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DRUG INTERACTIONS
Central Nervous System (CNS) Depressants
Concurrent use of other opioids, antihistamines, antipsychotics, antianxiety agents, or other CNS depressants (including sedatives, hypnotics, general anesthetics, antiemetics, phenothiazines, or other tranquilizers or alcohol) concomitantly with codeine sulfate may result in additive CNS depression, respiratory depression, hypotension, profound sedation, or coma. Use codeine sulfate with caution and in reduced dosages in patients taking these agents.
Mixed Agonist/Antagonist Opioid Analgesics
Do not administer mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic such as codeine sulfate. In these patients, mixed agonist/antagonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.
Anticholinergics
Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Antidepressants
Use of monoamine oxidase inhibitors (MAOIs) or tricyclic antidepressants with codeine sulfate may increase the effect of either the antidepressant or codeine. MAOIs markedly potentiate the action of morphine, the major metabolite of codeine. Codeine should not be used in patients taking MAOIs or within 14 days of stopping such treatment.
CYP2D6 and CYP3A4 Inhibitors and Inducers
Codeine is metabolized by the cytochrome P450 2D6 and 3A4 isoenzymes [see Clinical Pharmacology]. Patients taking CYP2D6 inhibitors or CYP3A4 inhibitors or inducers may demonstrate an altered response to codeine, therefore analgesic activity should be monitored.
Inhibitors of CYP2D6 or CYP3A4: Since the CYP2D6 and CYP3A4 isoenzymes play a major role in the metabolism of codeine, drugs that inhibit CYP3A4 (e.g., macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)), or CYP2D6 activity (e.g., certain cardiovascular drugs including amiodarone and quinidine as well as polycyclic antidepressants), may cause decreased clearance of codeine which could lead to an increase in codeine plasma concentrations. If coadministration with codeine sulfate oral solution is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing CYP450 inhibitors. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. [see Clinical Pharmacology]
Inducers of CYP3A4: CYP450 inducers, such as rifampin, carbamazepine, and phenytoin, may induce the metabolism of codeine and, therefore, may cause increased clearance of the drug which could lead to a decrease in codeine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to codeine. If co-administration with codeine sulfate oral solution is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing CYP3A4 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved.
Drug-Laboratory Test Interaction
Codeine may cause an elevation of plasma amylase and lipase due to the potential of codeine to produce spasm of the sphincter of Oddi. Determination of these enzyme levels may be unreliable for some time after an opiate agonist has been given.
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OVERDOSAGE
Symptoms
Acute overdose with codeine is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest, and death may occur.
Codeine may cause miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.
Treatment
Give primary attention to re-establishment of a patent airway and institution of assisted or controlled ventilation. Employ supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. Induction of emesis is not recommended because of the potential for CNS depression and seizures. Activated charcoal is recommended if the patient is awake and able to protect his/her airway. In persons who are at risk for abrupt onset of seizures or mental status depression, activated charcoal should be administered by medical or paramedical personnel capable of airway management to prevent aspiration in the event of spontaneous emesis. Severe agitation or seizures should be treated with an intravenous benzodiazepine.
The pure opioid antagonist, naloxone, is a specific antidote to respiratory depression resulting from opioid overdose. Since the duration of reversal is expected to be less than the duration of action of codeine sulfate, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to opioid antagonists is suboptimal or only brief in nature, administer additional antagonist as directed by the label of the product.
Do not administer opioid antagonists in the absence of clinically significant respiratory or circulatory depression secondary to codeine sulfate overdose. In an individual physically dependent on opioids, administration of the usual dose of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. Reserve use of an opioid antagonist for cases where such treatment is clearly needed. If it is necessary to treat serious respiratory depression in the physically dependent patient, initiate administration of the antagonist with care and titrate with smaller than usual doses.
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CONTRAINDICATIONS
Codeine sulfate is contraindicated in patients with known hypersensitivity to codeine or any components of the product. Persons known to be hypersensitive to certain other opioids may exhibit cross-sensitivity to codeine.
Codeine sulfate is contraindicated in patients with respiratory depression in the absence of resuscitative equipment.
Codeine sulfate is contraindicated in patients with acute or severe bronchial asthma or hypercarbia.
Codeine sulfate is contraindicated in any patient who has or is suspected of having paralytic ileus.
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DRUG ABUSE AND DEPENDENCE
Controlled Substance
Codeine sulfate is an opioid agonist and is a Schedule II controlled substance. Codeine sulfate can be abused and is subject to criminal diversion.
Abuse
Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.
"Drug seeking" behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated "loss" of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). "Healthcare provider shopping" to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.
The risks of misuse and abuse should be considered when prescribing or dispensing codeine sulfate. Concerns about abuse and addiction, should not prevent the proper management of pain, however, treatment of pain should be individualized, balancing the potential benefits and risks for each patient.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence. The converse is also true. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.
Codeine is intended for oral use only. Abuse of codeine poses a risk of overdose and death. The risk is increased with concurrent abuse of alcohol and other substances. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms.
[see Use in Specific Populations]
Dependence
Tolerance to opioids is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). The first sign of tolerance is usually a reduced duration of effect. Tolerance to different effects of opioids may develop to varying degrees and at varying rates in a given individual. There is also inter-patient variability in the rate and extent of tolerance that develops to various opioid effects, whether the effect is desirable (e.g., analgesia) or undesirable (e.g., nausea). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are frequent during chronic opioid therapy.
Instruct patients using codeine sulfate not to change their dose without first contacting their health care providers. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
In general, opioids should not be abruptly discontinued. [see Dosage and Administration]
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