2D6 genotype, which can lead to an increased exposure to the active metabolite morphine [

  see Warnings and Precautions (5.3)

  ]. Promethazine exerts a depressant effect on the respiratory center that is independent of and additive to that of other respiratory depressants, including codeine [

  see Warnings and Precautions (
  
  
  5.4)

  ]. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression includes discontinuation of Promethazine VC with Codeine Oral Solution, close observation, supportive measures, and use of opioid antagonists (eg., naloxone), depending on the patient’s clinical status [

  see Overdosage

  ]. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

  While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Promethazine VC with Codeine Oral Solution, the risk is greatest during the initiation of therapy, when Promethazine VC with Codeine Oral Solution is used concomitantly with other drugs that may cause respiratory depression [

  see Warnings and Precautions (
  
  
  5.10)

  ], in patients with chronic pulmonary disease or decreased respiratory reserve, and in patients with altered pharmacokinetics or altered clearance (eg, elderly, cachectic, or debilitated patients) [

  see Warnings and Precautions (
  
  
  5.6)

  ]. To reduce the risk of respiratory depression, proper dosing of Promethazine VC with Codeine Oral Solution is essential [

  see Dosage and Administration

  and

  Warnings and Precautions

  ]. Monitor patients closely, especially within the first 24 - 72 hours of initiating therapy or when used in patients at higher risk.

  Overdose of codeine in adults has been associated with fatal respiratory depression, and the use of codeine in children younger than 12 years of age has been associated with fatal respiratory depression when used as recommended [

  see Warnings and Precautions (
  
  
  5.3)

  ]. Accidental ingestion of even one dose of Promethazine VC with Codeine Oral Solution, especially by children, can result in respiratory depression and death.

  ,
  

  5.3 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 post‑operative 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:

  • Promethazine VC with Codeine Oral Solution is contraindicated in all children younger than 12 years of age [
    see
    Contraindications
    ].
  • Promethazine VC with Codeine Oral Solution is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [
    see
    Contraindications
    ].
  • 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
    Warnings and Precautions and Use in Specific Populations
    ].
  • 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
    Warnings and Precautions and Overdosage
    ].

  Lactation

  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

  Use in Specific Populations

  ].

  CYP2D6 Genetic Variability: Ultra-Rapid Metabolizers

  Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (eg, 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 (ie, 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

  Overdosage

  ]. Therefore, individuals who are ultra-rapid metabolizers should not use Promethazine VC with Codeine Oral Solution.

  ,
  

  5.4 Promethazine and Respiratory
  Depression

  Children

  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

  Warnings and Precautions

  ].

  Excessively large dosages of antihistamines, including promethazine hydrochloride, in pediatric patients may cause sudden death [

  see

  Overdosage

  ].

  Concomitant Conditions and Other Risk Factors

  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

  Warnings and Precautions

  ].

  ,
  

  5.5 Risks
  with Use in Pediatric Populations

  Children are particularly sensitive to the respiratory depressant effects of codeine [

  see Warnings and Precautions

  ].

  Use of Promethazine VC with Codeine Oral Solution in children also exposes them to the risks of addiction, abuse, and misuse [

  see Drug Abuse and Dependence ]

  , which can lead to overdose and death [see Warnings and Precautions (5.1), Overdosage (10)]. Because the benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks of use of codeine in pediatric patients, Promethazine VC with Codeine Oral Solution is not indicated for use in patients younger than 18 years of age [

  see Indications

  ,

  Use in Specific Populations

  ].

  ,
  

  5.6 Risks
  with Use in Other At-Risk Populations

  Unresponsive Cough

  The dosage of Promethazine VC with Codeine Oral Solution should not be increased if cough fails to respond; an unresponsive cough should be reevaluated in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease [

  see Dosage and Administration

  ].

  Asthma and Other Pulmonary Disease

  The use of Promethazine VC with Codeine Oral Solution in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated [

  see Contraindications

  ].

  Opioid analgesics and antitussives, including codeine, one of the active ingredients in Promethazine VC with Codeine Oral Solution, should not be used in patients with acute febrile illness associated with productive cough or in patients with 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.

