codeine/acetaminophen (Rx)

Brand and Other Names:Tylenol with Codeine, Tylenol #3, more...Tylenol #4
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet: Schedule III

  • 15mg/300mg
  • 30mg/300mg
  • 60mg/300mg

oral suspension: Schedule V

  • (12mg/120mg)/5mL

Mild to Moderately Severe Pain

Tablet: 15-60 mg codeine/dose PO q4-6hr; not to exceed 360 mg codeine/day or 4 g acetaminophen/day

Oral solution: 15 mL (36 mg/360 mg) PO q4hr PRN; not to exceed 4 g acetaminophen/day

Dosing considerations

  • Based on the dosage strength selected and pain severity/tolerance, the prescriber must determine the number of tablets for each dose and frequency of administration (typically q4-6hr)

Cough (Off-label)

15-30 mg codeine/dose PO q4-6hr; not to exceed 360 mg codeine/day or 4 g acetaminophen/day

Dosage Modifications

Renal impairment: Use caution

Hepatic impairment: May tolerate low-dose therapy in hepatic cirrhosis; avoid chronic use

Dosage Forms & Strengths

tablet: Schedule III

  • 15mg/300mg
  • 30mg/300mg
  • 60mg/300mg

oral suspension: Schedule V

  • (12mg/120mg)/5mL

Mild to Moderately Severe Pain

Tablet

  • <12 years: Contraindicated
  • ≥12 years: 0.5-1 mg codeine/kg/dose PO q4-6hr (not to exceed 5 doses q24hr); 10-15 mg acetaminophen/kg/dose PO q4-6hr (not to exceed 4 g acetaminophen q24hr)  
  • Alternatively, 15-60 mg/dose for codeine (not to exceed 360 mg q24hr) and 300-1000 mg/dose for acetaminophen (not to exceed 4 g q24hr); may repeat dose q4hr

Oral suspension

  • >12 years: 15 mL (36 mg/360 mg) PO q4hr prn
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Interactions

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            Adverse Effects

            Frequency Not Defined (Codeine)

            Constipation

            Drowsiness

            Hypotension

            Tachycardia or bradycardia

            Confusion

            Dizziness

            False feeling of well being

            Headache

            Lightheadedness

            Malaise

            Paradoxical CNS stimulation

            Restlessness

            Rash

            Urticaria

            Anorexia

            Nausea

            Vomiting

            Xerostomia

            Ureteral spasm

            Decreased urination

            Increased LFTs

            Burning at injection site

            Weakness

            Blurred vision

            Dyspnea

            Histamine release

            Frequency Not Defined (Acetaminophen)

            Pruritic maculopapular rash

            Urticaria

            Laryngeal edema

            Angioedema

            Anaphylactoid reaction

            Thrombocytopenia

            Leukopenia

            Pancytopenia

            Neutropenia

            Thrombocytopenic purpura

            Agranulocytosis

            Hepatotoxicity

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            Warnings

            Black Box Warnings

            Hepatotoxicity may occur with acetaminophen doses that exceed 4 g/day; take into account all acetaminophen-containing products that the patient is taking, including PRN doses and OTC products

            Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplantation or death

            New dosage limit allows no more than 325 mg/dosage unit for prescription medications that contain acetaminophen

            Healthcare professionals can direct patients to take 1 or 2 tablets, capsules, or other dosage units of a prescription product containing 325 mg of acetaminophen up to 6 times a day (12 dosage units) and still not exceed the maximum daily dose of acetaminophen of 4 g/day

            Accidental ingestion, especially by children,can result in a fatal overdose

            Addiction, Abuse and Misuse

            • Drug exposes patients and other users to the risks of opioid addiction, abuse and misuse, which can lead to overdose and death; assess each patient’s risk prior to prescribing drug, and monitor all patients regularly for the development of these behaviors and conditions
            • To ensure that the benefits of opioid analgesics outweigh risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products
            • Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS compliant education programs available to healthcare providers
            • Healthcare providers are strongly encouraged to complete a REMS-compliant education program, counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products, emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and consider other tools to improve patient, household, and community safety

            Life-Threatening Respiratory Depression

            • Serious, life-threatening, or fatal respiratory depression may occur with therapy
            • Monitor for respiratory depression, especially during initiation of therapy or following a dose increase
            • Respiratory depression and death reported following tonsillectomy and/or adenoidectomy in patients that appeared to be rapid metabolizers of codeine due to CYP2D6 polymorphism

            Ultra-rapid metabolism of codeine and other risk factors for life-threatening respiratory depression in children

            • Life-threatening respiratory depression and death have occurred in children who received codeine; most of reported cases occurred following tonsillectomy and/or adenoidectomy and many of the children had evidence of being ultra-rapid metabolizers of codeine due to a cytochrome P450 (CYP) 2D6 polymorphism
            • Avoid use of in adolescents 12-18 years of age who have other risk factors that may increase their sensitivity to respiratory depressant effects of codeine

