Usual Adult Dose for Pain

Initial dose: Acetaminophen (300 to 600 mg) and codeine (15 to 60 mg) orally every 4 hours as needed for pain

• Titrate to a dose that provides adequate analgesia and minimizes adverse reactions

Maximum doses: Acetaminophen 4000 mg/24 hours; Codeine: 360 mg/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.
• Codeine doses higher than 60 mg have not been shown to improve pain relief and are associated with an increased incidence of adverse effects; tolerance to codeine can develop with continued use.
• 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.

Usual Pediatric Dose for Pain

Less than 12 years: Contraindicated

12 to 18 years (postoperatively following a tonsillectomy and/or adenoidectomy): Contraindicated

12 to 18 years (with risk factors for respiratory depression): Avoid use

12 to 18 years: Use only if benefits outweigh potential risks

• Initial dose: Acetaminophen (300 to 600 mg) and codeine (15 to 60 mg) orally every 4 hours as needed for pain

Maximum doses: Acetaminophen 4000 mg/24 hours; Codeine: 360 mg/24 hours

Comments:

• Risk factors that increase sensitivity to the respiratory depressant effects of codeine include postoperative status, obstructive sleep apnea, obesity, and other conditions associated with hypoventilation syndromes (e.g., neuromuscular disease), concomitant use of other mediations that cause respiratory depression, and severe pulmonary disease.
• Initial doses should be individualized taking into account severity of pain, response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse.
• Codeine 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

Severe renal impairment: Use with caution; monitor therapy with renal function tests

Liver Dose Adjustments

Severe hepatic impairment: Use with caution; monitor therapy with liver function tests

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.

Discontinuation of Therapy in the Physically Dependent Patient:

• Taper gradually, by 25% to 50% every 2 to 4 days
• Monitor for signs and symptoms of withdrawal; if they occur, raise the dose to the previous level and taper more slowly
• Do not abruptly discontinue in the physically dependent patient

Precautions

US BOXED WARNINGS: ADDICTION, ABUSE AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; HEPATOTOXICITY; INTERACTIONS WITH DRUGS AFFECTING CYP450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS:

• 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.
• Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression may occur, especially during initiation or following a dose increase.
• Accidental Ingestion: Accidental ingestion of even 1 dose, especially by children, can result in a fatal overdose.
• 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 cases following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine due to CYP450 2D6 polymorphism; Codeine is contraindicated in pediatric patients younger than 12 years and in patients less than 18 years undergoing tonsillectomy and/or adenoidectomy. Avoid use in patients 12 to 18 years 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 opioid use is required for a prolonged period in a pregnant woman, the patient should be advised of the risk of neonatal opioid withdrawal syndrome and ensure 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 cases have been associated with use at doses that exceed 4 g per day and often involve more than one acetaminophen-containing product.
• Interactions with Drugs Affecting CYP450 Isoenzymes: The effects of concomitant use or discontinuation of CYP450 3A4 inducers/inhibitors or CYP450 2D6 inhibitors with codeine 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.

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

Consult WARNINGS section for additional precautions.

US Controlled Substance: Schedule III

Dialysis

Data not available

Other Comments

Administration advice:

• Take orally with or without food
• Patients should avoid use of more than one acetaminophen-containing product at a time.

Storage requirements:

• Protect from moisture and light

General:

• Because of the risks of addiction, abuse and misuse with codeine, 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.
• Drug-induced hepatotoxicity due to acetaminophen use is preventable; all patients and caregivers need to be educated how to use acetaminophen safely and what to do if more than the recommended dose is consumed.
• Hypersensitivity reactions and serious rashes have been reported with acetaminophen use.

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 skin reactions
• Monitor for the development of behaviors indicative of addiction, abuse, or misuse

Patient advice:

• 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, hepatotoxicity, and hypotension, as well as a number of potentially significant drug interactions; many of these events are avoidable with proper instructions and monitoring; patients should report stopping or starting any new medications and avoid alcohol during therapy.
• 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.
• 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.
• Patients should be instructed in proper disposal.