  Promethazine VC with Codeine Oral Solution-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution [

  see Warnings and Precautions

  ].

  Elderly, Cachectic, or Debilitated Patients:

  Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [

  see Warnings and Precautions

  ].

  Promethazine

  Signs and symptoms of overdosage with promethazine 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, tachycardia, hallucinations, gastrointestinal symptoms, convulsions, urinary retention, cardiac arrhythmias and coma) may be observed.

  Impaired secretion from sweat glands following toxic doses of drugs with anticholinergic side effects may predispose to hyperthermia.

  Phenylephrine

  Signs and symptoms of overdosage with phenylephrine include headache, vomiting, hypertension, reflex bradycardia, cardiac arrhythmias including ventricular premature beats and ventricular tachycardia, convulsions, and cerebral hemorrhage. Overdosage may also be associated with a sensation of fullness in the head and tingling of the extremities. Headache may be a symptom of hypertension. Bradycardia may be seen early in phenylephrine overdosage through stimulation of baroreceptors.

  Treatment of Overdose

  Treatment of overdosage is driven by the overall clinical presentation, and consists of discontinuation of Promethazine VC with Codeine Oral Solution together with institution of appropriate therapy. Give primary attention to the reestablishment of adequate respiratory exchange through provision of a patent and protected airway and the institution of assisted or controlled ventilation. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques. Gastric emptying may be useful in removing unabsorbed drug.

  The opioid antagonists, naloxone and nalmefene, are specific antidotes for respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to codeine overdose, administer an opioid antagonist. An antagonist should not be administered in the absence of clinically significant respiratory depression. Because the duration of opioid reversal is expected to be less than the duration of action of codeine in Promethazine VC with Codeine Oral Solution, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information. The respiratory depressant effects of promethazine are not reversed by opioid antagonists, such as naloxone.

  Because of the potential for promethazine to reverse epinephrine’s vasopressor effect, epinephrine should NOT be used to treat hypotension associated with promethazine overdose.

  Hemodialysis is not routinely used to enhance the elimination of codeine or promethazine from the body.

  Adrenergic receptor blocking agents (beta-blockers), such as propranolol, may be used for the treatment of cardiac toxicity due to phenylephrine.

  )
  
  ]
  
• Ultra-rapid metabolism of codeine and other risk factors for life-threatening respiratory depression in children [see
  
  Warnings and Precautions (
  

  5.3 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 post‑operative 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:

  • Promethazine VC with Codeine Oral Solution is contraindicated in all children younger than 12 years of age [
    see
    Contraindications
    ].
  • Promethazine VC with Codeine Oral Solution is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [
    see
    Contraindications
    ].
  • 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
    Warnings and Precautions and Use in Specific Populations
    ].
  • 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
    Warnings and Precautions and Overdosage
    ].

  Lactation

  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

  Use in Specific Populations

  ].

  CYP2D6 Genetic Variability: Ultra-Rapid Metabolizers

  Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (eg, 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 (ie, 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

  Overdosage

  ]. Therefore, individuals who are ultra-rapid metabolizers should not use Promethazine VC with Codeine Oral Solution.

  )
  
  ]
  
• Accidental overdose and death due to medication errors [see
  
  Warnings and Precautions (
  

  5.7 Risks of Accidental Overdose and Death due to Medication Errors

  Dosing errors can result in accidental overdose and death. To reduce the risk of overdose and respiratory depression, ensure that the dose of Promethazine VC with Codeine Oral Solution is communicated clearly and dispensed accurately [

  see Dosage and Administration

  ].

  Advise patients to always use an accurate milliliter measuring device when measuring and administering Promethazine VC with Codeine Oral Solution. Inform patients that a household teaspoon is not an accurate measuring device and such use could lead to overdosage and serious adverse reactions [

  see

  Overdosage

  ]. For prescriptions where a measuring device is not provided, a pharmacist can provide an appropriate calibrated measuring device and can provide instructions for measuring the correct dose.

