FDA label 535ff6e9-75b1-4eef-91c6-f5aa220c9166

WARNING: 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 CYP2D6 polymorphism. WARNING: 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 CYP2D6 polymorphism.

IMPORTANT: • Do not give CODEINE Sulfate Oral Solution to a child to treat pain after tonsillectomy or adenoidectomy surgery. • When you take CODEINE Sulfate Oral Solution, some or all of it changes into morphine in your body. • In some children and adults this happens very quickly, and can cause you to stop breathing and cause death due to an overdose. • Women who breastfeed should talk to their healthcare provider before taking CODEINE Sulfate Oral Solution. • When you take CODEINE Sulfate Oral Solution, some or all of it changes into morphine in your body. • In some women, this happens very quickly. Codeine and morphine pass into your breast milk. A large amount of morphine can cause your baby to die. • Call your healthcare provider or get emergency medical help right away if anyone taking CODEINE Sulfate Oral Solution, or your breastfeeding baby has any of the symptoms listed below: • Increased sleepiness • Confusion • Difficulty breathing • Shallow breathing • Limpness • Your baby has difficulty breastfeeding • Keep Codeine Sulfate Oral Solution in a safe place away from children. Accidental use by a child is a medical emergency and can cause death. If a child accidentally takes Codeine Sulfate, get emergency help right away.

