Usual Adult Dose for Pain

Initial dose: 2 capsules orally every 4 hours as needed
Maximum dose: 5 doses or 10 capsules in 24 hours; no more than 2 capsules should be taken within any 4-hour period.

Comment:

• Individualize therapy taking into account patients pain severity, prior analgesic treatment experiences, and risk factors for addiction, abuse, and misuse.

Use: For the management of moderate to moderately severe pain that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Renal Dose Adjustments

Dose adjustment may be required; however, no specific guidelines have been suggested; consider a lower dose in patients with renal impairment

Liver Dose Adjustments

Use with caution; both acetaminophen and dihydrocodeine are metabolized by the liver; acetaminophen, especially at higher doses, may cause hepatotoxicity

Dose Adjustments

Use with caution in elderly patients.

Use with caution in patients with biliary tract disease including pancreatitis.

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:

• DEATH RELATED TO ULTRA-RAPID METABOLISM OF CODEINE TO MORPHINE:

Respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to a CYP450 2D6 polymorphism.

• HEPATOTOXICITY: Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the case of liver injury are associated with the use of acetaminophen at doses that exceed 4000 mg/day, and often involve more than 1 acetaminophen containing product.
• ADDICTION, ABUSE, AND MISUSE: This drug exposes patients and other users to the risk of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient prior to prescribing and monitor all patients regularly for the development of these behaviors or conditions.
• RISK EVALUATION AND MITIGATION STRATEGY (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 of these products; 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, especially during initiation or following a dose increase.
• ACCIDENTAL INGESTION: May result in fatal overdose, especially in children.
• NEONATAL OPOID WITHDRAWAL SYNDROME: Prolonged use during pregnancy can result in neonatal withdrawal syndrome, which may be life-threatening if not recognized and treated; treatment should be according to protocols developed by neonatology experts. Pregnant women should be advised of the risk and ensure that appropriate treatment will be available.
• CYTOCHROME P450 3A4 INTERACTION: Concomitant use with CYP450 3A4 inhibitors may result in increased concentrations which could increase or prolong adverse reactions and cause potentially fatal respiratory depression. Additionally, discontinuation of a concomitantly used CYP450 3A4 inducer may increase plasma concentrations. Monitor patients receiving CYP450 3A4 inhibitors and inducers.
• RISK FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS: Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for patients in whom alternative treatment options are inadequate; 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; do not take more than 2 capsules in any 4-hour period

Storage requirements:

• Protect from light and moisture

General:

• Reserve use for patients who are unable to tolerate non-opioid analgesics and/or for those who non-opioid analgesics have not provided adequate analgesia.
• Acetaminophen induced hepatotoxicity is mostly preventable if maximum daily doses are not exceeded; patients should not use more than 1 acetaminophen-containing product at a time as this has been shown to increase the risk.
• Serious skin reaction may occur with acetaminophen use; discontinue at first appearance of skin rash or any other sign of hypersensitivity.

Monitoring:

• Monitor for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and after dose increases
• Monitor for signs of orthostatic hypotension, especially in those whose blood pressure is already compromised
• Monitor for signs of addiction, abuse or misuse
• Monitor for skin rash or other signs of hypersensitivity

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. They should know that a genetic mutation may result in greater toxicity in some patients.
• Patients should be advised to check with their pharmacist or healthcare provider before starting or stopping any medications, including over the counter products and supplements.
• Patients should be instructed not to drive or operate heavy machinery until they know how this drug effects them.
• Patients should be advised not to drink alcohol or take other CNS depressants with this drug.
• Patients should be advised to store this drug safely out of the sight and reach of children.
• Women who are pregnant or are planning to become pregnant should discuss this with their healthcare provider.