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Codeine Phosphate

Class: Opiate Agonists
Note: This monograph also contains information on Codeine, Codeine Sulfate
VA Class: CN101
Chemical Name: (5α,6α)-7,8-Didehydro-4,5-epoxy-3-methoxy-17-methyl-morphan-6-ol phosphate
Molecular Formula: C18H21NO3•H3PO4•½H2O
CAS Number: 41444-62-6
Brands: Ascomp with Codeine (combination), Cheratussin AC (combination), Codar GF (combination), Coditussin AC, Fioricet with Codeine, Fiorinal with Codeine, Guaiatussin AC, Mar-Cof CG, M-Clear WC, RelCof-C, Robafen AC, Soma Compound with Codeine, Tylenol with Codeine

Warning

    Ultrarapid Metabolism of Codeine to Morphine
  • Respiratory depression and death associated with codeine use for postoperative pain management following tonsillectomy and/or adenoidectomy reported in children who were ultrarapid metabolizers of CYP2D6 substrates.122 123 124 130 (See Contraindications and also see Pediatric Use under Cautions and see Elimination under Pharmacokinetics.)

    Concomitant Use with Benzodiazepines or Other CNS Depressants
  • Concomitant use of opiate agonists with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.416 417 418 700 701 702 703 704

  • Avoid concomitant use of opiate antitussives and benzodiazepines or other CNS depressants.700 704

  • Reserve concomitant use of opiate analgesics and benzodiazepines or other CNS depressants for patients in whom alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy and monitor closely for respiratory depression and sedation.700 703 (See Specific Drugs under Interactions.)

Introduction

Opiate agonist; phenanthrene derivative.a b

Uses for Codeine Phosphate

Pain

Symptomatic relief of mild to moderately severe pain122 123 that is not relieved by a nonopiate analgesic.b d e f

Combinations of codeine and aspirin or acetaminophen may produce additive analgesic effects because of differing mechanisms of action.b

In symptomatic treatment of acute pain, reserve opiate analgesics for pain resulting from severe injuries, severe medical conditions, or surgical procedures, or when nonopiate alternatives for relieving pain and restoring function are expected to be ineffective or are contraindicated.431 432 433 435 Use smallest effective dosage for shortest possible duration since long-term opiate use often begins with treatment of acute pain.411 431 434 435 Optimize concomitant use of other appropriate therapies.432 434 435 (See Managing Opiate Therapy for Acute Pain under Dosage and Administration.)

Generally use opiates for management of chronic pain (i.e., pain lasting >3 months or past the time of normal tissue healing410 411 412 413 ) that is not associated with active cancer treatment, palliative care, or end-of-life care only if other appropriate nonpharmacologic and nonopiate pharmacologic strategies have been ineffective and expected benefits for both pain relief and functional improvement are anticipated to outweigh risks.411 412 413 414 422 429

If used for chronic pain, opiate analgesics should be part of an integrated approach that also includes appropriate nonpharmacologic modalities (e.g., cognitive-behavioral therapy, relaxation techniques, biofeedback, functional restoration, exercise therapy, certain interventional procedures) and other appropriate pharmacologic therapies (e.g., nonopiate analgesics, analgesic adjuncts such as selected anticonvulsants and antidepressants for certain neuropathic pain conditions).411 412 413 422 429

Available evidence insufficient to determine whether long-term opiate therapy for chronic pain results in sustained pain relief or improvements in function and quality of life411 423 431 432 436 or is superior to other pharmacologic or nonpharmacologic treatments.432 Use is associated with serious risks (e.g., opiate use disorder, overdose).411 431 436 (See Managing Opiate Therapy for Chronic Noncancer Pain under Dosage and Administration.)

Cough

Symptomatic relief of nonproductive cough, alone or in combination with other antitussives or expectorants.a

Codeine Phosphate Dosage and Administration

General

Managing Opiate Therapy for Acute Pain

  • Optimize concomitant use of other appropriate therapies.432 434 435

  • When opiate analgesia required, use conventional (immediate-release) opiates in smallest effective dosage and for shortest possible duration, since long-term opiate use often begins with treatment of acute pain.411 431 434 435

  • When sufficient for pain management, use lower-potency opiate analgesics given in conjunction with acetaminophen or an NSAIA on as-needed (“prn”) basis.432

  • For acute pain not related to trauma or surgery, limit prescribed quantity to amount needed for expected duration of pain severe enough to require opiate analgesia (generally ≤3 days and rarely >7 days).411 433 434 435 Do not prescribe larger quantities for use in case pain continues longer than expected;411 432 instead, reevaluate patient if severe acute pain does not remit.411 431 435

  • For moderate to severe postoperative pain, provide opiate analgesic as part of a multimodal regimen that also includes acetaminophen and/or NSAIAs and other pharmacologic (e.g., certain anticonvulsants, regional local anesthetic techniques) and nonpharmacologic therapy as appropriate.430 431 432

  • Oral administration of conventional opiate analgesics generally preferred over IV administration in postoperative patients who can tolerate oral therapy.430 431

  • Scheduled (around-the-clock) dosing frequently is required during immediate postoperative period or following major surgery.430 432 When repeated parenteral administration is required, IV patient-controlled analgesia (PCA) generally is recommended.430 431

Managing Opiate Therapy for Chronic Noncancer Pain

  • Although specific recommendations may vary, common elements in clinical guideline recommendations include risk mitigation strategies, upper dosage thresholds, careful dosage titration, and consideration of risks associated with particular opiates and formulations, coexisting diseases, and concomitant drug therapy.410 411 414 415 423

  • Prior to initiating therapy, thoroughly evaluate patient; assess risk factors for misuse, abuse, and addiction;411 412 413 415 422 429 establish treatment goals (including realistic goals for pain and function); and consider how therapy will be discontinued if benefits do not outweigh risks.411 415

  • Regard initial opiate therapy for chronic noncancer pain as a therapeutic trial that will be continued only if there are clinically meaningful improvements in pain and function that outweigh treatment risks.411 412 413

