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Pronunciation
(KOE deen)
Generic Available (U.S.)
Yes
Index Terms
Controlled Substance
C-II
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of mild-to-moderate pain
Use: Dental
Treatment of postoperative pain
Use: Unlabeled/Investigational
Short-term relief of coughing in select patients
Pregnancy Risk Factor
C
Pregnancy Considerations
Adverse events have been observed in animal reproduction studies. Neonatal abstinence syndrome (NAS) has been observed in the newborn following maternal use of codeine during pregnancy. Symptoms of opioid withdrawal may include excessive crying, diarrhea, fever, hyper-reflexia, irritability, tremors, or vomiting. Perinatal stroke has also been reported.
Lactation
Enters breast milk/use caution (AAP rates “compatible”; AAP 2001 update pending)
Breast-Feeding Considerations
Codeine and its metabolite (morphine) are found in breast milk and can be detected in the serum of nursing infants. The relative dose to a nursing infant has been calculated to be ~1% of the weight-adjusted maternal dose. Higher levels of morphine may be found in the breast milk of lactating mothers who are “ultra-rapid metabolizers” of codeine; patients with two or more copies of the variant CYP2D6*2 allele may have extensive conversion to morphine and thus increased opioid-mediated effects. In one case, excessively high serum concentrations of morphine were reported in a breast-fed infant following maternal use of acetaminophen with codeine. The mother was later found to be an “ultra-rapid metabolizer” of codeine; symptoms in the infant included feeding difficulty and lethargy, followed by death. Caution should be used since most persons are not aware if they have the genotype resulting in “ultra-rapid metabolizer” status. When codeine is used in breast-feeding women, it is recommended to use the lowest dose for the shortest duration of time and observe the infant for increased sleepiness, difficulty in feeding or breathing, or limpness.
Contraindications
Hypersensitivity to codeine or any component of the formulation; respiratory depression in the absence of resuscitative equipment; acute or severe bronchial asthma or hypercarbia; presence or suspicion of paralytic ileus
Canadian labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to other opioid analgesics; cor pulmonale; acute alcoholism; delirium tremens; severe CNS depression; convulsive disorders; increased cerebrospinal or intracranial pressure; head injury; suspected surgical abdomen; use with or within 14 days of MAO inhibitors.
Warnings/Precautions
Concerns related to adverse effects:
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Constipation: Use may cause or aggravate constipation; chronic use may result in obstructive bowel disease, particularly in those with underlying intestinal motility disorders.
• Hypotension: May cause hypotension; use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics).
• Phenanthrene hypersensitivity: Use with caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists (hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone).
• Respiratory depression: May cause dose-related respiratory depression. The risk is increased in elderly patients, debilitated patients, and patients with conditions associated with hypoxia, hypercapnia, or upper airway obstruction.
Disease-related concerns:
• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenal insufficiency: Use with caution in patients with adrenal insufficiency, including Addison's disease.
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction; acute pancreatitis may cause constriction of sphincter of Oddi.
• CNS depression/coma: Use with caution in patients with CNS depression or coma.
• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.
• Gastrointestinal obstruction: Avoid use in patients with gastrointestinal obstruction, particularly paralytic ileus; chronic use may result in obstructive bowel disease.
• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur. May also interfere with pupillary response and consciousness, thereby, affecting neurologic examination.
• Hepatic impairment: Use with caution in patients with severe hepatic impairment.
• Obesity: Use with caution in patients who are morbidly obese.
• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.
• Renal impairment: Use with caution in patients with severe renal impairment.
• Respiratory disease: Use with caution in patients with pre-existing respiratory compromise (hypoxia and/or hypercapnia), COPD or other obstructive pulmonary disease, and kyphoscoliosis or other skeletal disorder which may alter respiratory function; critical respiratory depression may occur, even at therapeutic dosages.
• Seizure disorders: May induce or aggravate seizures; use with caution in patients with seizure disorders.
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
Concurrent drug therapy issues:
• Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.
Special populations:
• CYP2D6 “ultra-rapid metabolizers”: Use caution in patients with two or more copies of the variant CYP2D6*2 allele; may have extensive conversion to morphine and thus increased opioid-mediated effects.
• Debilitated patients: Use with caution in debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages.
• Elderly: Use with caution in the elderly; may be more sensitive to adverse effects. Consider decreasing the initial dose.
Dosage form specific issues:
• Sulfites: Some preparations contain sulfites which may cause allergic reactions.
Other warnings/precautions:
• Withdrawal: Concurrent use of agonist/antagonist analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Abrupt discontinuation following prolonged use may also lead to withdrawal symptoms.
Adverse Reactions
Frequency not defined.