5 WARNINGS AND PRECAUTIONS • Risk of death in ultra-rapid metabolizers: Conversion of codeine into its active metabolite, morphine, may occur more rapidly and completely resulting in higher than expected morphine levels and respiratory depression or death. (5.1) • Respiratory depression: Increased risk in elderly, debilitated patients, those suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction. (5.2) • Controlled substance: Codeine sulfate is a Schedule II controlled substance with an abuse liability similar to other opioids. (5.3) • CNS effects: Additive CNS depressive effects when used in conjunction with alcohol, other opioids, or illicit drugs. (5.4) • Elevation of intracranial pressure: May be markedly exaggerated in the presence of head injury, other intracranial lesions. (5.5) • Hypotensive effect: Increased risk with compromised ability to maintain blood pressure. (5.6) • Prolonged gastric obstruction: Do not administer codeine sulfate to patients with gastrointestinal obstruction, especially paralytic ileus. (5.7) • Pancreatic/biliary tract disease: May cause spasm of the sphincter of Oddi and diminish biliary and pancreatic secretions. (5.8) • Impaired mental/physical abilities: Caution must be used with potentially hazardous activities. ( 5.10 ) 5.1 Death Related to Ultra-Rapid Metabolism of Codeine to Morphine Respiratory depression and death have occurred in children who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine [see Use in Specific Populations (8.4)] . Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [see Overdosage (10.1)] . Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine is contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy [see Contraindications (4)] . When prescribing codeine, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose [see Use in Specific Populations (8), Overdosage (10.1)] . 5.2 Respiratory Depression Respiratory depression is the primary risk of codeine sulfate. Respiratory depression occurs more frequently in elderly or debilitated patients and in those suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction, in whom even moderate therapeutic doses may significantly decrease pulmonary ventilation. Codeine produces dose-related respiratory depression. Caution should be exercised when codeine sulfate is used postoperatively, in patients with pulmonary disease or shortness of breath, or whenever ventilatory function is depressed. Use opioids, including codeine sulfate, with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale and in patients having a substantially decreased respiratory reserve (e.g., severe kyphoscoliosis), hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of codeine sulfate may increase airway resistance and decrease respiratory drive to the point of apnea. Consider alternative non-opioid analgesics and use codeine sulfate only under careful medical supervision at the lowest effective dose in such patients [see Overdosage (10)]. 5.3 Misuse and Abuse of Opioids Codeine sulfate is an opioid agonist of the morphine-type and a Schedule II controlled substance. Such drugs are sought by drug abusers and people with addiction disorders. Diversion of Schedule II products is an act subject to criminal penalty. Patients should be assessed for their risk for opioid abuse or addiction prior to being prescribed opioids Codeine can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing codeine sulfate in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Codeine may be abused by crushing, chewing, snorting or injecting the product. Misuse and abuse of codeine sulfate poses a significant risk to the abuser that could result in overdose and death [see Drug Abuse and Dependence (9.2) ]. Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. 5.4 Interaction with Alcohol and Drugs of Abuse Codeine sulfate may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression, because respiratory depression, hypotension, profound sedation, coma or death may result. 5.5 Head Injury and Increased Intracranial Pressure Respiratory depressant effects of opioids and their capacity to elevate cerebrospinal fluid pressure resulting from vasodilation following CO 2 retention may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, opioids including codeine sulfate, can produce effects on pupillary response and consciousness, which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries. 5.6 Hypotensive Effect Codeine sulfate may cause severe hypotension in an individual whose ability to maintain blood pressure has already been compromised by a depleted blood volume or concurrent administration of drugs such as phenothiazines or general anesthetics. Codeine sulfate may produce orthostatic hypotension and syncope in ambulatory patients. Administer codeine sulfate with caution to patients in circulatory shock, as vasodilation produced by the drug may further reduce cardiac output and blood pressure. 5.7 Gastrointestinal Effects Do not administer codeine sulfate to patients with gastrointestinal obstruction, especially paralytic ileus because codeine sulfate diminishes propulsive peristaltic waves in the gastrointestinal tract and may prolong the obstruction. Chronic use of opioids, including codeine sulfate, may result in obstructive bowel disease especially in patients with underlying intestinal motility disorder. Codeine sulfate may cause or aggravate constipation. The administration of codeine sulfate may obscure the diagnosis or clinical course of patients with acute abdominal conditions. 5.8 Use in Pancreatic/Biliary Tract Disease Use codeine sulfate with caution in patients with biliary tract disease, including acute pancreatitis, as codeine sulfate may cause spasm of the sphincter of Oddi and diminish biliary and pancreatic secretions. 5.9 Special Risk Patients Use codeine sulfate with caution in patients with severe renal or hepatic impairment, hypothyrodism, Addison's disease, prostatic hypertrophy, or urethral stricture and in elderly or debilitated patients [see Use in Specific Populations (8.5) ]. The usual precautions should be observed and the possibility of respiratory depression should be kept in mind. Extreme caution should be exercised in the administration of codeine sulfate to patients with CNS depression, acute alcoholism, and delirium tremens. All opioids may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings. Keep Codeine Sulfate Oral Solution out of the reach of children. In case of accidental ingestion, seek emergency medical help immediately. 5.10 Driving and Operating Machinery Caution patients that codeine sulfate could impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Caution patients about the potential combined effects of codeine sulfate with other CNS depressants, including other opioids, phenothiazines, sedative/hypnotics, and alcohol [see Drug Interactions (7.1) ].

6 ADVERSE REACTIONS Serious adverse reactions associated with codeine are respiratory depression and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest. The most frequently observed adverse reactions with codeine administration include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, sweating, and constipation. Other adverse reactions include allergic reactions, euphoria, dysphoria, abdominal pain, and pruritis. Other less frequently observed adverse reactions expected from opioid analgesics, including codeine sulfate, include: Cardiovascular system : faintness, flushing, hypotension, palpitations, syncope Digestive System : abdominal cramps, anorexia, diarrhea, dry mouth, gastrointestinal distress, pancreatitis Nervous system : anxiety, drowsiness, fatigue, headache, insomnia, nervousness, shakiness, somnolence, vertigo, visual disturbances, weakness Skin and Appendages : rash, sweating, urticaria The most common adverse reactions include: drowsiness, light-headedness, dizziness, sedation, shortness of breath, nausea, vomiting, sweating, and constipation. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Roxane Laboratories, Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch