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Acetaminophen and Codeine

Pronunciation

Pronunciation

(a seet a MIN oh fen & KOE deen)

Index Terms

  • Acetaminophen/Codeine
  • Codeine and Acetaminophen
  • Codeine Phos/Acetaminophen
  • Emtec
  • Tylenol #2
  • Tylenol #3
  • Tylenol Codeine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Oral:

Generic: Acetaminophen 120 mg and codeine phosphate 12 mg per 5 mL (5 mL, 10 mL [DSC], 12.5 mL, 15 mL [DSC], 118 mL, 120 mL, 473 mL)

Suspension, Oral:

Capital/Codeine: Acetaminophen 120 mg and codeine phosphate 12 mg per 5 mL (473 mL) [fruit punch flavor]

Tablet, Oral:

Tylenol with Codeine #3: Acetaminophen 300 mg and codeine phosphate 30 mg [contains sodium metabisulfite]

Tylenol with Codeine #4: Acetaminophen 300 mg and codeine phosphate 60 mg [contains sodium metabisulfite]

Generic: Acetaminophen 300 mg and codeine phosphate 15 mg, Acetaminophen 300 mg and codeine phosphate 30 mg, Acetaminophen 300 mg and codeine phosphate 60 mg

Brand Names: U.S.

  • Capital/Codeine
  • Tylenol with Codeine #3
  • Tylenol with Codeine #4

Pharmacologic Category

  • Analgesic Combination (Opioid)
  • Analgesic, Opioid

Pharmacology

Acetaminophen: Although not fully elucidated, believed to inhibit the synthesis of prostaglandins in the central nervous system and peripherally block pain impulse generation; produces antipyresis from inhibition of hypothalamic heat-regulating center.

Codeine: Binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; causes cough suppression by direct central action in the medulla; produces generalized CNS depression.

Use: Labeled Indications

Mild to moderate pain: Relief of mild to moderate pain

Contraindications

Hypersensitivity to acetaminophen, codeine, or any component of the formulation; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy; significant respiratory depression

Canadian labeling: Additional contraindications (not in US labeling): Use in pediatric patients <12 years. Some products may contraindicate use in patients <18 years (refer to specific product labeling).

Documentation of allergenic cross-reactivity for opioids and related agents is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Note: Doses should be adjusted according to severity of pain and response of the patient. Adult doses ≥60 mg codeine fail to give commensurate relief of pain but merely prolong analgesia and are associated with an appreciably increased incidence of side effects.

US labeling:

Mild to moderate pain: Oral:

Solution or suspension: Acetaminophen 120 mg and codeine 12 mg per 5 mL: 15 mL every 4 hours as needed (maximum: Acetaminophen 4,000 mg per 24 hours)

Tablets: Acetaminophen (300 to 1,000 mg/dose) and codeine (15 to 60 mg/dose) every 4 hours as needed (maximum: Acetaminophen 4,000 mg and codeine 360 mg per 24 hours)

Canadian labeling:

Mild to moderate pain: Oral: Solution: Acetaminophen 160 mg and codeine 8 mg per 5 mL: 10 to 20 mL every 4 hours as needed (maximum: 100 mL [acetaminophen 3,200 mg and codeine 160 mg] per 24 hours)

Mild to severe pain: Oral: Tablets: Acetaminophen (300 to 600 mg/dose) and codeine (30 to 60 mg/dose) every 4 to 6 hours as needed (maximum: Acetaminophen 3,600 mg and codeine 360 mg per 24 hours)

Dosing: Geriatric

Refer to adult dosing. Use with caution and consider initiation at the low end of the dosing range; titrate slowly.

Dosing: Pediatric

US labeling: Mild to moderate pain: Oral: Acetaminophen 120 mg and codeine 12 mg per 5 mL:

Children 3 to 6 years: Solution or suspension: 5 mL 3 to 4 times daily as needed

Children 7 to 12 years: Solution or suspension: 10 mL 3 to 4 times daily as needed

Children >12 years and Adolescents: Solution or suspension: Refer to adult dosing

Canadian labeling: Children ≥12 years and Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling; use with caution in severe impairment.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; use with caution in severe impairment.

