Dosing and uses of Tuzistra XR, Tuxarin ER (codeine/chlorpheniramine)
Adult dosage forms and strengths
codeine/chlorpheniramine
extended-release oral suspension: Schedule III
- (14.7mg/2.8mg)/5mL (equivalent to 20mg codeine phosphate and 4mg chlorpheniramine maleate)
tablet, extended-release: Schedule III
- 40mg/5.6mg (equivalent to 54.3mg codeine phosphate and 8mg chlorpheniramine maleate)
Cough & Cold
Indicated for relief of cough and symptoms associated with upper respiratory tract allergies or common cold
Suspension: 10 mL PO q12hr; not to exceed 2 doses (20 mL) in 24 hr
Tablet: 1 tablet PO q12hr; not to exceed 2 doses/24 hr
Pediatric dosage forms and strengths
<18 years: Safety and efficacy not established
Geriatric dosage forms and strengths
Dose selection for an elderly patient should be made with caution, 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
Tuzistra XR, Tuxarin ER (codeine/chlorpheniramine) adverse (side) effects
Frequency not defined
Allergic: Allergic laryngospasm, nasal stuffiness, bronchospastic allergic reaction, hives, itching, swelling of face
Body as a whole: Asthenia, feeling of relaxation, redness or flushing of the face, unusual tiredness, weakness
Cardiovascular: Fast or slow heartbeat, hypertension, hypotension, orthostatic hypotension, palpitations, shock-like state, syncope
Dermatological system: Skin rash, pruritus, erythema, urticaria, excessive perspiration, dermatitis
Endocrine system: Changes in glucose utilization, decreased lactation, early menses, glycosuria, gynecomastia, hypoglycemia, increased appetite, increased libido, pheochromocytoma stimulation
Gastrointestinal system: Nausea and vomiting, constipation, abdominal distension, abdominal pain, acute pancreatitis, dry mouth, dyspepsia, epigastric distress, loss of appetite, diarrhea, gastro-esophageal reflux, gastrointestinal hypomotility
Genitourinary system: Ureteral spasm, urinary retention, dysuria, urinary frequency, urinary hesitancy, irritative bladder symptom
Nervous system: Blurred vision, diplopia, visual disturbances, confusion, dizziness, depression, drowsiness, sedation, headache, euphoria, facial dyskinesia, false sense of well-being, feeling faint, lightheadedness, general feeling of discomfort or illness, excitability, nervousness, agitation, restlessness, somnolence, insomnia, dyskinesia, irritability, tremor
Respiratory: Dryness of the pharynx and respiratory passages, laryngismus, atelectasis, wheezing, troubled breathing, respiratory depression, hiccups
Special senses: Labyrinthitis, tinnitus, vertigo, hypermetropia, increased lacrimation, mydriasis, photophobia
Warnings
Black box warnings
Respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism
Contraindications
Postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy (see Black box warnings and Cautions)
Known hypersensitivity to codeine, chlorpheniramine, or any of the inactive ingredients
Persons known to be hypersensitive to certain other opioids may exhibit cross-sensitivity to codeine
Cautions
Respiratory depression and death have occurred in children who received codeine in the postoperative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (ie, multiple copies of the gene for CYP2D6 or high morphine concentrations) (see Black box warnings and Contraindications)
Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine
Produces dose-related respiratory depression (fatalities reported) by directly acting on brain stem respiratory centers; may produce irregular and periodic breathing
Potential for dependence and abuse
Avoid use with head injuries; opioids produce adverse reactions that may obscure the clinical course of patients with head injuries
Codeine and chlorpheniramine produce drowsiness and may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks (driving, operating machinery)
Long-term use of opioids, including codeine, may result in constipation or obstructive bowel disease
Caution with acute abdominal conditions since the codeine may obscure the diagnosis or clinical course of patients with acute abdominal conditions; concurrent use of other anticholinergics with codeine may produce paralytic ileus
