preloder

Codeine Sulfate


Codeine sulfate

is also used to control coughing that is not controlled by non-narcotic cough suppressants. It works by acting on the brain to dull the cough reflex.
Dosing
Adult dosing:
Important Note:
  • Beers Criteria: Use caution or avoid use as potentially inappropriate in older adults.

  • General Dosage Information:
  • Individualize dosing regimen based on severity of pain, patient response, prior analgesic experience, and risk for addiction, abuse, or misuse, using the lowest effective dose for the shortest duration to achieve treatment goals

  • Pain (Mild to Moderate):
  • Initial, 15 to 60 mg orally every 4 hours as needed; individually titrate to a dose that provides adequate analgesia while minimizing adverse reactions; Maximum 360 mg/24 hours

  • Converting from other

    opioids

    :
  • Initial, determine total daily dosage of

    codeine sulfate

    tablets following a conservative approach due to interpatient variability in

    opioid

    potency; individually titrate to a dose that provides adequate analgesia while minimizing adverse reactions.
  • Discontinuation, taper ddose by 25% to 50% every 2 to 4 days; raise dose and taper more slowly if

    signs

    and

    symptoms

    of withdrawal occur.

  • Pediatric dosing:
    Important Note:
  • Beers Criteria: Use caution or avoid use as potentially inappropriate in older adults.

  • General Dosage Information:
  • Safety and effectiveness in pediatric
    patients
    younger than 18 years have not been established.

  • Indications
    FDA-Labeled Indications:
  • Pain (Mild to Moderate)

  • Mechanism of Action

    Codeine sulfate

    is an

    opioid

    agonist relatively selective for the mu-

    opioid

    receptor, but with a much weaker affinity than morphine. The analgesic properties of

    codeine

    have been speculated to come from its conversion to morphine, although the exact mechanism of analgesic action remains unknown.
    Adverse Effect
    Common:
    Dermatologic:
  • Sweating

  • Gastrointestinal:
  • Constipation
  • Nausea
  • Vomiting

  • Neurologic:
  • Dizziness
  • Lightheadedness
  • Sedated
  • Somnolence

  • Respiratory
    :
  • Dyspnea

  • Serious:
    Cardiovascular:
  • Cardiac arrest
  • Disorder of cardiovascular system
  • Circulatory

    Depression

  • Shock

  • Endocrine metabolic:
  • Adrenal insufficiency


  • Gastrointestinal:
  • Pancreatitis

  • Reproductive:
  • Deficiency of testosterone biosynthesis

  • Respiratory
    :

  • Respiratory
    arrest
  • Respiratory

    depression


  • Other:
  • Serotonin syndrome


  • Contraindication
  • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
  • Children younger than 12 years
  • Concurrent use of MAOIs or use of MAOIs within the last 14 days
  • Hypersensitivity to

    codeine

    or any other component of the product
  • Known or suspected gastrointestinal obstruction, including paralytic ileus
  • Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy
  • Significant
    respiratory

    depression

  • Interaction
    Inhibitors of CYP3A4:
    Clinical Impact:
  • The concomitant use of

    Codeine sulfate

    tablets with CYP3A4 inhibitors, may result in an increase in

    codeine

    plasma concentrations with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal
    respiratory
    depression, particularly when an inhibitor is added after a stable dose of

    Codeine sulfate

    tablets is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower

    codeine

    levels, greater norcodeine levels, and less metabolism via CYP2D6 with resultant lower morphine levels, resulting in decreased

    opioid

    efficacy or a withdrawal syndrome in
    patients
    who had developed physical dependence to codeine.

  • Intervention:
  • If concomitant use of CYP3A4 inhibitor is necessary, consider dosage reduction of

    Codeine sulfate

    tablets until stable drug effects are achieved. Monitor
    patients
    for
    respiratory
    depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the

    Codeine sulfate

    tablets dosage until stable drug effects are achieved. Monitor for

    signs

    of

    opioid

    withdrawal.

  • Examples:
  • Macrolide

    antibiotics

    (e.g.,

    erythromycin

    )
  • Azole-antifungal agents (e.g. ketoconazole)
  • Protease inhibitors (e.g., ritonavir)

  • CYP3A4 Inducers:
    Clinical Impact:
  • The concomitant use of

    Codeine sulfate

    tablets and CYP3A4 inducers can result in lower

    codeine

    levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine, resulting in decreased efficacy or onset of a withdrawal syndrome in
    patients
    who have developed physical dependence. After stopping a CYP3A4 inducer, as the effects of the inducer decline,

    codeine

    plasma concentrations may increase with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious
    respiratory
    depression.

