promethazine/codeine/phenylephrine (Rx)

Brand and Other Names:Prometh VC with Codeine Syrup
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

oral liquid: Schedule V

  • promethazine/codeine/phenylephrine
  • (6.25mg/10mg/5mg)/5mL

Cough

Temporary relief of cough and upper respiratory tract symptoms associated with allergies or common cold

5 mL PO q4-6hr, not to exceed 30 mL/24 hr

Administration

Administer with special measuring device for accurate dose

Dosage Forms & Strengths

promethazine/codeine/phenylephrine

oral liquid: Schedule V

  • promethazine/codeine/phenylephrine
  • (6.25mg/10mg/5mg)/5mL

Cough

<12 years: Contraindicated

12 years: 2.5-5 mL PO q4-6hr; not to exceed 30 mL/24hr

>12 years: 5 mL PO q4-6hr, not to exceed 30 mL/24 hr

Administration

Administer with special measuring device for accurate dose

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Adverse Effects

>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

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Warnings

Black Box Warnings

Because of the potential for fatal respiratory depression, do not administer promethazine and codeine concurrently to children <12 years of age

Postmarketing cases of respiratory depression, including fatalities reported with use of promethazine in pediatric patients; children may be particularly sensitive to additive respiratory depressant effects when promethazine is combined with other respiratory depressants, including codeine

Coadministration with benzodiazepines

  • Risks from concomitant use with benzodiazepines or other CNS depressants; concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death; reserve concomitant prescribing of this drug combination and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to minimum required; follow patients for signs and symptoms of respiratory depression and sedation
  • Addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion; risks from concomitant use with benzodiazepines or other CNS depressants; ultra- rapid metabolism of codeine and other risk factors for life-threatening respiratory depression in children; neonatal opioid withdrawal syndrome; interactions with drugs affecting cytochrome p450 isoenzymes; and hepatotoxicity

Postoperative pain in children

  • Deaths have occurred in children with obstructive sleep apnea who receive codeine for postoperative pain following tonsillectomy and/or adenoidectomy
  • Contraindicated in children <12 years and in children <18 years following tonsillectomy and/or adenoidectomy; avoid use in adolescents 12-18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine; codeine is converted to morphine by the liver; these children had evidence of being ultra-rapid metabolizers (via CYP2D6) of codeine, which is an inherited (genetic) ability that causes codeine to be converted rapidly into life-threatening or fatal amounts of morphine (see Pharmacology)
  • Concomitant use of opioids with benzodiazepines or other central nervous system (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

Contraindications

Promethazine

  • Hypersensitivity
  • Children <12 years (risk of potentially fatal respiratory depression)
  • Subcutaneous or intra-arterially administration
  • BPH
  • Narrow angle glaucoma
  • Pyloroduodenal obstruction, stenosing peptic ulcer, bladder neck obstruction
  • Severe CNS depression
  • Coma
  • Severe respiratory depression

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

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
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Pregnancy & Lactation

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.

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Pharmacology

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

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Formulary

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