  )
  
  ]
  
• Decreased mental alertness with impaired mental and/or physical abilities [see
  
  Warnings and Precautions (
  

  5.8 Activities Requiring Mental Alertness: Risks of Driving and
  Operating Machinery

  Codeine and promethazine, two of the active ingredients in Promethazine VC with Codeine Oral Solution, may produce marked drowsiness and impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Advise patients to avoid engaging in hazardous tasks requiring mental alertness and motor coordination after ingestion of Promethazine VC with Codeine Oral Solution. Avoid concurrent use of Promethazine VC with Codeine Oral Solution with alcohol or other central nervous system depressants because additional impairment of central nervous system performance may occur [

  see

  Warnings and Precautions

  ].

  )
  
  ]
  
• Interactions with benzodiazepines and other CNS depressants [see
  
  Warnings and Precautions (
  

  5.10 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

  Drug Interactions

  ].

  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

  Patient Counseling Information

  ].

  )
  
  ]
  
• Paralytic ileus, gastrointestinal adverse reactions [see
  
  Warnings and Precautions (
  

  5.11 Risks of Use in Patients with Gastrointestinal Conditions

  Promethazine VC with Codeine Oral Solution is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [

  see Contraindications

  ]. The use of codeine in Promethazine VC with Codeine Oral Solution may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

  The concurrent use of anticholinergics with Promethazine VC with Codeine Oral Solution may produce paralytic ileus [see

  Drug Interactions

  ].

  The codeine in Promethazine VC with Codeine Oral Solution may result in constipation or obstructive bowel disease, especially in patients with underlying intestinal motility disorders. Use with caution in patients with underlying intestinal motility disorders.

  The codeine in Promethazine VC with Codeine Oral Solution may cause spasm of the sphincter of Oddi, resulting in an increase in biliary tract pressure. Opioids may cause increases in serum amylase [

  see Warnings and Precautions

  ]. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

  Administration of promethazine has been associated with reported cholestatic jaundice.

  )
  
  ]
  
• Increased intracranial pressure [see
  
  Warnings and Precautions (
  

  5.12 Risks of Use in Patients with Head Injury, Impaired
  Consciousness, Increased Intracranial Pressure, or Brain Tumors

  Avoid the use of Promethazine VC with Codeine Oral Solution in patients with head injury, intracranial lesions, or a pre-existing increase in intracranial pressure. In patients who may be susceptible to the intracranial effects of CO₂retention (eg, those with evidence of increased intracranial pressure or brain tumors), Promethazine VC with Codeine Oral Solution may reduce respiratory drive, and the resultant CO₂retention can further increase intracranial pressure.

  Furthermore, opioids produce adverse reactions that may obscure the clinical course of patients with head injuries.

  )
  
  ]
  
• Obscured clinical course in patients with head injuries [see
  
  Warnings and Precautions (
  

  5.12 Risks of Use in Patients with Head Injury, Impaired
  Consciousness, Increased Intracranial Pressure, or Brain Tumors

  Avoid the use of Promethazine VC with Codeine Oral Solution in patients with head injury, intracranial lesions, or a pre-existing increase in intracranial pressure. In patients who may be susceptible to the intracranial effects of CO₂retention (eg, those with evidence of increased intracranial pressure or brain tumors), Promethazine VC with Codeine Oral Solution may reduce respiratory drive, and the resultant CO₂retention can further increase intracranial pressure.

  Furthermore, opioids produce adverse reactions that may obscure the clinical course of patients with head injuries.

  )
  
  ]
  
• Cardiovascular effects [see Warnings and Precautions (
  
  5.13 Cardiovascular and Central Nervous System Effects

  The phenylephrine contained in Promethazine VC with Codeine Oral Solution can produce cardiovascular and central nervous system effects in some patients such as, insomnia, dizziness, weakness, tremor, transient elevations in blood pressure, or arrhythmias. Central nervous system stimulation with convulsions or cardiovascular collapse with accompanying hypotension has also been reported. Phenylephrine can cause a decrease in cardiac output. In patients with hypertension or with peripheral vascular insufficiency, phenylephrine may cause ischemia, increasing the risk of gangrene or thrombosis of compromised vascular beds. Therefore, Promethazine VC with Codeine Oral Solution is contraindicated in patients with severe hypertension, coronary artery disease, or peripheral vascular insufficiency [see