  • Intervention:
  • If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy and

    signs

    of

    opioid

    withdrawal and consider increasing the

    Codeine sulfate

    tablets dosage as needed. If a CYP3A4 inducer is discontinued, consider

    Codeine sulfate

    tablets dosage reduction and monitor for

    signs

    of
    respiratory
    depression and sedation at frequent intervals.

  • Examples:
  • Rifampin
  • Carbamazepine
  • Phenytoin

  • Inhibitors of CYP2D6:
    Clinical Impact:
  • Codeine is metabolized by CYP2D6 to form morphine. The concomitant useconcomitant use of

    Codeine sulfate

    tablets and CYP2D6 inhibitors can increase the
    plasma concentration
    of codeine, but can decrease the
    plasma concentration
    of active metabolite morphine, which could result in reduced analgesic efficacy or

    symptoms

    of

    opioid

    withdrawal, particularly when an inhibitor is added after a stable dose of

    Codeine sulfate

    tablets is achieved.
  • After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the

    codeine

    plasma concentration
    will decrease but the active metabolite morphine
    plasma concentration
    will increase, which could increase or prolong adverse reactions and may cause potentially fatal
    respiratory
    depression.

  • Intervention:
  • If concomitant use with a CYP2D6 inhibitor is necessary, or if a CYP2D6 inhibitor is discontinued after concomitant use, consider dosage adjustment of

    Codeine sulfate

    tablets and monitor
    patients
    closely at frequent intervals. If concomitant use with CYP2D6 inhibitors is necessary, follow the patient for reduced efficacy or

    signs

    and

    symptoms

    of

    opioid

    withdrawal and consider increasing the

    Codeine sulfate

    tablets as needed. After stopping use of a CYP2D6 inhibitor, consider reducing the

    Codeine sulfate

    tablets and monitor the patient for

    signs

    and

    symptoms

    of
    respiratory
    depression or sedation.

  • Examples:
  • Paroxetine
  • Fluoxetine
  • Bupropion
  • Quinidine

  • Benzodiazepines

    and Other Central Nervous System (CNS) Depressants:

    Clinical Impact:
  • Due to additive pharmacologic effect, the concomitant use of

    benzodiazepines

    or other CNS depressants, including alcohol, can increase the risk of hypotension,
    respiratory
    depression, profound sedation, coma, and death.

  • Intervention:
  • Reserve concomitant prescribing of these drugs for use in
    patients
    for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow
    patients
    closely for

    signs

    of
    respiratory
    depression and sedation.

  • Examples:
  • Benzodiazepines

    and other sedatives/hypnotics
  • Anxiolytics
  • Tranquilizers
  • Muscle relaxants
  • General anesthetics
  • Antipsychotics
  • Other

    opioids

  • Alcohol

  • Serotonergic Drugs:
    Clinical Impact:
  • The concomitant use of

    opioids

    with other drugs that affect the serotonergic neurotransmitter system has resulted in

    serotonin syndrome

    .

  • Intervention:
  • If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue

    Codeine sulfate

    tablets if

    serotonin syndrome

    is suspected.

  • Examples:
  • Selective serotonin reuptake inhibitors (SSRIs)
  • Serotonin and norepinephrine reuptake inhibitors (SNRIs)
  • Tricyclic antidepressants (TCAs)
  • Triptans

  • 5-HT3 receptor antagonists:
  • Drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol) Monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

  • Monoamine Oxidase Inhibitors (MAOIs):
    Clinical Impact:
  • MAOI interactions with

    opioids

    may manifest as

    serotonin syndrome

    or

    opioid

    toxicity (e.g.,
    respiratory
    depression, coma).

  • Intervention:
  • Do not use

    Codeine sulfate

    tablets in
    patients
    taking MAOIs or within 14 days of stopping such treatment. If urgent use of an

    opioid

    is necessary, use test doses and frequent titration of small doses of other

    opioids

    (such as oxycodone, hydrocodone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and

    signs

    and

    symptoms

    of CNS and
    respiratory
    depression.