  • Prior to and periodically during therapy, discuss with patients known risks and realistic benefits and patient and clinician responsibilities for managing therapy.411 412 413 414 415

  • Some experts recommend initiating opiate therapy for chronic noncancer pain with conventional (immediate-release) opiate analgesics prescribed at lowest effective dosage.411 415 Individualize opiate selection, initial dosage, and dosage titration based on patient’s health status, prior opiate use, attainment of therapeutic goals, and predicted or observed harms.412 413

  • Evaluate benefits and harms within 1–4 weeks following initiation of therapy or dosage increase411 413 and reevaluate on ongoing basis (e.g., at least every 3 months411 ) throughout therapy.411 412 413 Document pain intensity and level of functioning and assess progress toward therapeutic goals, presence of adverse effects, and adherence to prescribed therapies.412 413 422 423 Anticipate and manage common adverse effects (e.g., constipation, nausea and vomiting, cognitive and psychomotor impairment).412 413 415 If benefits do not outweigh harms, optimize other therapies and taper opiate to lower dosage or taper and discontinue opiate.411 412 413 415

  • When repeated dosage increases required, evaluate potential causes and reassess relative benefits and risks.412 413 Although evidence is limited, some experts state that opiate rotation may be considered in patients with intolerable adverse effects or inadequate benefit despite dosage increases.412 413 415

  • Higher dosages require particular caution,410 412 415 including more frequent and intensive monitoring or referral to specialist.411 412 413 Greater benefits of high-dose opiates for chronic pain not established in controlled clinical studies; higher dosages associated with increased risks (motor vehicle accidents, overdosage, opiate use disorder).411 415 423 424 425 426

  • CDC states that primary care clinicians should carefully reassess individual benefits and risks before prescribing dosages equivalent to ≥50 mg of morphine sulfate daily (approximately ≥330 mg of codeine daily) for chronic pain and should avoid dosages equivalent to ≥90 mg of morphine sulfate daily or carefully justify decision to prescribe such dosages.411 Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80–120 mg of morphine sulfate daily.423 431 Some states have established opiate dosage thresholds (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with specialist is mandated or recommended)411 420 421 423 or have mandated risk-management strategies (e.g., review of state prescription drug monitoring program [PDMP] data prior to prescribing).411 419 423

  • Recommended strategies for managing risks include written treatment agreements or plans (e.g., “contracts”), urine drug testing, review of state PDMP data, and risk assessment and monitoring tools.410 411 412 413 414 415 422 423 429

  • Taper and discontinue opiate therapy if patient engages in serious or repeated aberrant drug-related behaviors or drug abuse or diversion.412 413 415 Offer or arrange treatment for patients with opiate use disorder.411 412 413

  • Consider providing concomitant naloxone for patients at increased risk of opiate overdosage (e.g., those with history of overdose or substance use disorder, those receiving ≥50 mg of morphine sulfate [or equivalent] daily, those receiving benzodiazepines concomitantly, those with medical conditions that could increase sensitivity to opiate effects).411 431

Administration

Oral Administration

Administer orally.a b

Dosage

Available as codeine phosphate and codeine sulfate; dosage expressed in terms of the salt.d e g

Use lowest effective dosage and shortest duration of therapy consistent with treatment goals of the patient.411 413 431 432 435

When switching patients receiving chronic opiate therapy from one opiate analgesic to another, generally reduce the calculated equianalgesic dosage of the new opiate agonist by about 25–50% to avoid inadvertent overdosage.410 412 This calculation does not apply when switching to methadone; consult specific recommendations for methadone dosage.412

When used concomitantly with other CNS depressants, use lowest effective dosages and shortest possible duration of concomitant therapy.700 703 (See Specific Drugs under Interactions.)

Pediatric Patients

Cough
Oral

Children ≥12 years of age: 10–20 mg every 4–6 hours.a (See Pediatric Use under Cautions.)

Pain
Oral

3 mg/kg or 100 mg/m2 daily in 6 divided doses.b Alternatively, 0.5 mg/kg or 15 mg/m2 every 4–6 hours.b f (See Pediatric Use under Cautions.)

Adults

Cough
Oral

10–20 mg every 4–6 hours.a

Pain
Oral

30 mg every 4 hours as needed; usual dosage range is 15–60 mg every 4 hours as needed.b d e

Nonopiate-containing analgesic fixed combinations: Nonopiate component may limit dosage of opiate component.117 119 120 121 Nonopiate analgesics are available in various fixed ratios with codeine and also are available in many other prescription and OTC preparations; ensure that therapy is not duplicated and that nonopiate dosage does not exceed maximum recommended dosages.117 118 119 121

Individualize initial dosage, taking into account patient's prior opiate use; concurrent drug therapy; degree of opiate tolerance; medical condition; type and severity of pain; and risk factors for addiction, abuse, and misuse.122 123

Prescribing Limits

Pediatric Patients

Cough
Oral

Children: ≥12 years of age: Maximum 120 mg daily.a

Adults

Cough
Oral

Maximum 120 mg daily.a

Pain
Oral

Maximum 360 mg daily.122 123

For acute pain not related to trauma or surgery, limit prescribed quantity to amount needed for the expected duration of pain severe enough to require opiate analgesia (generally ≤3 days and rarely >7 days).411 433 434 435

CDC recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to ≥50 mg of morphine sulfate daily (approximately ≥330 mg of codeine daily) for chronic pain and avoid dosages equivalent to ≥90 mg of morphine sulfate daily or carefully justify their decision to prescribe such dosages.411 Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80–120 mg of morphine sulfate daily.423 431

Some states have set prescribing limits (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with a specialist is mandated or recommended).411 420 421 423

Special Populations

Geriatric Patients

Reduce dosage in older patients.a b

Cautions for Codeine Phosphate

Contraindications

  • Known hypersensitivity to codeine or any ingredient in the formulation.c d e f

  • In children <12 years of age for the management of pain or cough and cold.705 (See Pediatric Use under Cautions.)

  • In children <18 years of age for the management of postoperative pain following tonsillectomy and/or adenoidectomy.122 123 124 130 705

  • Known or suspected paralytic ileus.122 123

Warnings/Precautions

Warnings

Respiratory Depression

Possible dose-related respiratory depressionc d e (occurs infrequently with oral antitussive doses).a

Potential for increased viscosity of bronchial secretions and suppression of cough reflex, with subsequent respiratory insufficiency, in patients with asthma or pulmonary emphysema who indiscriminately use antitussives.a

Consider offering naloxone when opiate agonists are prescribed for patients at increased risk of opiate overdosage (e.g., those with history of overdose or substance use disorder, those receiving ≥50 mg of morphine sulfate [or equivalent] daily, those receiving benzodiazepines concomitantly, those with medical conditions that could increase sensitivity to opiates).411 431

CNS Depression

Performance of activities requiring mental alertness and physical coordination may be impaired.a c d e f

Concurrent use with other CNS depressants may potentiate CNS depression and result in profound sedation, respiratory depression, coma, or death.d e 700 703 704 (See Specific Drugs under Interactions.)

Abuse Potential

Possible tolerance, psychologic dependence, and physical dependence following prolonged administration.a Abuse potential similar to that of morphine.d e f

Pharmacogenomics

Ultrarapid metabolizers of CYP2D6 substrates are likely to have higher than expected serum concentrations of morphine, the active metabolite of codeine.705 (See Elimination under Pharmacokinetics.) FDA states codeine should not be used in such patients.705

Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use of opiates, including codeine, and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiate agonists, alcohol) may result in profound sedation, respiratory depression, coma, and death.416 417 418 700 701 702 703 704 Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.416 417 418 435 700 701

Avoid concomitant use of CNS depressants with codeine antitussives;700 704 reserve concomitant use with codeine-containing analgesics for patients in whom alternative treatment options are inadequate.700 703 (See Specific Drugs under Interactions.)

Adrenal Insufficiency

Adrenal insufficiency reported in patients receiving opiate agonists or opiate partial agonists.400 Manifestations are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.400

If adrenal insufficiency is suspected, perform appropriate laboratory testing promptly and provide physiologic (replacement) dosages of corticosteroids; taper and discontinue the opiate agonist or partial agonist to allow recovery of adrenal function.400 If the opiate agonist or partial agonist can be discontinued, perform follow-up assessment of adrenal function to determine if corticosteroid replacement therapy can be discontinued.400 In some patients, switching to a different opiate improved symptoms.400

Sulfite Sensitivity

Some formulations contain sulfites, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.f

General Precautions

Increased Intracranial Pressure or Head Trauma

Potential for increased respiratory depressant effects and elevation of CSF pressure in patients with increased intracranial pressure, head trauma, or other intracranial lesions.c d e f

Adverse effects of opiates may obscure the existence, extent, or course of intracranial pathology.d e f g

Acute Abdominal Conditions

Administration may complicate assessment of patients with acute abdominal conditions.c d e f

Postoperative Patients

Suppression of cough reflex following thoracotomy or laparotomy may lead to postoperative retention of secretions; cautious use recommended.a

Debilitated and Special Risk Patients

Use with caution in debilitated patients and in those with hypothyroidism, Addison’s disease, and prostatic hypertrophy or urethral stricture.a d e f

Hypogonadism

Hypogonadism or androgen deficiency reported in patients receiving long-term opiate agonist or opiate partial agonist therapy;400 401 402 403 404 causality not established.400 Manifestations may include decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility.400 Perform appropriate laboratory testing in patients with manifestations of hypogonadism.400

Fixed-combination Preparations

When used in fixed combination with other drug(s), consider the cautions, precautions, and contraindications associated with the other drug(s).b

Specific Populations

Pregnancy

Category C.f

Lactation

Distributed into milk; use not recommended.a 705 Risk of opiate toxicity in nursing infants, especially if mother is an ultrarapid metabolizer of CYP2D6 substrates.705

Opiate toxicity resulting in neonatal death reported in the nursing infant of a woman receiving codeine; woman was an ultrarapid metabolizer of codeine.104 105 106 107 113 705 (See Metabolism and see Special Populations under Pharmacokinetics.) Somnolence also reported more frequently in nursing infants exposed to acetaminophen/codeine compared with nursing infants exposed to acetaminophen alone; some mothers were ultrarapid metabolizers of CYP2D6 substrates.705

If infant is exposed to codeine through breast milk, caregiver should monitor closely for manifestations of opiate toxicity (e.g., sedation, difficulty breast-feeding or breathing, hypotonia) and seek immediate medical treatment for the infant if such manifestations occur.705

Pediatric Use

Manufacturers state safety and efficacy of single-entity codeine preparations for the management of mild to moderately severe pain not established in pediatric patients <18 years of age.122 123

Use as an analgesic or antitussive contraindicated in children <12 years of age.705 Use as analgesic also contraindicated in children <18 years of age following tonsillectomy and/or adenoidectomy.122 123 124 130 705 FDA states that use for management of pain or cough and cold is not recommended in children 12–18 years of age who are obese or have conditions such as obstructive sleep apnea or compromised respiratory function.705 (Contraindication to antitussive use in children <12 years of age is required in labeling of prescription codeine-containing cough and cold preparations; FDA is considering additional regulatory action for codeine-containing cough and cold preparations available without prescription in some states.705 )

Serious adverse events, including deaths, reported in children <18 years of age, mostly in those <12 years of age; children who are obese, have obstructive sleep apnea or severe lung disease, or have evidence of ultrarapid metabolism of CYP2D6 substrates are at increased risk.122 123 124 125 126 127 130 705 (See Boxed Warning and see Elimination under Pharmacokinetics.) If codeine is used in children 12–18 years of age, caregivers should monitor closely for manifestations of opiate toxicity and seek immediate medical treatment for the child if such manifestations occur.705

Risk of overdosage and toxicity (including death) in children <2 years of age receiving OTC preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection.10115 10116 Clinicians should ask caregivers about use of OTC cough/cold preparations to avoid overdosage.

