promethazine/codeine/phenylephrine (Rx)

>10%

Codeine

• Constipation
• Drowsiness

Frequency Not Defined (Promethazine)

Sedation (common)

Confusion (common)

Disorientation (common)

Adverse anticholinergic effects (dry mouth, blurred vision)

Photosensitivity

Extrapyramidal symptoms

Tachycardia

Bradycardia Leukopenia (rare)

Agranulocytosis (rare)

Obstructive jaundice

Frequency Not Defined (Codeine)

Confusion

Dizziness

False feeling of well being

Headache

Lightheadedness

Malaise

Paradoxical CNS stimulation

Restlessness

Seizure (with excessive doses)

Weakness

Blurred vision

Hypotension (especially with IV use)

Tachycardia

Bradycardia

Dyspnea

Respiratory depression

Anorexia

Nausea

Vomiting

Xerostomia

Rash

Urticaria

Ureteral spasm

Urination decreased

LFT's increased

Histamine release

Anaphylactoid reaction (rare)

Frequency Not Defined (Phenylephrine)

HTN

Reflex bardycardia

Anxiety

Headache

Burning

Rebound congestion

Sneezing

Pulmonary edema

Extravasation

Contraindications

Promethazine

• Hypersensitivity
• Children <12 years (risk of potentially fatal respiratory depression)
• Subcutaneous or intra-arterially administration
• BPH
• Narrow-angle glaucoma, urinary retention, severe hypertension, severe coronary artery disease, or peripheral vascular insufficiency (ischemia may result with risk of gangrene or thrombosis of compromised vascular beds)
• Pyloroduodenal obstruction, stenosing peptic ulcer, bladder neck obstruction
• Severe CNS depression
• Coma
• Severe respiratory depression
• A history of an idiosyncratic reaction to promethazine or to other phenothiazines

Codeine

• Children <12 years
• Absolute: acute abdominal condition, diarrhea associated w/ toxins, pseudomembranous colitis, respiratory depression
• Postoperative use in children (<18 years) following tonsillectomy and/or adenoidectomy (see Black Box Warnings)
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days
• Significant respiratory depression
• Porphyria
• Treatment of lower respiratory tract symptoms, including asthma
• Known or suspected gastrointestinal obstruction, including paralytic ileus

Phenylephrine

• Hypersensitivity to phenylephrine or sulfites
• Severe hypertension
• Ventricular tachycardia
• Closed-angle glaucoma
• Do not use within 14 days of MAO inhibitors
• Risk of hypertension

Cautions

Concomitant use of opioids, including promethazine HCl and codeine phosphate 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

Opioid analgesics and antitussives, including codeine, one of the active ingredients in this drug combination, 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

Dosing errors can result in accidental overdose and death; to reduce risk of overdose and respiratory depression, ensure that the dose of this medication is communicated clearly and dispensed accurately

Avoid use in patients with head injury, intracranial lesions, or a pre-existing increase in intracranial pressure; in patients who may be susceptible to intracranial effects of CO₂ retention (eg, those with evidence of increased intracranial pressure or brain tumors), this medication may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure

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 reported in patients following a single administration of promethazine; therapy if a paradoxical reaction occurs

The codeine and promethazine in this drug combination may increase frequency of seizures in patients with seizure disorders, and may increase risk of seizures occurring in other clinical settings associated with seizures; monitor patients with a history of seizure disorders for worsened seizure control during therapy

MAOIs may potentiate 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

Effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex; use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine

Promethazine

• Caution in CVD, asthma, hepatic impairment, peptic ulcer, respiratory impairment; 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; avoid use of promethazine HCl and codeine phosphate oral solution in patients on these medications
• Anaphylaxis in susceptible individuals
• May impair ability to drive or perform hazardous tasks
• Monitor closely with cardiovascular disease, hepatic impairment, Reye syndrome, history of sleep apnea
• Depresses hypothalamic thermoregulatory mechanism; exposure to extreme temperatures may cause hypo- or hyperthermia
• Antiemetic effect may obscure toxicity of chemotherapeutic drugs
• Concomitant use of opioids, including promethazine HCl and codeine phosphate oral solution, with benzodiazepines, or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death; avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol
• 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 increased susceptibility to dystonias with promethazine HCl use
• The respiratory-depressant effects of narcotic analgesics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in presence of head injury, intracranial lesions, or a pre-existing increase in intracranial pressure; narcotics may produce adverse reactions which may obscure clinical course of patients with head injuries
• A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) reported in association with promethazine HCl alone or in combination with antipsychotic drugs; 1) management of NMS should include 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
• Promethazine should be used with caution in patients with bone-marrow depression; leukopenia and agranulocytosis reported, usually when promethazine HCl has been used in association with other known marrow-toxic agents

Codeine

• Cardiac arrhythmias, drug abuse/dependence, emotional lability, gallbladder disease, head injury, hepatic impairment, hypothyroidism, increased ICP, prostatic hypertrophy, renal impairment, seizures w/ epilepsy, urethral stricture, urinary tract surgery
• Risk of life-threatening side effects in nursing babies, especially if mother is an ultra-rapid metabolizer of codeine
• Ibuprofen is more effective than codeine for pain from musculoskeletal injuries in children
• Avoid use in adolescents 12-18 years of age who have other risk factors that may increase sensitivity to respiratory depressant effects of codeine unless benefits outweigh risks; 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 lowest effective dose for shortest period of time and inform patients and caregivers about risks and the signs of morphine overdose
• Dosage of codeine 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
• Narcotic analgesics or cough suppressants, including codeine, should not be used in patients with severe asthma or those with frequent asthma attacks
• Codeine may produce orthostatic hypotension in ambulatory patients
• Codeine may cause or aggravate constipation