  • Examples:
  • Phenelzine
  • Tranylcypromine
  • Linezolid

  • Mixed Agonist/Antagonist and Partial Agonist

    opioid

    Analgesics

    :

    Clinical Impact:
  • May reduce the analgesic effect of

    Codeine sulfate

    tablets and/or precipitate withdrawal

    symptoms

    .

  • Intervention:
  • Avoid concomitant use.

  • Examples:
  • Butorphanol
  • Nalbuphine
  • Pentazocine
  • Buprenorphine

  • Muscle Relaxants:
    Clinical Impact:
  • Codeine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of
    respiratory

    depression

    .

  • Intervention:
  • Monitor
    patients
    for

    signs

    of
    respiratory

    depression

    that may be greater than otherwise expected and decrease the dosage of

    Codeine sulfate

    tablets and/or the muscle relaxant as necessary

  • Diuretics:
    Clinical Impact:
  • Opioids

    can reduce the efficacy of

    diuretics

    by inducing the release of antidiuretic hormone.

  • Intervention:
  • Monitor
    patients
    for

    signs

    of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

  • Anticholinergic Drugs:
    Clinical Impact:
  • The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

  • Intervention:
  • Monitor
    patients
    for

    signs

    of urinary retention or reduced gastric motility when

    Codeine sulfate

    tablets are used concomitantly with anticholinergic drugs.

  • Phamacokinetics
    Absorption:
    Time for Maximum
    Plasma concentration
    (Tmax):
  • Oral: 60 minutes
  • Effects of food: no effect

  • Distribution:
  • Plasma Protein binding: 7% to 25%
  • Volume of Distribution (Vd): 3 to 6 L/kg

  • Metabolism:
  • Hepatic via CYP2D6, CYP3A4, and UDP-glucuronosyltransferase 2B7 and 2B4
  • Morphine: active metabolite

  • Excretion:
  • Renal: 90%; approximately 10% unchanged

  • Elimination:
  • Codeine: 3 hours
  • Metabolites of codeine: 3 hours

  • Precaution
  • Beers Criteria: Avoid in elderly
    patients
    with a history of falls or fractures (excludes pain management due to recent fractures or joint replacement), as ataxia, impaired psychomotor function, syncope, and additional falls may occur. If use is necessary consider reducing use of other CNS-active agents that increase risk of falls and fractures and implement other strategies to reduce risk of falls.
  • Abuse, misuse, or

    opioid

    addiction may occur; use cautiously in
    patients
    with a history of substance abuse or mental illness
  • Avoid use in adolescents aged 12 to 18 years who are obese or have
    respiratory
    conditions (e.g., obstructive sleep apnea or compromised
    respiratory
    function) due to increased risk of
    respiratory

    depression

    .
  • Avoid use in
    patients
    with impaired consciousness and coma.
  • Biliary tract disease, including acute pancreatitis; may cause spasm of sphincter of Oddi and increased amylase. Monitoring recommended.
  • Breastfeeding while receiving treatment with

    codeine

    is not recommended, especially in mothers who have the CYP2D6 ultra-rapid metabolizer genotype, due to serious adverse reactions in breastfed infants including sedation or
    respiratory
    respiratory

    depression

    that could result in death
  • Circulatory shock
    patients
    , may cause vasodilation and further reduce cardiac output and blood pressure; avoid use
  • Elderly, cachectic, or debilitated
    patients
    are more likely to experience
    respiratory

    depression

    ; Monitoring recommended, especially during initiation and titration and when given concomitantly with other drugs that may cause
    respiratory

    depression

    . Consider non

    opioid

    analgesics

  • Head injury, intracranial lesions, or increased intracranial pressure; may elevate cerebrospinal fluid pressure resulting in excessive
    respiratory

    depression

    ; adverse reactions to

    opioid

    may obscure clinical course of head injury. Monitoring recommended, especially during initiation
  • Hypotension, severe, orthostatic hypotension, and syncope may occur in ambulatory
    patients
    ; increased risk in
    patients
    whose ability to maintain blood pressure has been compromised by reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitoring recommended during initiating or titrating dose
  • Hypoxia, hypercapnia, or pre existing
    respiratory

    depression

    ; increased risk of severe
    respiratory

    depression

    even at recommended doses
  • Long-term use of

    opioids

    may be associated with decreased sex hormone levels and

    symptoms

    such as reduced interest in sex, impotence, or infertility. Laboratory evaluation may be warranted.
  • Opioids

    may rarely lead to

    adrenal insufficiency

    due to inadequate amounts of cortisol. If

    adrenal insufficiency

    is suspected, perform diagnostic testing, treat with corticosteroids if confirmed, wean patient off of

    opioid

    if appropriate, and continue to assess adrenal function.
  • Potentially life-threatening

    serotonin syndrome

    may occur, particularly with concomitant use of serotonergic drugs.
  • Seizures;