Geriatric Use

Use with caution.d e f g (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution in patients with severe hepatic impairment.d e f g

Renal Impairment

Use with caution in patients with severe renal impairment.d e f

Common Adverse Effects

When used for pain relief (particularly in ambulatory patients not experiencing severe pain): lightheadedness, dizziness, sedation, nausea, vomiting, sweating.d e f

When used at antitussive doses: nausea, vomiting, constipation (with repeated doses), dizziness, sedation, palpitation, pruritus.a

Interactions for Codeine Phosphate

Drugs Associated with Serotonin Syndrome

Risk of serotonin syndrome when used with other serotonergic drugs.400 May occur at usual dosages.400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.400 (See Advice to Patients.)

If concomitant use of other serotonergic drugs is warranted, monitor patients for serotonin syndrome, particularly during initiation of therapy and dosage increases.400

If serotonin syndrome is suspected, discontinue codeine, other opiate therapy, and/or any concurrently administered serotonergic agents.400

Specific Drugs

Drug

Interaction

Comments

Anticholinergic agents

Possible paralytic ileusf

Antidepressants, SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), SNRIs (e.g., desvenlafaxine, duloxetine, milnacipran, venlafaxine), tricyclic antidepressants (TCAs), mirtazapine, nefazodone, trazodone, vilazodone

Risk of serotonin syndrome400

TCAs: Opiates may potentiate antidepressant effectc

If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue codeine, the antidepressant, and/or any concurrently administered opiates or serotonergic agents400

TCAs: Use with caution; reduce dosage of codeinec

Antiemetics, 5-HT3 receptor antagonists (e.g., dolasetron, granisetron, ondansetron, palonosetron)

Risk of serotonin syndrome400

If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue codeine, the 5-HT3 receptor antagonist, and/or any concurrently administered opiates or serotonergic agents400

Antipsychotics (e.g., aripiprazole, asenapine, cariprazine, chlorpromazine, clozapine, fluphenazine, haloperidol, iloperidone, loxapine, lurasidone, molindone, olanzapine, paliperidone, perphenazine, pimavanserin, quetiapine, risperidone, thioridazine, thiothixene, trifluoperazine, ziprasidone)

Risk of profound sedation, respiratory depression, hypotension, coma, or death700 703 704 706

Codeine analgesics: Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy; monitor closely for respiratory depression and sedation700 703

In patients receiving codeine for analgesia, initiate antipsychotic, if required, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response700 703

In patients receiving an antipsychotic, initiate codeine, if required for analgesia, at reduced dosage and titrate based on clinical response700 703

Codeine antitussives: Avoid concomitant use700 704

Benzodiazepines (e.g., alprazolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam, triazolam)

Risk of profound sedation, respiratory depression, hypotension, coma, or death416 417 418 700 701 703 704 706

Whenever possible, avoid concomitant use410 411 415 435

Codeine analgesics: Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy; monitor closely for respiratory depression and sedation700 703

In patients receiving codeine for analgesia, initiate benzodiazepine, if required for any indication other than epilepsy, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response700 703

In patients receiving a benzodiazepine, initiate codeine, if required for analgesia, at reduced dosage and titrate based on clinical response700 703

Codeine antitussives: Avoid concomitant use700 704

Consider offering naloxone to patients receiving opiates and benzodiazepines concomitantly411 431

Buspirone

Risk of serotonin syndrome400

If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue codeine, buspirone, and/or any concurrently administered opiates or serotonergic agents400

CNS depressants (e.g., other opiate agonists, general anesthetics, tranquilizers, phenothiazines, alcohol)

Additive CNS effects;a d e f increased risk of profound sedation, respiratory depression, hypotension, coma, or death700 703 704 706

Codeine analgesics: Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy; monitor closely for respiratory depression, sedation, and hypotension;700 703 avoid alcohol use700

In patients receiving codeine for analgesia, initiate CNS depressant, if required for any indication other than epilepsy, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response700 703

In patients receiving a CNS depressant, initiate codeine, if required for analgesia, at reduced dosage and titrate based on clinical response700 703

Codeine antitussives: Avoid concomitant use700 704

Dextromethorphan

Risk of serotonin syndrome400

If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue codeine, dextromethorphan, and/or any concurrently administered opiates or serotonergic agents400

5-HT1 receptor agonists (triptans; e.g., almotriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan)

Risk of serotonin syndrome400

If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue codeine, the triptan, and/or any concurrently administered opiates or serotonergic agents400

Lithium

Risk of serotonin syndrome400

If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue codeine, lithium, and/or any concurrently administered opiates or serotonergic agents400

MAO inhibitors (e.g., isocarboxazid, linezolid, methylene blue, phenelzine, selegiline, tranylcypromine)

Risk of serotonin syndrome400

If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue codeine, the MAO inhibitor, and/or any concurrently administered opiates or serotonergic agents400

Sedative/hypnotic agents (e.g., butabarbital, eszopiclone, pentobarbital, ramelteon, secobarbital, suvorexant, zaleplon, zolpidem)

Risk of profound sedation, respiratory depression, hypotension, coma, or death700 703 704 706

Codeine analgesics: Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy; monitor closely for respiratory depression and sedation700 703

In patients receiving codeine for analgesia, initiate sedative/hypnotic, if required, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response700 703

In patients receiving a sedative/hypnotic, initiate codeine, if required for analgesia, at reduced dosage and titrate based on clinical response700 703

Codeine antitussives: Avoid concomitant use700 704

Skeletal muscle relaxants (e.g., baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, metaxalone, methocarbamol, orphenadrine, tizanidine)

Risk of profound sedation, respiratory depression, hypotension, coma, or death700 703 704 706

Cyclobenzaprine: Risk of serotonin syndrome400

Codeine analgesics: Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy; monitor closely for respiratory depression and sedation700 703

In patients receiving codeine for analgesia, initiate skeletal muscle relaxant, if required, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response700 703

In patients receiving a skeletal muscle relaxant, initiate codeine, if required for analgesia, at reduced dosage and titrate based on clinical response700 703

Codeine antitussives: Avoid concomitant use700 704

Cyclobenzaprine: If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue codeine, cyclobenzaprine, and/or any concurrently administered opiates or serotonergic agents400

