warnings and cautions
5 WARNINGS AND PRECAUTIONS Respiratory depression: Increased risk in elderly, debilitated patients, those suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction. ( 5.1 ) Controlled substance: Codeine sulfate is a Schedule II controlled substance with an abuse liability similar to other opioids. ( 5.2 ) Risk of abuse: Assess patients for their risks for opioid abuse or addiction prior to prescribing codeine sulfate oral solution ( 5.2 ) CNS effects: Additive CNS depressive effects when used in conjunction with alcohol, other opioids, or illicit drugs. ( 5.3 ) Elevation of intracranial pressure: May be markedly exaggerated in the presence of head injury, other intracranial lesions. ( 5.4 ) Hypotensive effect: Increased risk with compromised ability to maintain blood pressure. ( 5.5 ) Prolonged gastric obstruction: Do not administer codeine sulfate to patients with gastrointestinal obstruction, especially paralytic ileus. ( 5.6 ) Pancreatic/biliary tract disease: May cause spasm of the sphincter of Oddi and diminish biliary and pancreatic secretions. ( 5.7 ) 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 overdose symptoms. ( 5.9 ) Impaired mental/physical abilities: Caution must be used with potentially hazardous activities. ( 5.10 ) 5.1 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 doserelated 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) ] 5.2 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. 5.3 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. 5.4 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. 5.5 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. 5.6 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. 5.7 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. 5.8 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. 5.9 Ultra-Rapid Metabolizers of Codeine Some individuals may be ultra-rapid metabolizers due to a specific CYP2D6*2x2 genotype. 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 experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. 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. When physicians prescribe codeine-containing drugs, they should choose the lowest effective dose for the shortest period of time and inform their patients about these risks and the signs of morphine overdose. [see Use in Specific Populations (8.3) ] 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) ]