Dosing and uses of Promethazine/codeine
Adult dosage forms and strengths
promethazine/codeine
oral liquid: Schedule V
- (6.25mg/10mg)/5mL
Cough
Temporary relief cough and upper respiratory tract symptoms associated with allergies or common cold
6.25 mg/10 mg (5 mL) PO q4-6hr; not to exceed 30 mL/24 hr
Renal Impairment
Caution; may need to initiate at a lower dose
Hepatic Impairment
Caution; may need to initiate at a lower dose
Administration
Administer with special measuring device for accurate dose
Pediatric dosage forms and strengths
Cough
<6 years: Use contraindicated
6-12 years: 2.5-5 mL PO q4-6hr; not to exceed 30 mL/24hr
>12 years: 6.25 mg/10 mg (5 mL) PO q4-6hr; not to exceed 30 mL/24 hr
Administration
Administer with special measuring device for accurate dose
Promethazine/codeine adverse (side) effects
>10% (Codeine)
Constipation
Drowsiness
Frequency not defined (Promethazine)
Sedation (common)
Confusion (common)
Disorientation (common)
Adverse anticholinergic effects (dry mouth, blurred vision)
Photosensitivity
EPs
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)
Warnings
Black box warnings
Because of the potential for fatal respiratory depression, do not administer promethazine and codeine concurrently to children <6 years of age
Postmarketing cases of respiratory depression, including fatalities have been reported with the use of promethazine in children <2 years of age
Postoperative pain in children
- Deaths have occurred in children with obstructive sleep apnea who receive codeine for postoperative pain following tonsillectomy and/or adenoidectomy
- 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)
Contraindications
Postoperative use in children following tonsillectomy and/or adenoidectomy (see Black box warnings)
Promethazine
- Hypersensitivity
- Newborn/premature infants, <2 years (risk of potentially fatal respiratory depression)
- Subcutaneous or intra-arterially administration
- Benign prostatic hypertrophy
- Narrow angle glaucoma
- Pyloroduodenal obstruction, stenosing peptic ulcer, bladder neck obstruction
- Severe CNS depression
- Coma, severe respiratory depression
Codeine
- Absolute: acute abdominal condition, diarrhea associated w/ toxins, pseudomembranous colitis, respiratory depression
- Relative: asthma (acute), inflammatory bowel disease, respiratory impairment
Cautions
Promethazine
- Caution in CVD, asthma, hepatic impairment, peptic ulcer, respiratory impairment
- 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
Codeine
- Caution in 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
Pregnancy and lactation
Pregnancy category: C
Lactation: codeine excreted in breast milk; promethazine undetermined; use while nursing not recommended due to infant risk
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.
Pharmacology of Promethazine/codeine
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
Promethazine
Onset: 20 min
Duration: 4-6 hr
Bioavailability: 25% (oral)
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
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