St. John’s wort (Hypericum perforatum)

Risk of serotonin syndrome400

If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue codeine, St. John’s wort, and/or any concurrently administered opiates or serotonergic agents400

Tryptophan

Risk of serotonin syndrome400

If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400

If serotonin syndrome suspected, discontinue codeine, tryptophan, and/or any concurrently administered opiates or serotonergic agents400

Codeine Phosphate Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration.a b e f g

Onset

Onset occurs in 15–30 minutes.a b Peak analgesic effects occur within 2 hours;g peak antitussive effects within 1–4 hours.i

Duration

Analgesic effects persist for 4–6 hours.b g Antitussive effects may persist for 4 hours.i

Distribution

Extent

Rapidly distributed into various body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen, and kidney.g Distributed into milk.b Readily crosses the placenta.c

Protein Binding

Not bound to plasma proteins.g

Elimination

Metabolism

Metabolized in liver, principally by CYP3A4 and to a lesser extent (10%) by CYP2D6 to O-demethylated morphine, the active metabolite.b 108 109 110 112

Metabolism of codeine influenced by CYP2D6 polymorphism; genetic differences in drug metabolism affect drug response.108 109 110 112 114 Individuals may be described as poor, extensive, or ultrarapid metabolizers of CYP2D6 substrates.108 109 110 112 114

Elimination Route

Excreted mainly in urine with negligible amounts of codeine and its metabolites found in feces.b g

Half-life

About 2.5–3 hours.f g

Special Populations

Individuals who carry the genotype associated with ultrarapid metabolism of CYP2D6 substrates (approximately 1–7% of Caucasians, 10–30% of Ethiopians and Saudi Arabians) convert codeine to morphine more rapidly and completely than other individuals; ultrarapid metabolizers are likely to have higher than expected serum concentrations of morphine.107 108 110 112 114

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at <40°C (preferably 15–30°C).b

Solution

Tight, light-resistant containers at <40°C (preferably 15–30°C).h Protect from freezing.h

Actions

  • Principal pharmacologic effects are on CNS and intestines.c d e

  • Mild analgesic effect.b d e f Acts at several sites within the CNS involving several systems of neurotransmitters to produce analgesia; precise mechanism of action not fully elucidated.c

  • Suppresses cough reflex by direct effect on cough center in medulla of brain.a

  • Exerts drying effect on respiratory tract mucosa and increases viscosity of bronchial secretions.a

  • Antitussive activity is less than that of morphine (on a weight basis).a

Advice to Patients

  • Potential for drug to impair mental alertness or physical coordination; use caution when driving or operating machinery until effects on individual are known.d e f

  • Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with benzodiazepines or other CNS depressants, including alcohol and other opiates, either therapeutically or illicitly.700 703 704 Avoid concomitant use of CNS depressants with codeine antitussives;700 704 also avoid concomitant use with codeine analgesics unless use is supervised by clinician.700 703 Importance of informing patients that codeine should not be combined with alcohol.700

  • Potential risk of serotonin syndrome with concurrent use of codeine and other serotonergic agents.400 Importance of immediately contacting clinician if manifestations of serotonin syndrome (e.g., agitation, hallucinations, tachycardia, labile BP, fever, excessive sweating, shivering, shaking, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea) develop.400

  • Potential risk of adrenal insufficiency.400 Importance of contacting clinician if manifestations of adrenal insufficiency (e.g., nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, hypotension) develop.400

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as alcohol consumption and any concomitant diseases.d e f Importance of limiting alcohol intake.f

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.d e f

  • Risk of morphine toxicity in nursing infants of women taking codeine, especially if the woman is an ultrarapid metabolizer of the drug.104 105 106 113 705 Importance of not taking codeine while nursing.705 Advise patients to immediately seek medical attention if symptoms of opiate overdosage (e.g., sedation, difficulty breathing, hypotonia, poor feeding) develop in nursing infants exposed to codeine.104 105 113 705

  • Risk of morphine toxicity in children, especially those who are obese, have respiratory diseases, or have evidence of ultrarapid metabolism of codeine.122 123 124 125 126 127 130 705 Importance of not giving codeine to children <12 years of age for management of pain or cough and cold705 or to children <18 years of age for pain relief following tonsillectomy and/or adenoidectomy.122 123 124 130 705 Importance of monitoring children receiving codeine for clinical manifestations of morphine toxicity (e.g., slow, shallow, difficult, or noisy breathing; confusion; unusual sleepiness) and seeking immediate medical attention for the child if symptoms develop.705 10125

  • Possible risk (although causality not established) of hypogonadism or androgen deficiency with long-term opiate agonist or partial agonist use.400 Importance of informing clinician if decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility occurs.400

  • Importance of advising patients of other important precautionary information.d e (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970.d e

Codeine Phosphate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Bulk

Crystals

Bulk

Powder

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Acetaminophen and Codeine Phosphate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

120 mg/5 mL Acetaminophen and Codeine Phosphate 12 mg/5 mL*

Acetaminophen and Codeine Phosphate Oral Solution ( C-V)

Tablets

300 mg Acetaminophen and Codeine Phosphate 15 mg*

Acetaminophen and Codeine Phosphate Tablets ( C-III)

300 mg Acetaminophen and Codeine Phosphate 30 mg*

Acetaminophen and Codeine Phosphate Tablets ( C-III)

Tylenol with Codeine No. 3 ( C-III)

Janssen

300 mg Acetaminophen and Codeine Phosphate 60 mg*

Acetaminophen and Codeine Phosphate Tablets ( C-III)

Tylenol with Codeine No. 4 ( C-III)

Janssen

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Guaifenesin and Codeine Phosphate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

100 mg/5 mL Guaifenesin and Codeine Phosphate 6.3 mg/5 mL

RelCof-C (C-V)

Burel

M-Clear WC (C-V)

R.A. McNeil

100 mg/5 mL Guaifenesin and Codeine Phosphate 10 mg/5 mL*

Cheratussin AC ( C-V)

Qualitest

Guaiatussin AC ( C-V)