            Neonatal Opioid Withdrawal Syndrome

            • Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts; if opioid use is required for a prolonged period in a pregnant woman, advise patient of risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

            Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

            • The effects of concomitant use or discontinuation of CYP3A4 inducers, CYP3A4 inhibitors, or CYP2D6 inhibitors with codeine are complex; use of CYP3A4 inducers, CYP3A4 inhibitors, or CYP2D6 inhibitors with drug requires careful consideration of effects on parent drug, codeine, and active metabolite, morphine

            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 with
            • 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

            Contraindications

            Children <12 years

            Post-operative management in children <18 years following tonsillectomy and/or adenoidectomy

            Patients with significant respiratory depression, 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 last 14 days

            Known or suspected gastrointestinal obstruction, including paralytic ileus

            Hypersensitivity to codeine, acetaminophen, or ingredients

            Hepatitis or severe hepatic/renal impairment

            Cautions

            Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplantation and death; risk increases in individuals with underlying liver disease, alcohol ingestion, and/or use of more than 1 acetaminophen-containing product (see Black Box Warnings)

            Acetaminophen: Risk for rare, but serious skin reactions that can be fatal; these reactions include Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP); symptoms may include skin redness, blisters and rash

            Acetaminophen may cause serious an potentially fatal skin reactions

            Patients with G6PD deficiency

            Use caution in repeated administration in patients with anemia or with cardiovascular, pulmonary, or renal disease

            Use caution in patients with history of porphyria

            May cause hypotension; use with caution in patients with hypovolemia

            Codeine may cause depression; avoid driving car or operating heavy machinery

            Use caution in patients with conditions associated with hypoxia, hypercapnia, upper respiratory obstruction, or debilitated patients

            May increase respiratory depressant effects; caution with head injury, COPD, or other conditions associated with decreased respiratory drive

            Use caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists including oxymorphone, levorphanol, oxycodone, or hydrocodone

            Codeine may cause tolerance/dependency

            May obscure diagnosis or clinical course of patients with acute abdominal conditions and may worsen gastrointestinal ileus due to reduced GI motility

            Use cuation in adrenal insufficiency, billiary tract impairment, patients susceptible to intracranial effects of CO2 retention, G6PD deficiency, head trauma, prostatic hyperplasia, hepatic/renal impairment, thyroid dysfunction, seizure disorder, or respiratory disease (COPD)

            Codeine may cause or exacerbate constipation; chronic use may result in obstructive bowel disease, especially in patients with existing intestinal motility disorders; reduce potential for constipation by taking preventive measures, including the increase of fiber intake and the use of stool softeners

            Long-term use in patients with adrenal insufficiency may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis

            Use with caution in patients with biliary tract dysfunction, including pancreatitis; may increase amylase/lipase levels and may cause constriction of sphincter of Oddi

            Healthcare providers should choose lowest effective dose for shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose

            Death reported in nursing infant exposed to high levels of morphine in breast milk because mother was an ultra-rapid metabolizer of codeine; breastfeeding is not recommended during treatment

            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 for signs of hypotension after initiating or titrating dosage; in patients with circulatory shock, drug may cause vasodilatation that can further reduce cardiac output and blood pressure; avoid use in circulatory shock

            Therapy may obscure diagnosis or clinical course in patients with acute abdominal conditions; therapy may cause spasm of sphincter of Oddi; opioids may cause increases in serum amylase; monitor patients with biliary tract disease,including acute pancreatitis, for worsening symptoms

            Codeine 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

            Do not abruptly discontinue drug in a patient physically dependent on opioids; when discontinuing therapy in a physically dependent patient, gradually taper the dosage

            Addiction potential

            • Therapy exposes users to the risks of addiction, abuse, and misuse; addiction can occur in patients appropriately prescribed therapy and can occur at recommended dosages; assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing therapy; 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)
            • Patients at increased risk may be prescribed opioids, but use in such patients necessitates intensive counseling about risks and proper use of drug along with intensive monitoring for signs of addiction, abuse, and misuse

            Adrenal insufficiency

            • Cases of adrenal insufficiency reported with opioid use, more often following > 1 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 suspected, confirm diagnosis with diagnostic testing as soon as possible; if adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids; wean 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

            Respiratory depression

            • Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended; respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death; management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on patient’s clinical status; carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids
            • Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia; opioid use increases risk of CSA in a dose dependent fashion; in patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper

            Ultra-rapid metabolism of codeine and other risk factors for life-threatening respiratory depression in children

            • Life-threatening respiratory depression and death have occurred in children who received codeine; codeine is subject to variability in metabolism based upon CYP2D6 genotype, which can lead to an increased exposure to active metabolite morphine
            • Based upon post-marketing reports, children <12 years appear to be more susceptible to respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression; for example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine
            • Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effects
            • Avoid use in adolescents 12-18 years of age who have other risk factors that may increase their sensitivity to respiratory depressant effects of codeine unless benefits outweigh risks; risk factors include conditions associated with hypoventilation, such as post-operative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression

            Drug interaction overview

            • Concomitant use with all CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (eg, ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of CYP3A4 inducer such as rifampin, carbamazepine, and phenytoin, may increase codeine plasma concentrations with subsequently greater metabolism by CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression
            • Concomitant use with all CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor may result in lower codeine levels, greater norcodeine levels, and less metabolism via CYP2D6 with resultant lower morphine levels; this may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal; follow patients receiving the drug and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when used in combination with inhibitors and inducers of CYP3A4
            • If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued, consider dosage reduction until stable drug effects are achieved; monitor patients for respiratory depression and sedation at frequent intervals; if concomitant use of a CYP3A4 inducer is necessary or if a CYP3A4 inhibitor is discontinued, consider increasing the dosage of the drug until stable drug effects are achieved; monitor for signs of opioid withdrawal
            • Concomitant use with Codeine with all CYP2D6 inhibitors (eg, amiodarone, quinidine) may result in an increase in codeine plasma concentrations and a decrease in active metabolite morphine plasma concentration which could result in analgesic efficacy reduction or symptoms of opioid withdrawal; discontinuation of a concomitantly used CYP2D6 inhibitor may result in a decrease in codeine plasma concentration and an increase in active metabolite morphine plasma concentration which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression
            • Follow patients receiving CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when administered in conjunction with inhibitors of CYP2D6
            • If concomitant use with a CYP2D6 inhibitor necessary, follow patient for signs of reduced efficacy or opioid withdrawal and consider increasing
            • Dosage; after stopping use of a CYP2D6 inhibitor, consider reducing dosage and follow the patient for signs and symptoms of respiratory depression or sedation

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            Pregnancy & Lactation

            Pregnancy

            There are no adequate and well-controlled studies in pregnant women; use during pregnancy only if potential benefit justifies potential risk to fetus

            Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in neonate and neonatal opioid withdrawal syndrome shortly after birth

            Inform female patients of reproductive potential that prolonged use of drug during pregnancy can result in neonatal opioid withdrawal syndrome,which may be life-threatening if not recognized and treated

            Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight; onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of drug by newborn; observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly

            Inform female patients of reproductive potential that therapy can cause fetal harm and for patient to inform prescriber of a known or suspected pregnancy

            Inform patients that chronic use of opioids may cause reduced fertility; it is not known whether these effects on fertility are reversible

            Labor and delivery

            • Not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate; opioid analgesics, including can prolong labor through actions which temporarily reduce strength, duration, and frequency of uterine contractions

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

            Limited published studies report that acetaminophen passes rapidly into human milk with similar levels in milk and plasma; average and maximum neonatal doses of 1% and 2%, respectively, of weight-adjusted maternal dose are reported after a single oral administration of 1 gram APAP; there is one well documented report of rash in a breast-fed infant that resolved when mother stopped acetaminophen use and recurred when she resumed acetaminophen use

            If infants are exposed to drug through breast milk, they should be monitored for excess sedation and respiratory depression; withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped

            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: Opioid agonist; analgesia; blocks pain impulse generation and inhibits ascending pain pathways, thus altering the perception and response to pain; inhibits cough by acting centrally in the medulla; causes CNS depression

            Acetaminophen: Nonopioid, nonsalicylate analgesic; may work peripherally to block pain impulse generation; acts on hypothalamus to produce antipyresis

            Absorption

            Bioavailability: Codeine (53%); acetaminophen (100%)

            Onset: 0.5-1 hr

            Duration: 4-6 hr

            Peak effect: 1-1.5 hr

            Distribution

            Protein bound: Codeine (<25%); acetaminophen (10-25%), higher with toxic concentrations

            Vd: Codeine (3-6 L/kg); acetaminophen (1 L/kg)

            Metabolism

            Codeine

            • Via hepatic UGT2B7 and UGT2B4 to codeine-6-glucuronide
            • 10% of codeine is metabolized in liver to morphine by CYP2D6; the active morphine metabolite has a higher affinity for opioid receptors; also via CYP3A4 to norcodeine
            • CYPD2D6 poor metabolizers may not achieve adequate analgesia
            • Ultrarapid metabolizers (up to 7% of whites and up to 30% of Asian and African populations) may experience increased toxicity due to rapid conversion to morphine

            Acetaminophen

            • Metabolized in liver by microsomal enzyme systems
            • 80-85% conjugated principally with glucuronic acid and to a lesser extent with sulfuric acid and cysteine
            • 4% metabolized by CYP450 to toxic metabolite (N acetyl-p-benzoquinoneimine, N-acetylimidoquinone [NAPQI]), which is further detoxified by conjugation with glutathione; high doses may deplete fixed amount of glutathione in body, causing NAPQI accumulation

            Elimination

            Codeine

            • Half-life: 3 hr
            • Excretion: Urine (90%)

            Acetaminophen

            • Half-life: 2-4 hr
            • Excretion: Urine (90-100%; principally as acetaminophen glucuronide with acetaminophen sulfate/mercaptate)
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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
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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