Cardiovascular: Bradycardia, cardiac arrest, circulatory depression, flushing, hyper-/hypotension, palpitation, shock, syncope, tachycardia
Central nervous system: Abnormal dreams, agitation, anxiety, apprehension, chills, coordination impaired, depression, disorientation, dizziness, drowsiness, dysphoria, euphoria, faintness, fatigue, hallucinations, headache, insomnia, intracranial pressure increased, lightheadedness, nervousness, sedation, shakiness, somnolence, vertigo
Dermatologic: Pruritus, rash, urticaria
Gastrointestinal: Abdominal cramps/pain, anorexia, biliary tract spasm, constipation, diarrhea, nausea, pancreatitis, taste disturbance, vomiting, xerostomia
Genitourinary: Urinary hesitancy/retention
Neuromuscular & skeletal: Paresthesia, rigidity, tremor, weakness
Ocular: Blurred vision, diplopia, miosis, nystagmus, visual disturbances
Respiratory: Bronchospasm, dyspnea, laryngospasm, respiratory arrest, respiratory depression
Miscellaneous: Allergic reaction, diaphoresis
Metabolism/Transport Effects
Substrate of CYP2D6 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alvimopan: Analgesics (Opioid) may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification
Ammonium Chloride: May increase the excretion of Analgesics (Opioid). Risk C: Monitor therapy
Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). Risk C: Monitor therapy
Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Analgesics (Opioid). Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy
CYP2D6 Inhibitors (Moderate): May diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk D: Consider therapy modification
Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Mixed Agonist / Antagonist Opioids: May diminish the analgesic effect of Analgesics (Opioid). Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk D: Consider therapy modification
Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: Analgesics (Opioid) may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk C: Monitor therapy
Somatostatin Analogs: May decrease the metabolism of Codeine. The formation of two major codeine metabolites (morphine and norcodeine) may be impaired by somatostatin analogs. Risk C: Monitor therapy
Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). Risk C: Monitor therapy
Thiazide Diuretics: Analgesics (Opioid) may enhance the orthostatic hypotensive effect of Thiazide Diuretics. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.
Herb/Nutraceutical: St John's wort may decrease codeine levels. Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).
Storage
Store at 15°C to 30°C (59°F to 86°F). Protect from light.
Mechanism of Action
Binds to opioid receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; causes cough suppression by direct central action in the medulla; produces generalized CNS depression
Pharmacodynamics/Kinetics
Onset of action: Oral: Immediate release: 0.5-1 hour
Peak effect: Oral: Immediate release: 1-1.5 hours
Duration: Immediate release: 4-6 hours
Distribution: ~3-6 L/kg
Protein binding: ~7% to 25%
Metabolism: Hepatic via UGT2B7 and UGT2B4 to codeine-6-glucuronide, via CYP2D6 to morphine (active), and via CYP3A4 to norcodeine. Morphine is further metabolized via glucuronidation to morphine-3-glucuronide and morphine-6-glucuronide (active).
Bioavailability: 53%
Half-life elimination: ~3 hours
Time to peak, plasma: Immediate release: 1 hour; Controlled release (Canadian availability; not available in the U.S.): 3.3 hours
Excretion: Urine (~90%, ~10% of the total dose as unchanged drug); feces
Dosage
Oral:
Pain management (analgesic): Note: These are guidelines and do not represent the maximum doses that may be required in all patients. Doses should be titrated to pain relief/prevention.
Children (unlabeled use): Initial: 0.5-1 mg/kg/dose every 4 hours as needed; maximum: 60 mg/dose (American Pain Society, 2008)
Adults:
Immediate release: Initial: 15-60 mg every 4 hours as needed; maximum total daily dose: 360 mg/day; patients with prior opioid exposure may require higher initial doses. Note: The American Pain Society recommends an initial dose of 30-60 mg for adults with moderate pain (American Pain Society, 2008).
Controlled release: Codeine Contin® (Canadian availability; not available in U.S.): Note: Titrate at intervals of ≥48 hours until adequate analgesia has been achieved. Daily doses >600 mg/day should not be used; patients requiring higher doses should be switched to an opioid approved for use in severe pain. In patients who receive both Codeine Contin® and an immediate release or combination codeine phosphate product for breakthrough pain, the rescue dose of codeine base should be ≤12.5% of the total daily Codeine Contin® dose.
Opioid-naive patients: Initial: 50 mg every 12 hours
Conversion from immediate release codeine phosphate preparations: Codeine phosphate preparations contain ~75% codeine base. Therefore, patients who are switching from immediate release codeine phosphate preparations may be transferred to a ~25% lower total daily dose of Codeine Contin®, equally divided into 2 daily doses.
Conversion from a combination codeine product (eg, codeine with acetaminophen or aspirin): See table:
Number of 30 mg Codeine Combination Tablets Daily
Initial Dose of Codeine Contin®
Maintenance Dose of Codeine Contin®
≤6
50 mg every 12 h
100 mg every 12 h
7-9
100 mg every 12 h
150 mg every 12 h
10-12
150 mg every 12 h
200 mg every 12 h
>12
200 mg every 12 h
200-300 every 12 h (maximum: 300 mg every 12 h)
Table has been converted to the following text.