Hi-Tech

Guaifenesin AC Cough Syrup ( C-V)

Guaifenesin and Codeine Phosphate Oral Solution ( C-V)

Robafen AC ( C-V)

Major

200 mg/5 mL Guaifenesin and Codeine Phosphate 8 mg/5 mL

Codar GF ( C-V)

Respa

200 mg/5 mL Guaifenesin and Codeine Phosphate 10 mg/5 mL

Coditussin AC ( C-V)

Glendale

225 mg/5 mL Guaifenesin and Codeine Phosphate 7.5 mg/5 mL

Mar-Cof CG ( C-V)

Marnel

Codeine phosphate is also commercially available in combination with other antihistamines, decongestants, and expectorants.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Other Codeine Phosphate Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

30 mg with Acetaminophen 300 mg, Butalbital 50 mg, and Caffeine 40 mg*

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules (C-III)

Fioricet with Codeine ( C-III)

Actavis

30 mg with Acetaminophen 325 mg, Butalbital 50 mg, and Caffeine 40 mg*

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules ( C-III)

30 mg with Aspirin 325 mg, Butalbital 50 mg, and Caffeine 40 mg*

Ascomp with Codeine ( C-III)

Nexgen

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules ( C-III)

Fiorinal with Codeine ( C-III)

Allergan

Tablets

16 mg with Aspirin 325 mg and Carisoprodol 200 mg*

Carisoprodol, Aspirin, and Codeine Phosphate Tablets ( C-III)

Soma Compound with Codeine ( C-III)

Meda

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Codeine Sulfate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Bulk

Powder

Oral

Tablets

15 mg*

Codeine Sulfate Tablets ( C-II)

30 mg*

Codeine Sulfate Tablets ( C-II)

60 mg*

Codeine Sulfate Tablets ( C-II)

AHFS DI Essentials. © Copyright 2017, Selected Revisions November 13, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

Only references cited for selected revisions after 1984 are available electronically.

104. Food and Drug Administration. FDA public health advisory: use of codeine by some breastfeeding mothers may lead to life-threatening side effects in nursing babies. Rockville, MD; 2007 Aug 17. From FDA website.

105. Food and Drug Administration. FDA Alert: Use of codeine products in nursing mothers. 2007 Aug 17. From FDA website.

106. Food and Drug Administration. Codeine products used by nursing mothers. Medwatch alert. Rockville, MD; 2007 Aug 17. From FDA website.

107. Koren G, Cairns J, Chitayat D et al. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet. 2006; 368:704. [PubMed 16920476]

108. Kirchheiner J, Schmidt H, Tzvetkov M et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J. 2007; 7:257-65. [PubMed 16819548]

109. Meyer UA. Pharmacogenetics and adverse drug reactions. Lancet. 2000; 356:1667-71. [PubMed 11089838]

110. Gasche Y, Daali Y, Fathi M et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004; 351:2827-31. [PubMed 15625333]

111. Roche Molecular Systems, Inc. AmpliChip CYP450 Test for in vitro diagnostic use. Branchburg, NJ; 2007 July.

112. Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral codeine: a genetic variant-an ultra-rapid metabolizer. Paediatr Anaesth. 2007; 17: 684-7. [PubMed 17564651]

113. Food and Drug Administration. FDA warning on codeine use by nursing mothers. FDA News. Rockville, MD; 2007 Aug 17. From FDA website.

114. Weinshilboum R. Inheritance and drug response. N Engl J Med. 2003; 348:529-37. [PubMed 12571261]

117. Jackson KC II, Lipman AG. Nonopioid analgesics. In: Lipman AG, ed. Pain management for primary care clinicians. Bethesda, MD: American Society of Health-System Pharmacists; 2004:43-58.

118. Cranmer KW, Mason M. Special considerations in geriatric pain management. In: Lipman AG, ed. Pain management for primary care clinicians. Bethesda, MD: American Society of Health-System Pharmacists; 2004:219-232.

119. Fakata KL, Miaskowski C, Lipman AG. Chronic malignant pain. In: Lipman AG, ed. Pain management for primary care clinicians. Bethesda, MD: American Society of Health-System Pharmacists; 2004:139-52.

120. McNicol E, Carr DB. Pharmacological treatment of pain. In: McCarberg B, Passik SD, eds. Expert guide to pain management. Philadelphia: American College of Physicians; 2005:145-78.

121. American Pain Society. Principles of analgesic use in the treatment of acute pain and cancer pain. 5th edition. Glenview, IL; 2003:3,9,13,14.

122. Lannett Company, Inc. Codeine sulfate tablets prescribing information. Philadelphia, PA; 2013 Apr. From DailyMed website

123. TAGI Pharma, Inc. Codeine sulfate oral solution prescribing information. South Beloit, IL; 2013 Apr. From DailyMed website.

124. Food and Drug Administration. Safety review update of codeine use in children; new Boxed Warning and Contraindication on use after tonsillectomy and/or adenoidectomy. FDA News. Rockville, MD; 2013 Feb 20. From FDA website

125. Kelly LE, Rieder M, van den Anker J et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics. 2012; 129:e1343-7. [PubMed 22492761]

126. Ciszkowski C, Madadi P, Phillips MS et al. Codeine, ultrarapid-metabolism genotype, and postoperative death. N Engl J Med. 2009; 361:827-8. [PubMed 19692698]

127. Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral codeine: a genetic variant - an ultra-rapid metabolizer. Paediatr Anaesth. 2007; 17:684-7. [PubMed 17564651]

128. Yellon RF, Kenna MA, Cladis FP et al. What is the best non-codeine postadenotonsillectomy pain management for children?. Laryngoscope. 2014; :. [PubMed 24867607]

129. Prows CA, Zhang X, Huth MM et al. Codeine-related adverse drug reactions in children following tonsillectomy: a prospective study. Laryngoscope. 2014; 124:1242-50. [PubMed 24122716]

130. Qualitest Pharmaceuticals. Acetaminophen and codeine phosphate oral solution prescribing information. Huntsville, AL; 2014 Mar. From DailyMed website.

