warnings and cautions
5 WARNINGS AND PRECAUTIONS 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 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. Opioid related 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. Opioids, including codeine sulfate, should be used 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. Alternative non-opioid analgesics should be considered, and codeine sulfate should be employed only under careful medical supervision at the lowest effective dose in such patients. [see 10 OVERDOSAGE] 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. 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. Misuse and abuse of codeine sulfate poses a significant risk to the abuser that could result in overdose and death. Codeine may be abused by crushing, chewing, snorting or injecting the product. [see 9 DRUG ABUSE AND DEPENDENCE] Concerns about abuse and addiction 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, produce adverse reactions which may obscure the clinical course of 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. Codeine sulfate should be administered 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 Codeine sulfate should not be administered 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. 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 Codeine sulfate should be used in 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 As with other opioids, codeine sulfate should be used with caution in elderly or debilitated patients and those with severe impairment of hepatic or renal function, hypothyrodism, Addison’s disease, prostatic hypertrophy or urethral stricture. [see 8 USE IN SPECIFIC POPULATIONS] The usual precautions should be observed and the possibility of respiratory depression should be kept in mind. 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. 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 8 USE IN SPECIFIC POPULATIONS] 5.10 Driving and Operating Machinery Patients should be cautioned 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. Patients should also be cautioned about the potential combined effects of codeine sulfate with other CNS depressants, including opioids, phenothiazines, sedative/hypnotics, and alcohol. [see 7 DRUG INTERACTIONS]