Acetaminophen and Codeine

Acetaminophen and codeine phosphate tablets are indicated for the management of mild to moderate pain, where treatment with an opioid is appropriate and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy,, reserve opioid analgesics, including codeine phosphate for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

Codeine 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. The precise mechanism of the analgesic properties of acetaminophen is not established but is thought to involve central actions. Pharmacodynamics Effects on the Central Nervous System Codeine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Codeine causes miosis, even in total darkness.

Important Dosage and Administration Instructions Acetaminophen and codeine phosphate tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of acetaminophen and codeine phosphate tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic.

Acetaminophen and codeine phosphate tablets are contraindicated for: • All children younger than 12 years of age • Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Acetaminophen and codeine phosphate tablets are contraindicated in patients with: • Significant respiratory depression. • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment. • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days. • Known or suspected gastrointestinal obstruction, including paralytic ileus.

BOXED WARNING WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF ACETAMINOPHEN AND CODEINE PHOSPHATE TABLETS, USP Addiction, Abuse, and Misuse Because the use of acetaminophen and codeine phosphate tablets 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 reassess all patients regularly for the development of these behaviors and conditions. Addiction, Abuse, and Misuse Acetaminophen and codeine phosphate tablets contain codeine. Codeine in combination with acetaminophen, is a Schedule III controlled substance. As an opioid, acetaminophen and codeine phosphate tablets expose users to the risks of addiction, abuse, and misuse. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed acetaminophen and codeine phosphate tablets.

The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse • Life-Threatening Respiratory Depression • Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children • Neonatal Opioid Withdrawal Syndrome • Interactions with CNS Depressants • Severe Hypotension • Gastrointestinal Adverse Reactions • Seizures • Withdrawal • Opioid-Induced Hyperalgesia and Allodynia The following adverse reactions have been identified during post-approval use of acetaminophen and codeine phosphate tablets. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

CYP2D6 Inhibitors Codeine is metabolized by CYP2D6 to form morphine. The concomitant use of acetaminophen and codeine phosphate tablets and CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, bupropion, quinidine) 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 acetaminophen and codeine phosphate 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.

Store Acetaminophen and Codeine Phosphate Tablets, USP at 20° to 25°C (68° to 77°F). Store acetaminophen and codeine phosphate tablets securely and dispose of properly.