131. European Medicines Agency. Codeine not to be used in children below 12 years for cough and cold. London, UK. 2015 Apr 24. From EMA website.

400. US Food and Drug Administration. Drug safety communication: FDA warns about several safety issues with opioid pain medicines; requires label changes. Silver Spring, MD; 2016 Mar 22. From FDA website.

401. Katz N, Mazer NA. The impact of opioids on the endocrine system. Clin J Pain. 2009; 25:170-5. [PubMed 19333165]

402. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL et al. Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer. 2004; 100:851-8. [PubMed 14770444]

403. Abs R, Verhelst J, Maeyaert J et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab. 2000; 85:2215-22. [PubMed 10852454]

404. Fraser LA, Morrison D, Morley-Forster P et al. Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women. Exp Clin Endocrinol Diabetes. 2009; 117:38-43. [PubMed 18523930]

410. Nuckols TK, Anderson L, Popescu I et al. Opioid prescribing: a systematic review and critical appraisal of guidelines for chronic pain. Ann Intern Med. 2014; 160:38-47. [PubMed 24217469]

411. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016. MMWR Recomm Rep. 2016; 65:1-49. [PubMed 26987082]

412. Chou R, Fanciullo GJ, Fine PG et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009; 10:113-30. [PubMed 19187889]

413. Management of Opioid Therapy for Chronic Pain Working Group, US Department of Veterans Affairs and Department of Defense. VA/DoD clinical practice guideline for management of opioid therapy for chronic pain. 2010 May.

414. Chou R, Cruciani RA, Fiellin DA et al. Methadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain. 2014; 15:321-37. [PubMed 24685458]

415. Manchikanti L, Abdi S, Atluri S et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2--guidance. Pain Physician. 2012; 15(3 Suppl):S67-116.

416. Park TW, Saitz R, Ganoczy D et al. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study. BMJ. 2015; 350:h2698. [PubMed 26063215]

417. Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths From Combined Use of Opioids and Benzodiazepines. Am J Prev Med. 2015; 49:493-501. [PubMed 26143953]

418. Dasgupta N, Funk MJ, Proescholdbell S et al. Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose Mortality. Pain Med. 2016; 17:85-98. [PubMed 26333030]

419. Prescription Drug Monitoring Program Training and Technical Assistance Center (PDMP TTAC). Criteria for mandatory enrollment or query of PDMP. From PDMP TTAC website. Accessed 2016 Sep 14.

420. National Alliance for Model State Drug Laws (NAMSLD). Overview of state pain management and prescribing policies. From NAMSLD webiste. Accessed 2016 Sep 14.

421. Bennett A (Maine Office of Governor). Augusta, ME: 2016 Apr 19. Governor signs major opioid prescribing reform bill. Press release.

422. American Academy of Pain Medicine (AAPM). Use of opioids for the treatment of chronic pain. A statement from the American Academy of Pain Medicine. From AAPM website. 2013 Feb.

423. Franklin GM, American Academy of Neurology. Opioids for chronic noncancer pain: a position paper of the American Academy of Neurology. Neurology. 2014; 83:1277-84. [PubMed 25267983]

424. Dunn KM, Saunders KW, Rutter CM et al. Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med. 2010; 152:85-92. [PubMed 20083827]

425. Gomes T, Mamdani MM, Dhalla IA et al. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med. 2011; 171:686-91. [PubMed 21482846]

426. Bohnert AS, Valenstein M, Bair MJ et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011; 305:1315-21. [PubMed 21467284]

429. Paice JA, Portenoy R, Lacchetti C et al. Management of Chronic Pain in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016; 34:3325-45. [PubMed 27458286]

430. Chou R, Gordon DB, de Leon-Casasola OA et al. Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016; 17:131-57. [PubMed 26827847]

431. Washington State Agency Medical Directors' Group (AMDG). Interagency guideline on prescribing opioids for pain, 3rd ed. From Washington State AMDG website. 2015 Jun.

432. Hegmann KT, Weiss MS, Bowden K et al. ACOEM practice guidelines: opioids for treatment of acute, subacute, chronic, and postoperative pain. J Occup Environ Med. 2014; 56:e143-59.

433. Cantrill SV, Brown MD, Carlisle RJ et al. Clinical policy: critical issues in the prescribing of opioids for adult patients in the emergency department. Ann Emerg Med. 2012; 60:499-525. [PubMed 23010181]

434. Thorson D, Biewen P, Bonte B et al, for Institute for Clinical Systems Improvement (ICSI). Acute pain assessment and opioid prescribing protocol. From ICSI website. 2014 Jan.

435. New York City Department of Health and Mental Hygiene. New York City emergency department discharge opioid prescribing guidelines. From NYC Health website. 2013 Jan.

436. Chou R, Deyo R, Devine B et al. The effectiveness and risks of long-term opioid treatment of chronic pain. Evidence report/technology assessment No. 218. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); 2014 Sep.

700. US Food and Drug Administration. Drug safety communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning. Silver Spring, MD; 2016 Aug 31. From FDA website.

701. Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010. JAMA. 2013; 309:657-9. [PubMed 23423407]

702. Jones CM, Paulozzi LJ, Mack KA et al. Alcohol involvement in opioid pain reliever and benzodiazepine drug abuse-related emergency department visits and drug-related deaths - United States, 2010. MMWR Morb Mortal Wkly Rep. 2014; 63:881-5. [PubMed 25299603]

703. Hertz S. Letter to manufacturers of opioid analgesics: safety labeling change notification. Silver Spring, MD: US Food and Drug Administration. Accessed 2017 Mar 20.

704. Seymour S. Letter to manufacturers of opioid antitussives: safety labeling change notification. Silver Spring, MD: US Food and Drug Administration. Accessed 2017 Mar 20.

705. Food and Drug Administration. Drug safety communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. Silver Spring, MD; 2017 Apr 20. From FDA website.

706. Janssen Pharmaceuticals, Inc. Tylenol with Codeine (acetaminophen and codeine phosphate) tablets prescribing information. Titusville, NJ; 2017 Jan.