Administration

Shake suspension well before administering dose.

Storage

Store at 20°C to 25°C (68°F to 77°F); protect from light.

Drug Interactions

Alcohol (Ethyl): May enhance the hepatotoxic effect of Acetaminophen. Monitor therapy

Alvimopan: Analgesics (Opioid) may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Consider therapy modification

Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of Analgesics (Opioid). Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy

Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Analgesics (Opioid). Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Barbiturates: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Exceptions: Amobarbital; Butabarbital; Butalbital; Methohexital; PENTobarbital; Secobarbital; Thiopental. Monitor therapy

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Busulfan: Acetaminophen may increase the serum concentration of Busulfan. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CarBAMazepine: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Monitor therapy

Cholestyramine Resin: May decrease the absorption of Acetaminophen. Effect is minimal if cholestyramine is administered 1 hour after acetaminophen. Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

CYP2D6 Inhibitors (Moderate): May diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Monitor therapy

CYP2D6 Inhibitors (Strong): May diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Consider therapy modification

Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy

Dasatinib: Acetaminophen may enhance the hepatotoxic effect of Dasatinib. Dasatinib may increase the serum concentration of Acetaminophen. Consider therapy modification

Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Dimethindene: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Diuretics: Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics. Analgesics (Opioid) may diminish the therapeutic effect of Diuretics. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Eluxadoline: Analgesics (Opioid) may enhance the constipating effect of Eluxadoline. Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Fosphenytoin-Phenytoin: May decrease the serum concentration of Acetaminophen. Specifically, serum concentrations of acetaminophen may be decreased (leading to decreased efficacy), but the formation of the toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite may be increased (leading to increased hepatotoxicity). Monitor therapy

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Imatinib: Acetaminophen may enhance the hepatotoxic effect of Imatinib. Monitor therapy

Isoniazid: May enhance the adverse/toxic effect of Acetaminophen. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

LamoTRIgine: Acetaminophen may decrease the serum concentration of LamoTRIgine. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

MAO Inhibitors: May enhance the adverse/toxic effect of Codeine. Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyraPONE: May increase the serum concentration of Acetaminophen. More importantly, by inhibiting the conjugative metabolism of acetaminophen, metyrapone may shift the metabolism towards the oxidative route that produces a hepatotoxic metabolite. Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mipomersen: Acetaminophen may enhance the hepatotoxic effect of Mipomersen. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Mixed Agonist / Antagonist Opioids: May diminish the analgesic effect of Analgesics (Opioid). Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Avoid combination

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nalmefene: May diminish the therapeutic effect of Analgesics (Opioid). Management: Avoid the concomitant use of nalmefene and opioid analgesics. Discontinue nalmefene 1 week prior to any anticipated use of opioid analgesics. If combined, larger doses of opioid analgesics will likely be required. Consider therapy modification

Naltrexone: May diminish the therapeutic effect of Analgesics (Opioid). Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification

Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when nitric oxide is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Phenylephrine (Systemic): Acetaminophen may increase the serum concentration of Phenylephrine (Systemic). Monitor therapy

Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Monitor therapy

Probenecid: May increase the serum concentration of Acetaminophen. Probenecid may also limit the formation of at least one major non-toxic metabolite, possibly increasing the potential for formation of the toxic NAPQI metabolite. Consider therapy modification

Ramosetron: Analgesics (Opioid) may enhance the constipating effect of Ramosetron. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonin Modulators: Analgesics (Opioid) may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy

Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Somatostatin Analogs: May decrease the metabolism of Codeine. The formation of two major codeine metabolites (morphine and norcodeine) may be impaired by somatostatin analogs. Monitor therapy

SORAfenib: Acetaminophen may enhance the hepatotoxic effect of SORAfenib. SORAfenib may increase the serum concentration of Acetaminophen. Consider therapy modification

Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Tetracaine (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Acetaminophen may enhance the anticoagulant effect of Vitamin K Antagonists. This appears most likely with daily acetaminophen doses exceeding 1.3 or 2 g/day for multiple consecutive days. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Test Interactions

See individual agents.

