Usual Adult Dose for Pain

Initial dose: 15 to 60 mg orally up to every 4 hours as needed
Maximum dose: 360 mg in 24 hours

Comments:

• Initial doses should be individualized taking into account severity of pain, response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse.
• Doses higher than 60 mg have not been shown to improve pain relief and are associated with an increased incidence of adverse effects.
• Because of the risks of addiction, abuse and misuse, the lowest effective dose for the shortest duration consistent with individual patient treatment goals should be used.
• Monitor patients closely for respiratory depression within the first 24 to 72 hours of initiating therapy and following any increase in dose.

Use: For the management of mild to moderate pain where treatment with an opioid is appropriate and from which alternative treatments are inadequate.

Renal Dose Adjustments

Use with caution; start with lower doses or with longer dosing intervals and titrate slowly while carefully monitoring for side effects.

Liver Dose Adjustments

Use with caution; start with lower doses or with longer dosing intervals and titrate slowly while carefully monitoring for side effects.

Dose Adjustments

Elderly: Use caution, usually starting at the low end of the dosing range

CONVERSION from other Opioids:

• If it is necessary to switch from another opioid to codeine, a conservative approach is recommended as it is safest to underestimate the codeine dose than to overestimate and manage an adverse reaction due to overdose.

Interactions with Drugs Affecting CYP450 Isoenzymes: The effects of concomitant use or discontinuation of CYP450 3A4 inducers/inhibitors or CYP450 2D6 inhibitors are complex; concomitant use requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine.

Safe Reduction or Discontinuation of Therapy:

• Discontinuation/reduction plans should be individualized and take into consideration multiple factors such as type of pain, dose and duration of treatment, and patient specific physical and psychological attributes; patients should receive ongoing care and follow-up that addresses agreed upon and realistic goals.
• While there are no standard opioid tapering schedules suitable for all patients, good clinical practice dictates tapering in small increments (e.g., no greater than 10% to 25% of the total daily dose) at 2 to 4-week intervals; patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.
• When an opioid analgesic is being discontinued due to a suspected substance use disorder, patients should be evaluated and treated, or referred for evaluation and treatment of a substance use disorder; treatment should include evidence-based approaches, such as medication assisted treatment.
• When discontinuing or reducing opioid doses in patients who have been receiving therapy for an extended period and/or at higher doses for chronic pain, a multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic.

Precautions

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for all opioids intended for outpatient use. The new FDA Opioid Analgesic REMS is a designed to assist in communicating the serious risks of opioid pain medications to patients and health care professionals. It includes a medication guide and elements to assure safe use. For additional information: www.accessdata.fda.gov/scripts/cder/rems/index.cfm

US BOXED WARNINGS: RISK OF MEDICATION ERRORS; ADDICTION, ABUSE AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYP450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS:

• Risk of Medication Errors: Ensure accuracy when prescribing, dispensing, and administering the oral solution; dosing errors due to confusion between mg and mL, and other codeine solutions of different concentrations can result in accidental overdose and death.
• Addiction, Abuse, and Misuse: This drug exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing and monitor all patients regularly for the development of these behaviors or conditions.
• Opioid Analgesic REMS: To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, a REMS is required for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged: to complete a REMS-compliant education program; counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal; emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist; and consider other tools to improve patient, household, and community safety.
• Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression may occur; monitor for respiratory depression, especially during initiation and following dose increases.
• Accidental Ingestion: Accidental ingestion of even 1 dose, especially by children, can result in a fatal overdose of codeine.
• Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children: Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP450 2D6 polymorphism. This drug is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of this drug in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
• Neonatal Opioid Withdrawal Syndrome: Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If prolonged opioid use is required in a pregnant woman, the patient should be advised of the risk of neonatal opioid withdrawal syndrome and ensure appropriate treatment will be available.
• Interactions with Drugs Affecting CYP450 Isoenzymes: The effects of concomitant use or discontinuation of CYP450 3A4 inducers/inhibitors or CYP450 2D6 inhibitors are complex; concomitant use requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine.
• Concomitant Use with Benzodiazepines or Other CNS Depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Concomitant use should be reserved for use in patients for whom alternative treatment options are inadequate. If needed, limit dose and duration to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation.

CONTRAINDICATIONS:

• Use in children less than 12 years
• Postoperative pain management following tonsillectomy and/or adenoidectomy in patients less than 18 years
• Significant respiratory depression
• Acute or severe bronchial asthma, in an unmonitored setting or in the absence of resuscitative equipment
• Concurrent use of MAOIs or use within 14 days
• Known or suspected gastrointestinal obstruction, including paralytic ileus
• Hypersensitivity to codeine (e.g., anaphylaxis)

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

US Controlled Substance: Schedule II

Dialysis

Data not available

Other Comments

Administration advice:

• Take orally with or without food

Oral Solution:

• A calibrated device should be used to ensure accurate measurement of dose
• Dosing errors have resulted from confusion between mg and mL when prescribing, dispensing, and administering oral solution; ensure that dose is communicated clearly and dispensed accurately

Storage requirements:

• Protect from moisture and light

General:

• Because of the risks of addiction, abuse and misuse, the lowest dose for the shortest duration consistent with individual patient treatment goals should be used.
• Frequent communication between members of the healthcare team, patients, and their caregiver/family is important during periods of changing analgesic requirements; if the level of pain increases after dose stabilization, an attempt should be made to identify the source of increased pain before increasing the dose of pain medication.
• Patients who are ultra-rapid metabolizers of codeine due to a CYP450 2D6 polymorphism, will convert codeine more rapidly and completely to morphine resulting in unexpectedly high morphine levels, which may be life-threatening.

Monitoring:

• Monitor for respiratory depression, especially during initiation and following any increase in dose; close monitoring will be necessary in patients at increased risk and/or those receiving concomitant medications that increase the risk of respiratory depression
• Monitor for signs of hypotension
• Monitor for signs of constipation
• Monitor for the development of behaviors indicative of addiction, abuse, or misuse

Patient advice:

• Patients should be instructed to read the US FDA-approved Medication Guide each time this drug is dispensed; they should understand the safe use, serious risks, and proper storage and disposal of this drug.
• Patients should understand that this drug, even when taken as recommended can result in addiction, abuse, and misuse; instruct patients not to share their drug with others and protect their drug from theft or misuse.
• Patients should understand the risks of life-threatening respiratory depression and when this risk is greatest, patients should be aware that a genetic mutation may result in greater toxicity in some patients; patients and caregivers should be instructed to get emergency help right away if too much drug is taken or if breathing problems occur.
• Patients should understand this drug has potentially serious side effects including adrenal insufficiency, severe constipation, and hypotension, as well as potentially significant drug interactions, especially with other CNS depressants, including alcohol; patients should be instructed to speak with a healthcare professional if any new symptoms or side effects occur.
• Breastfeeding is not recommended while taking this drug; nursing mothers should be instructed to seek immediate medical attention for infants experiencing increased sleepiness, difficulty breastfeeding, breathing difficulties, or limpness.
• Women of child bearing potential should understand that prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome and that prompt recognition and treatment will be necessary.
• This drug may cause drowsiness, dizziness, or impair thinking or motor skills; patients should avoid driving or operating machinery until adverse effects are determined.
• Patients should be instructed not to discontinue this drug without first discussing a tapering plan with their healthcare provider.
• Advise patients to store this drug safely out of the sight and reach of children; accidental use by a child is a medical emergency and can result in death.

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