10100. US Food and Drug Administration. Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use; tentative final monograph for OTC antitussive drug products. [21 CFR Part 341] Fed Regist. 1983; 43:48576-95.

10101. Committee on Drugs, American Academy of Pediatrics. Use of codeine- and dextromethorphan-containing cough syrups in pediatrics. Pediatrics. 1978; 62:118-22. [PubMed 683771]

10102. von Muhlendahl KE, Krienke EG, Scherf-Rahne B et al. Codeine intoxication in childhood. Lancet. 1976; 2:303-5. [PubMed 59870]

10103. Food and Drug Administration. Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use; final monograph for OTC antitussive drug products [21 CFR Parts 310, 341, and 369] Fed Regist. 1987; 52:30042-57.

10104. FDA public health advisory: use of codeine by some breastfeeding mothers may lead to life-threatening side effects in nursing babies. Rockville, MD; 2007 Aug 17. From FDA website ().

10105. Food and Drug Administration. FDA Alert: Use of codeine products in nursing mothers. 2007 Aug 17. From FDA website ().

10106. Food and Drug Administration. Codeine products used by nursing mothers. Medwatch alert. Rockville, MD; 2007 Aug 17. From FDA website ().

10107. Koren G, Cairns J, Chitayat D et al. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet. 2006; 368:704. [PubMed 16920476]

10108. Kirchheiner J, Schmidt H, Tzvetkov M et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J. 2007; 7:257-65. [PubMed 16819548]

10109. Meyer UA. Pharmacogenetics and adverse drug reactions. Lancet. 2000; 356:1667-71. [PubMed 11089838]

10110. Gasche Y, Daali Y, Fathi M et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004; 351:2827-31. [PubMed 15625333]

10111. Roche Molecular Systems, Inc. AmpliChip CYP450 Test for in vitro diagnostic use. Branchburg, NJ; 2007 July.

10112. Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral codeine: a genetic variant-an ultra-rapid metabolizer. Paediatr Anaesth. 2007; 17:684-7. [PubMed 17564651]

10113. Food and Drug Administration. FDA warning on codeine use by nursing mothers. FDA News August 17, 2007. From FDA website ().

10114. Weinshilboum R. Inheritance and drug response. N Engl J Med. 2003; 348: 529-37. [PubMed 12571261]

10115. Srinivasan A, Budnitz D, Shehab N et al. Infant deaths associated with cough and cold medications—two states, 2005. MMWR Morb Mortal Wkly Rep. 2007; 56:1-4. [PubMed 17218934]

10116. Food and Drug Administration. Cough and cold medications in children less than two years of age. Rockville, MD; 2007 Jan 12. From FDA website.

10117. Kelly LE, Rieder M, van den Anker J et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics. 2012; 129:e1343-7. [PubMed 22492761]

10118. Ciszkowski C, Madadi P, Phillips MS et al. Codeine, ultrarapid-metabolism genotype, and postoperative death. N Engl J Med. 2009; 361:827-8. [PubMed 19692698]

10119. Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral codeine: a genetic variant - an ultra-rapid metabolizer. Paediatr Anaesth. 2007; 17:684-7. [PubMed 17564651]

10120. Yellon RF, Kenna MA, Cladis FP et al. What is the best non-codeine postadenotonsillectomy pain management for children?. Laryngoscope. 2014; :. [PubMed 24867607]

10121. Prows CA, Zhang X, Huth MM et al. Codeine-related adverse drug reactions in children following tonsillectomy: a prospective study. Laryngoscope. 2014; 124:1242-50. [PubMed 24122716]

10122. Lannett Company, Inc. Codeine sulfate tablets prescribing information. Philadelphia, PA; 2013 Apr. From DailyMed website

10123. TAGI Pharma, Inc. Codeine sulfate oral solution prescribing information. South Beloit, IL; 2013 Apr. From DailyMed website.

10124. Food and Drug Administration. Safety review update of codeine use in children; new Boxed Warning and Contraindication on use after tonsillectomy and/or adenoidectomy. FDA News. Rockville, MD; 2013 Feb 20. From FDA website

10125. Food and Drug Administration. Drug safety communication: FDA evaluating the potential risks of using codeine cough-and-cold medicines in children. Silver Spring, MD; 2015 Jul 1. From FDA website

10126. European Medicines Agency. Codeine not to be used in children below 12 years for cough and cold. London, UK. 2015 Apr 24. From EMA website.

10400. US Food and Drug Administration. Drug safety communication: FDA warns about several safety issues with opioid pain medicines; requires label changes. Silver Spring, MD; 2016 Mar 22. From FDA website.

a. AHFS Drug Information 2003. McEvoy GK, ed. Codeine. Bethesda, MD: American Society of Health-System Pharmacists; 2003:2570-2.

b. AHFS Drug Information 2003. McEvoy GK, ed. Codeine. Bethesda, MD; American Society of Health-System Pharmacists; 2003:2027-8.

c. AHFS drug information 2003. McEvoy GK, ed. Opiate agonists general statement. Bethesda, MD: American Society of Hospital Pharmacists; 2002:2022-7.

d. Roxane Laboratories. Codeine sulfate tablets prescribing information. Columbus, OH. 2001 Jul.

e. Roxane Laboratories. Codeine sulfate oral solution prescribing information. Columbus, OH. 2000 Dec.

f. Ortho-McNeil. Tylenol with Codeine (acetaminophen and codeine phosphate) tablets prescribing information. In: Physicians’ desk reference. 56th ed. Montvale, NJ: Medical Economics Company Inc; 2002: 2595-6.

g. Novartis. Fioricet with Codeine (butalbital, acetaminophen, caffeine, and codeine phosphate) capsules prescribing information. East Hanover, NJ. 2002 Oct.

h. USPDI: Drug information for the health care professional. Johnson KW, ed. 23th ed. Greenwood Village CO: Micromedex; 2003;2068-70.

i. Monarch Pharmaceuticals. Nucofed (codeine phosphate, pseudoephedrine hydrochloride, and guaifenesin) expectorant syrup. Bristol, TN; 1998 Sep.

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