Codeine

Codeine Sulfate 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 Sulfate Tablets, 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 Sulfate Tablets are an opioid agonist, indicated for the management of mild to moderate pain, where treatment with an opioid is appropriate and for which alternative treatments are inadequate.

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.

• Codeine Sulfate 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. Reserve titration to higher doses of Codeine Sulfate 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. Clinical guidelines on opioid prescribing for some acute pain conditions are available.

Codeine Sulfate 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. Codeine Sulfate Tablets are also 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. • Hypersensitivity to codeine (e.g., anaphylaxis). • Children younger than 12 years of age.

Boxed warning (serious and life-threatening risks from use of codeine sulfate tablets): Addiction, Abuse, and Misuse Because the use of Codeine Sulfate 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. • Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation.

The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse • Life-Threatening Respiratory Depression • Interactions with Benzodiazepines and Other CNS Depressants • Neonatal Opioid Withdrawal Syndrome • Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children • Opioid-Induced Hyperalgesia and Allodynia • Adrenal Insufficiency • Severe Hypotension • Gastrointestinal Adverse Reactions • Seizures • Withdrawal The following adverse reactions associated with the use of codeine were identified in clinical studies or postmarketing reports. 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.

Table 1 includes clinically significant drug interactions with Codeine Sulfate Tablets. Table 1: Clinically Significant Drug Interactions with Codeine Sulfate Tablets 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.

Storage Store at 20° to 25°C (68° to 77°F), excursions permitted between 15° to 30°C (59° to 86°F). Protect from moisture. Store Codeine Sulfate Tablets securely and dispose of properly.