Caution in elderly or debilitated patients and those with asthma, persistent or chronic cough, hypothyroidism, Addison disease, prostatic hypertrophy, or urethral stricture
Both codeine and chlorpheniramine are extensively metabolized by the liver; caution with severe hepatic impairment
Avoid in patients with head injury, intra-cranial lesions, or increased intracranial pressure
Avoid concurrent use of alcohol or other central nervous system depressants
Measure dose only with an accurate mL measuring device
Pregnancy and lactation
Pregnancy
Pregnancy category: C
Codeine
- As with all opioids, administration of codeine to the mother shortly before delivery may result in some degree of respiratory depression in the newborn, especially if higher doses are used
- Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent
- Withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever
Chlorpheniramine
- A retrospective study found a small, but statistically significant, association between maternal use of chlorpheniramine and inguinal hernia and eye or ear anomalies in children
Lactation
Codeine is secreted in human breast milk
Use caution if administered to a nursing woman; prescribe the lowest dose for shortest period of time to achieve desired effect; inform mothers when to seek immediate medical care and how to identify signs and symptoms of neonatal toxicity (eg, drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone)
In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent
If a woman is an ultra-rapid metabolizer of codeine, higher-than-expected serum levels of codeine's active metabolite (morphine) may be achieved, leading to higher-than-expected levels of morphine in breast milk
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 Tuzistra XR, Tuxarin ER (codeine/chlorpheniramine)
Mechanism of action
Codeine: Semisynthetic narcotic antitussive and analgesic with multiple actions qualitatively similar to those of morphine; believed to act centrally on the cough center
Chlorpheniramine: Propylamine derivative antihistamine drug (H1 receptor antagonist) that also possesses anticholinergic and sedative activity; prevents released histamine from dilating capillaries and causing edema of the respiratory mucosa
Absorption
Peak plasma time
- Codeine: 2.19 hr
- Chlorpheniramine: 6.52 hr
Peak plasma concentration
- Codeine: 51.4 ng/mL
- Chlorpheniramine: 7.84 ng/mL
AUC
- Codeine: 348.5 ng•h/mL
- Chlorpheniramine: 304.3 ng•h/mL
Distribution
Protein bound
- Codeine: 7-25%
- Chlorpheniramine: 70%
Vd
- Codeine: 3-6 L/kg
- Chlorpheniramine: 3.2 L/kg
Metabolism
Codeine
- ~70-80% is metabolized by conjugation with glucuronic acid to codeine-6glucuronide (C6G) and via O-demethylation to morphine (~5-10%) and N-demethylation to norcodeine (~10%) respectively
- UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major enzymes mediating glucurodination of codeine to C6G
- CYP2D6 and CYP3A4 are the major enzymes mediating O-demethylation and N-demethylation of codeine, respectively
- Morphine and norcodeine are further metabolized by conjugation with glucuronic acid
- Morphine and its M6 glucuronide conjugate are pharmacologically active
- Whether C6G has pharmacological activity is unknown
- Norcodeine and M3 glucuronide conjugate of morphine are generally not considered to be pharmacologically active
Chlorpheniramine
- Rapidly and extensively metabolized via demethylation in the liver, forming monodesmethyl and didesmethyl derivatives
- Oxidative metabolism of chlorpheniramine is catalyzed by CYP2D6
Elimination
Half-life
- Codeine: 5 hr
- Chlorpheniramine: 21.45 hr
Excretion
- Codeine: 90% urine (~10% as unchanged drug)
- Chlorpheniramine: Drug and its metabolites are primarily excreted through the kidneys, with large individual variation that depends on urine pH and flow rate
Pharmacogenomics
5-10% 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 whites and up to 30% of Asian and African populations) may have increased toxicity due to rapid conversion
Administration
Instructions
Take with or without food
Shake well before measuring dose
Measure with an accurate mL measuring device; do not use a household teaspoon to measure the dose
Storage
Room temperature at 20-25°C (68-77°F); excursions permitted from 15-30°C (59-86°F)
