codeine/chlorpheniramine (Rx)

Brand and Other Names:Tuzistra XR, Tuxarin ER
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & 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 in adults (>18 years)

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

<18 years: Safety and efficacy not established

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

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Interactions

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            Adverse 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

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            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

            Contraindicated in children <12 years; avoid use in <18 years of age following tonsillectomy and/or adenoidectomy or 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

            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 CYP2D6 and polymorphism

            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

            Known hypersensitivity to codeine, chlorpheniramine, or product components

            Children <12 years

            Postoperative management in children <18 years following tonsillectomy and/or adenoidectomy (see Black Box Warnings and Cautions)

            Persons known to be hypersensitive to other opioids exhibiting 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

            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

            Produces dose-related respiratory depression (fatalities reported) by directly acting on brain stem respiratory centers; may produce irregular and periodic breathing

            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 during treatment

            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

            Concomitant use of opioids, 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

            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

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            Pregnancy & Lactation

            Pregnancy

            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

            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

            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 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

            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

            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

            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

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            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)

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.