  Contraindications

  ], and should be used with caution in patients with other cardiovascular disorders, including patients with arteriosclerosis, elderly individuals, or patients with poor cerebral circulation.
  )]
  
• Neuroleptic Malignant Syndrome [see
  
  Warnings and Precautions (
  

  5.14 Risk of 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 (eg., 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, avoid use of Promethazine VC with Codeine Oral Solution in patients with a history consistent with NMS.

  )
  
  ]
  
• Paradoxical reactions, including dystonias [see
  
  Warnings and Precautions (
  

  5.15 Risk of Paradoxical Reactions, including Dystonias

  Promethazine VC with Codeine Oral Solution contains promethazine, a phenothiazine. Phenothiazines are associated with dystonic reactions, particularly in pediatric patients who have an acute illness associated with dehydration. Paradoxical reactions, including dystonia, torticollis, tongue protrusion, hyperexcitability, and abnormal movements have been reported in patients following a single administration of promethazine. Discontinue Promethazine VC with Codeine Oral Solution if a paradoxical reaction occurs.

  )
  
  ]
  
• Seizures [see
  
  Warnings and Precautions (
  

  5.16 Increased Risk of Seizures in Patients with Seizure Disorders

  The codeine and promethazine in Promethazine VC with Codeine Oral Solution may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Promethazine VC with Codeine Oral Solution therapy.

  )
  
  ]
  
• Interactions with MAOI [see
  
  Warnings and Precautions (
  

  5.17 Co-administration with Monoamine Oxidase Inhibitors (MAOIs)

  Concurrent use of Promethazine VC with Codeine Oral Solution is contraindicated in patients receiving monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping such therapy [

  see Contraindications

  ]. MAOIs may potentiate the effects of morphine, codeine’s active metabolite, including respiratory depression, coma, and confusion MAOIs. The cardiac pressor response may be potentiated and acute hypertensive crisis may occur when phenylephrine containing preparations are used with prior administration of MAOIs [

  see Drug Interactions

  ].

  )
  
  ]
  
• Bone-marrow suppression [see
  
  Warnings and Precautions (
  

  5.18 Bone-Marrow Depression

  Promethazine VC with Codeine 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.

  )
  
  ]
  
• Severe hypotension [see
  
  Warnings and Precautions (
  

  5.19 Severe Hypotension

  Promethazine VC with Codeine Oral Solution may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (eg., phenothiazines or general anesthetics) [

  see Drug Interactions (
  
  
  7.4)

  ]. Monitor these patients for signs of hypotension after initiating Promethazine VC with Codeine Oral Solution.

  In patients with circulatory shock, Promethazine VC with Codeine Oral Solution may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Promethazine VC with Codeine Oral Solution in patients with circulatory shock.

  )
  
  ]
  
• Neonatal Opioid Withdrawal Syndrome [see
  
  Warnings and Precautions (
  

  5.20 Neonatal Opioid Withdrawal Syndrome

  Promethazine VC with Codeine Oral Solution is not recommended for use in pregnant women. Prolonged use of Promethazine VC with Codeine Oral Solution during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see

  Use in Specific Populations

  and

  Patient Counseling Information

  ].

  )
  
  ]
  
• Adrenal insufficiency [see
  
  Warnings and Precautions (
  

  5.21 Adrenal Insufficiency

  Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

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The following adverse reactions have been identified during clinical studies, in the literature, or during post-approval use of codeine, promethazine, and/or phenylephrine. Because these reactions may be reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The most common adverse reactions to Promethazine VC with Codeine Oral Solution include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, constipation, shortness of breath, sweating, tachycardia, arrhythmias including premature ventricular contractions, CNS stimulation including anxiety, restlessness, nervousness, tremor, and irritability.

Other reactions include:

No specific drug interaction studies have been conducted with Promethazine VC with Codeine Oral Solution.