Phenylephrine

• Caution in cerebrovascular insufficiency, CVD, HTN, DM, thyroid disease, prostatic hypertrophy, geriatrics

Hypotension

• Therapy 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); monitor these patients for signs of hypotension after initiating therapy
• Patients with circulatory shock, therapy may cause vasodilation that can further reduce cardiac output and blood pressure; avoid use in patients with circulatory shock

Addiction, abuse, misuse

• Although risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed this medication; addiction can occur at recommended dosages and if drug is misused or abused; risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (eg, major depression).
• Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion; consider these risks when prescribing or dispensing this medication; strategies to reduce these risks include prescribing the drug in smallest appropriate quantity and advising patient on proper disposal of unused drug
• Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product

Cardiovascular and central nervous system effects

• The phenylephrine contained in this drug combination 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 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, therapy is contraindicated in patients with severe hypertension, coronary artery disease, or peripheral vascular insufficiency and should be used with caution in patients with other cardiovascular disorders, including patients with arteriosclerosis, elderly individuals, or patients with poor cerebral circulation

Gastrointestinal conditions

• This medication is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic; therapy 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
• Therapy 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
• Therapy may cause spasm of sphincter of Oddi, resulting in an increase in biliary tract pressure; opioids may cause increases in serum amylase; monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms
• Administration of promethazine has been associated with reported cholestatic jaundice

Mental alertness

• Codeine and promethazine, two of the active ingredients in this medication, may produce marked drowsiness and impair mental and/or physical abilities required for 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 this drug combination; avoid concurrent use with alcohol or other central nervous system depressants because additional impairment of central nervous system performance may occur

Respiratory depression

• Codeine produces dose-related respiratory depression by directly acting on 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 active metabolite morphine
• 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 patient’s clinical status; carbon dioxide (CO 2) 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 this drug combination, the risk is greatest during the initiation of therapy, when used concomitantly with other drugs that may cause respiratory depression 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)
• To reduce risk of respiratory depression, proper dosing is essential; monitor patients closely, especially within first 24-72 hours of initiating therapy or when used in patients at higher risk
• Accidental ingestion of even one dose of this medication, especially by children, can result in respiratory depression and death
• Children may be particularly sensitive to the additive respiratory depressant effects when promethazine is combined with other respiratory depressants; excessively large dosages of antihistamines, including promethazine hydrochloride, in pediatric patients may cause sudden death

Ultra-rapid metabolism

• Based upon post-marketing reports, children younger than 12 years old appear to be more susceptible to respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression
• Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to respiratory depressant effect
• 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); individuals who are ultra-rapid metabolizers should not use this medication

Neuroleptic malignant syndrome

• 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
• Since recurrences of NMS have been reported with phenothiazines, avoid use of this drug combination in patients with a history consistent with NMS

Neonatal opioid withdrawal syndrome

• Therapy is not recommended for use in pregnant women; prolonged use 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 risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

Adrenal insufficiency

• Cases of adrenal insufficiency 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 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 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

Pregnancy

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome; available data in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage

Labor and delivery

• Use of codeine during labor may lead to respiratory depression in the neonate; opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates; an opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate; use is not recommended in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate; opioid analgesics, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions; however, this effect is not consistent and may be offset by increased rate of cervical dilation, which tends to shorten labor; monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression

Lactation

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; at least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because mother was an ultra-rapid metabolizer of codeine; breastfeeding not recommended

There is no information on effects of codeine milk production; because of potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, breastfeeding is not recommended during treatment

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Promethazine: Antidopaminergic effect due to blocking mesolimbic dopamine receptors and alpha-adrenergic receptors in the brain; antihistaminic effect due to blocking H1-receptors

Codeine: Narcotic agonist analgesic with antitussive activity, mu receptor agonist

Phenylephrine: Strong alpha effects resulting in increased PVR and BP and decreased cardiac output and renal perfusion

Promethazine

Onset: 20 min

Duration: 4-6 hr

Bioavailability: 25% (PO)

Protein Bound: 93%

Vd: 12.9-17.7 L/hr

Metabolism: hepatic P450 enzyme CYP2D6

Metabolites: promethazine sulfoxide and glucuronides (inactive)

Excretion: Urine, feces

Dialyzable: No

Codeine

Half-Life: 3-4 hr

Onset: 30-60 min

Metabolism: Inactive but metabolized to morphine by CYP2D6 (missing in 5-10% of population)

Duration: 4-6 hr

Peak Plasma Time: 0.5-1 hr

Vd: 3-6 L/kg

Bioavailability: 53%

Protein Bound: 25%

Excretion: Urine (90%), feces

Phenylephrine

Half-Life: 2-3 hr

Onset (blood pressure): 10-15 min (SC/IM)

Duration (blood pressure): 15-20 min (IV); 1-2 hr (IM)

Vd: 26-61 L

Bioavailability: ≤ 38%

Metabolism: Extensivly in intestinal wall, moderately in liver

Metabolites: M-hydroxymandelic acid (inactive)

Excretion: Urine: 80-90%

Pharmacogenomics

10% of codeine is metabolized to morphine by CYP2D6; the active morphine metabolite has a higher affinity for opioid receptors

CYP2D6 poor metabolizers may not achieve adequate analgesia

Ultra-rapid metabolizers (up to 7% of Caucasians and up to 30% of Asian and African populations) may have increased toxicity due to rapid conversion