Adverse Reactions

Also see individual agents.

Frequency not defined:

Central nervous system: Dizziness, drowsiness, dysphoria, euphoria, sedation, serotonin syndrome

Dermatologic: Pruritus, skin rash

Endocrine & metabolic: Adrenocortical insufficiency

Gastrointestinal: Abdominal pain, constipation, nausea, vomiting

Hematologic & oncologic: Agranulocytosis, thrombocytopenia

Hypersensitivity: Hypersensitivity reaction

Respiratory: Dyspnea

<1% (Limited to important or life-threatening): Hypogonadism (Brennan 2013; Debono 2011), respiratory depression

ALERT: U.S. Boxed Warning

Risk of Medication Errors:

Ensure accuracy when prescribing, dispensing, and administering acetaminophen 120 mg/codeine phosphate 12 mg per 5mL. Dosing errors due to confusion between mg and mL, and other acetaminophen/codeine oral suspensions of different concentrations can result in accidental overdose and death.

Addiction, Abuse, and Misuse:

Acetaminophen/codeine exposes patient 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 acetaminophen/codeine, and monitor all patients regularly for the development of these behaviors or conditions.

Life-Threatening Respiratory Depression:

Serious, life-threatening, or fatal respiratory depression may occur with use of acetaminophen/codeine. Monitor for respiratory depression, especially during initiation of acetaminophen/codeine or following a dose increase.

Accidental Ingestion:

Accidental ingestion of even one dose of acetaminophen/codeine, especially by children, can result in a fatal overdose of acetaminophen/codeine.

Neonatal Opioid Withdrawal Syndrome:

Prolonged use of acetaminophen/codeine 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 the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Hepatotoxicity:

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at dosages that exceed 4,000 mg/day, and often involve more than one acetaminophen-containing product.

Death related to ultra-rapid metabolism of codeine to morphine:

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 cytochrome P450 (CYP-450) 2D6 polymorphism.

Cytochrome P450 3A4 Interaction:

The concomitant use of acetaminophen/codeine with all CYP3A4 inhibitors may result in an increase in codeine plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used CYP3A4 inducer may result in an increase in codeine plasma concentration. Monitor patients receiving acetaminophen/codeine and any CYP3A4 inhibitor or inducer.

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: Codeine may cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Constipation: Codeine may cause or aggravate constipation; chronic use may result in obstructive bowel disease, particularly in those with underlying intestinal motility disorders. May also be problematic in patients with unstable angina and patients post-myocardial infarction. Consider preventive measures (eg, stool softener, increased fiber) to reduce the potential for constipation.

• Hepatotoxicity: [US Boxed Warning]: Acetaminophen may cause severe hepatotoxicity, potentially requiring liver transplant or resulting in death; hepatotoxicity is usually associated with excessive acetaminophen intake (>4 g/day in adults). Risk is increased with alcohol use, preexisting liver disease, and intake of more than one source of acetaminophen-containing medications. Chronic daily dosing in adults has also resulted in liver damage in some patients.

• Hypersensitivity/anaphylactic reactions: Hypersensitivity and anaphylactic reactions have been reported with acetaminophen use; discontinue immediately if symptoms of allergic or hypersensitivity reactions occur. Use with caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists (hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone).

• Hypotension: Codeine may cause hypotension; use with caution in patients with hypovolemia or cardiovascular disease (including acute MI).