    Opioids

    may induce or aggravate. Monitoring recommended
  • Respiratory
    impairment (e.g., pulmonary disease, COPD, and
    patients
    with substantially decreased
    respiratory
    reserve (e.g., severe kyphosis); increased risk of decreased
    respiratory
    drive; non

    opioid

    analgesics

    should be considered
  • Pregnancy Category
  • C (FDA)
  • A (AUS)
  • Breast Feeding
  • Infant risk has been demonstrated.
  • Monitoring
  • Relief of pain is indicative of efficacy.
  • Continually reassess the maintenance of pain control and the need for continued

    opioid

    use.
  • Signs

    of addiction, abuse, or misuse: At baseline and regularly thereafter
  • Signs

    and

    symptoms

    of
    respiratory

    depression

    : Especially within 24 to 72 hours following treatment initiation and after dose increases, and particularly in high risk
    patients
    (elderly, cachectic, and debilitated
    patients
    and those with pre existing
    respiratory

    depression

    or otherwise significantly reduced
    respiratory
    reserve)
  • Signs

    or

    symptoms

    of
    respiratory

    depression

    or sedation:
    patients
    receiving concomitant

    benzodiazepines

    or CNS depressants
  • Signs

    and

    symptoms

    of sedation and
    respiratory

    depression

    :
    patients
    susceptible to the intracranial effects of carbon dioxide retention, particularly during initiation of therapy
  • Signs

    and

    symptoms

    of hypotension: Ambulatory
    patients
    on initiation and with dose titration, especially when ability to maintain blood pressure is compromised
  • Exacerbation of biliary tract disease
  • Worsened seizure control:
    Patients
    with a history of seizure disorders
  • Dosage Form
    Oral Solution:
  • 30 MG/5 ML

  • Oral Tablet:
  • 15 MG
  • 30 MG
  • 60 MG

  • Treatment
    Management of Mild to Moderate Toxicity:
  • Patients
    may only need observation.

  • Management of Severe Toxicity:
  • Administer oxygen and assist ventilation for
    respiratory

    depression

    . Naloxone is the antidote indicated for severe toxicity (
    respiratory
    or CNS

    depression

    ). Orotracheal intubation for airway protection should be performed early in cases of obtundation and/or
    respiratory

    depression

    that do not respond to naloxone, or in
    patients
    who develop severe acute lung injury.

  • Toxicology
    TOXICITY:
  • Infants and children may demonstrate unusual sensitivity to

    opioids

    and habituated adults may have extreme tolerance to

    opioids

    .

  • Adult:
  • The estimated lethal dose of

    codeine

    in adults is 7 to 14 mg/kg.

  • Children:
  • Ingestion of greater than 1 mg/kg of

    codeine

    may produce

    symptoms

    . Ingestion of more than 5 mg/kg of

    codeine

    has caused
    respiratory
    arrest.

  • Patient Counselling or Clinical Teaching
  • Advise patient to report

    symptoms

    of
    respiratory

    depression

    .
  • Tell patient to avoid activities requiring mental alertness or coordination until drug effects are realized, as drug may cause lightheadedness, dizziness, or sedation.
  • Instruct patient to report

    symptoms

    of orthostatic hypotension or syncope.
  • Warn patient to report

    symptoms

    of severe constipation.
  • Side effects may include drowsiness, dyspnea, nausea, vomiting, sweating, rash, and pruritus.
  • Instruct patient to report

    symptoms

    of

    serotonin syndrome

    .
  • Warn patient to reports

    symptoms

    of

    adrenal insufficiency

    .
  • Advise patient against sudden discontinuation after long-term use to avoid withdrawal

    symptoms

    .
  • Instruct patient to avoid alcohol or other CNS depressants.
  • Category of Codeine Sulfate :
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