• Respiratory depression: [US Boxed Warning]: Serious, life-threatening, or fatal respiratory depression may occur; monitor for respiratory depression, especially during initiation of or following a dose increase. The risk is increased in elderly patients; debilitated patients; patients with conditions associated with hypoxia, hypercapnia, or upper airway obstruction; and patients who are CYP2D6 "ultrarapid metabolizers."

• Skin reactions: Rarely, acetaminophen may cause serious and potentially fatal skin reactions such as acute generalized exanthematous pustulosis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Discontinue treatment if severe skin reactions develop or any other signs of hypersensitivity.

Disease-related concerns:

• Abdominal conditions: Codeine may obscure diagnosis or clinical course of patients with acute abdominal conditions. May worsen gastrointestinal ileus due to reduced GI motility. Avoid use in patients with GI obstruction, particularly paralytic ileus; chronic use may result in obstructive bowel disease.

• Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioids, usually following more than 1 month of use. Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis (Brennan 2013).

• Biliary tract impairment: Use codeine with caution in patients with biliary tract dysfunction, including acute pancreatitis; may cause constriction of sphincter of Oddi; may increase amylase/lipase levels.

• CNS depression/coma: Avoid use of codeine in patients with CNS depression or coma as these patients are susceptible to intracranial effects of CO2 retention.

• Drug abuse: Use opioids for chronic pain with caution in patients at increased risk for misuse; factors associated with increased risk include previous substance use disorder, younger age, concomitant depression (major), and psychotropic medication use. Consider offering naloxone prescriptions in patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents/day orally), and concomitant benzodiazepine use (Dowell [CDC 2016]).

• G6PD deficiency: Use acetaminophen with caution in patients with known G6PD deficiency.

• Head trauma: Use codeine with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur. May also interfere with pupillary response and consciousness, thereby, affecting neurologic examination.

• Hepatic impairment: Use with caution in patients with severe hepatic impairment, including alcoholic liver disease.

• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic stress disorder) due to increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (Dowell [CDC 2016]).

• Obesity: Use codeine with caution in patients who are morbidly obese.

• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

• Renal impairment: Use with caution in patients with severe renal impairment.

• Respiratory disease: Use codeine with caution in patients with preexisting respiratory compromise (hypoxia and/or hypercapnia), COPD or cor pulmonale and other obstructive pulmonary disease, and kyphoscoliosis or other skeletal disorder which may alter respiratory function; critical respiratory depression may occur, even at therapeutic dosages.

• Seizure disorder: Use codeine with caution in patients with a history of seizure disorder.

• Sleep-disordered breathing: Use opioids with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing, including HF and obesity. Avoid opioids in patients with moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).

• Thyroid dysfunction: Use codeine with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues:

• CYP3A4 interactions: [US Boxed Warning]: Use with all CYP3A4 inhibitors may result in increased codeine plasma concentrations and prolonged opioid adverse reactions which may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitant CYP3A4 inducer may result in increased codeine plasma concentrations and prolonged opioid adverse reactions. Monitor patients receiving any CYP3A4 inhibitor or inducer.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Sedatives: Effects may be potentiated when used with other CNS depressants (eg, sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). In the setting of chronic pain, avoid prescribing opioids and benzodiazepines concurrently whenever possible; epidemiologic studies suggest there is an increased risk for potentially fatal overdose with concurrent use (Dowell [CDC 2016]).

Special populations:

• CYP2D6 “ultrarapid metabolizers”: Use caution in patients with two or more copies of the variant CYP2D6*2 allele; may have extensive conversion to morphine and thus increased opioid-mediated effects. Avoid the use of codeine in these patients; consider alternative analgesics such as morphine or a nonopioid agent (Crews, 2012). The occurrence of this phenotype is seen in 0.5% to 1% of Chinese and Japanese, 0.5% to 1% of Hispanics, 1% to 10% of Caucasians, 3% of African-Americans, and 16% to 28% of North Africans, Ethiopians, and Arabs.

• Cachectic or debilitated patients: Use with caution in debilitated or cachectic patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages.

• Elderly: Use with caution in the elderly; may be more sensitive to adverse effects. Use opioids for chronic pain with caution in this age group; monitor closely due to an increased potential for risks, including certain risks such as falls/fracture, cognitive impairment, and constipation. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increasing the risk for respiratory depression or overdose (Dowell [CDC 2016]).

• Neonates: Neonatal withdrawal syndrome: [US Boxed Warning]: Prolonged use of acetaminophen/codeine during pregnancy can cause neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, ensure appropriate treatment is available and warn of the risk to the neonate; monitor neonate closely. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. Onset, duration and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.

• Pediatric: [US Boxed Warning]: Respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and were found to have evidence of being ultrarapid metabolizers of codeine due to a CYP2D6 polymorphism. Deaths have also occurred in nursing infants after being exposed to high concentrations of morphine because the mothers were ultrarapid metabolizers. Use of codeine is contraindicated in the postoperative pain management of children who have undergone tonsillectomy and/or adenoidectomy. Health Canada does not recommend use of codeine containing products in children <12 years.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.

• Metabisulfite: Some products may contain metabisulfite which may cause allergic reactions.

• Oral suspensions: [US Boxed Warning]: Dosing errors due to confusion between mg and mL, and other acetaminophen/codeine oral suspensions of different concentrations can result in accidental overdose and death. Ensure accuracy when prescribing, dispensing, and administering oral suspension.

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP ["Inactive" 1997]; Zar 2007).

Other warnings/precautions:

• Abuse potential: [US Boxed Warning]: A cetaminophen/codeine 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 acetaminophen/codeine, and monitor all patients regularly for the development of these behaviors or conditions. Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.

• Accidental ingestion: [US Boxed Warning]: Accidental ingestion of even one dose of acetaminophen/codeine, especially by children, can result in a fatal overdose of acetaminophen/codeine.

• Appropriate use: Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder) in outpatient setting in adults: Opioids should not be used as first-line therapy for chronic pain management (pain >3-month duration or beyond time of normal tissue healing) due to limited short-term benefits, undetermined long-term benefits, and association with serious risks (eg, overdose, MI, auto accidents, risk of developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg, NSAIDs, acetaminophen, certain anticonvulsants and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and non-opioid therapy, as appropriate. Prior to initiation, known risks of opioid therapy should be discussed and realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Therapy should be initiated at the lowest effective dosage using immediate-release opioids (instead of extended-release/long-acting opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be re-evaluated when increasing dosage to ≥50 morphine milligram equivalents (MME)/day orally; dosages ≥90 MME/day orally should be avoided unless carefully justified (Dowell [CDC 2016]).

• Dosage limit: Limit acetaminophen dose from all sources (prescription, OTC, combination products) and all routes of administration to <4 g/day in adults.

• Withdrawal: Concurrent use of agonist/antagonist analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Abrupt discontinuation following prolonged use may also lead to withdrawal symptoms.

Monitoring Parameters

Relief of pain, respiratory and mental status, blood pressure, heart rate, bowel function; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013); signs/symptoms of addiction, abuse, or misuse

Alternate recommendations: Chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. Re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Urine drug testing is recommended prior to initiation and re-checking should be considered at least yearly (includes controlled prescription medications and illicit drugs of abuse). State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (Dowell [CDC 2016]).

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination. Refer to individual monographs.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience abdominal pain, nausea, or vomiting. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), severe dizziness, passing out, confusion, severe constipation, severe loss of strength and energy, urinary retention, change in amount of urine passed, chills, pharyngitis, mood changes, severe headache, difficulty breathing, slow breathing, shallow breathing, noisy breathing, bruising, bleeding, vision changes, severe fatigue, sexual dysfunction (males), amenorrhea, decreased libido, infertility, signs of adrenal gland problems (severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss), signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, arrhythmia, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea), severe nausea, severe vomiting, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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