Number of 30 mg codeine combination tablets daily: ≤6 tablets/day
Initial dose of Codeine Contin®: 50 mg every 12 hours
Maintenance dose of Codeine Contin®: 100 mg every 12 hours
Number of 30 mg codeine combination tablets daily: 7-9 tablets/day
Initial dose of Codeine Contin®: 100 mg every 12 hours
Maintenance dose of Codeine Contin®: 150 mg every 12 hours
Number of 30 mg codeine combination tablets daily: 10-12 tablets/day
Initial dose of Codeine Contin®: 150 mg every 12 hours
Maintenance dose of Codeine Contin®: 200 mg every 12 hours
Number of 30 mg codeine combination tablets daily: >12 tablets/day
Initial dose of Codeine Contin®: 200 mg every 12 hours
Maintenance dose of Codeine Contin®: 200-300 mg every 12 hours (maximum: 300 mg every 12 hours)
Conversion from another opioid analgesic: Using the patient's current opioid dose, calculate an equivalent daily dose of codeine phosphate. A ~25% lower dose of Codeine Contin® should then be initiated, equally divided into 2 daily doses.
Discontinuation of therapy: Note: Gradual dose reduction is recommended if clinically appropriate. Initially reduce the total daily dose by 50% and administer equally divided into 2 daily doses for 2 days followed by a 25% reduction every 2 days thereafter.
Treatment of cough (unlabeled use): Adults: Reported doses vary; range: 7.5-120 mg/day as a single dose or in divided doses (Bolser, 2006; Smith, 2010); Note: The American College of Chest Physicians does not recommend the routine use of codeine as an antitussive in patients with upper respiratory infections (Bolser, 2006).
Dosing adjustment in renal impairment:
Manufacturer's recommendations: Clearance may be reduced; active metabolites may accumulate. Initiate at lower doses or longer dosing intervals followed by careful titration.
Alternate recommendations: The following guidelines have been used by some clinicians (Aronoff, 2007):
Clcr 10-50 mL/minute: Administer 75% of dose
Clcr <10 mL/minute: Administer 50% of dose
Dosing adjustment in hepatic impairment: No dosage adjustment provided in manufacturer's labeling (has not been studied); however, initial lower doses or longer dosing intervals followed by careful titration are recommended.
Dental Usual Dosing
Postoperative pain: Adults: Oral: 30 mg every 4-6 hours as needed; patients with prior opiate exposure may require higher initial doses. Usual range: 15-120 mg every 4-6 hours as needed
Administration: Oral
May administer without regard to meals. Take with food or milk to decrease adverse GI effects.
Controlled release tablets: Codeine Contin® (Canadian availability; not available in U.S.): Tablets should be swallowed whole; do not chew, dissolve, or crush. All strengths may be halved, except the 50 mg tablets; half tablets should also be swallowed intact.
Monitoring Parameters
Pain relief, respiratory and mental status, blood pressure, heart rate
Reference Range
Therapeutic: Not established; Toxic: >1.1 mcg/mL
Test Interactions
Some quinolones may produce a false-positive urine screening result for opioids using commercially-available immunoassay kits. This has been demonstrated most consistently for levofloxacin and ofloxacin, but other quinolones have shown cross-reactivity in certain assay kits. Confirmation of positive opioid screens by more specific methods should be considered.
Patient Education
May cause physical and/or psychological dependence. Do not use alcohol, sedatives, tranquilizers, antihistamines, or pain medications without consulting prescriber. Maintain adequate hydration, unless instructed to restrict fluid intake. May cause dizziness, drowsiness, confusion, agitation, impaired coordination, or blurred vision; nausea or vomiting; loss of appetite; or constipation (if unresolved, consult prescriber about use of stool softeners). Report confusion, insomnia, excessive nervousness, excessive sedation or drowsiness, or shakiness; acute GI upset; respiratory difficulty or shortness of breath; facial flushing, rapid heartbeat, or palpitations; urinary difficulty; unusual muscle weakness; or vision changes.
Geriatric Considerations
The elderly may be particularly susceptible to CNS depression and confusion as well as the constipating effects of narcotics.
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: May be administered to patients with chronic cough prior to surgical cases such as cataract extraction under MAC anesthesia to prevent movement during the procedure.
Evidence-Based Information: The 2002 ACCM/SCCM guidelines for analgesia (critically ill adult) recommend against using codeine because of its lack of potency, histamine release (may cause hypotension), potential accumulation of active metabolites. The guidelines recommend fentanyl in patients who need immediate pain relief because of its rapid onset of action; fentanyl or hydromorphone is preferred in patients who are hypotensive or have renal dysfunction.
Cardiovascular Considerations
Codeine may cause constipation which may be problematic in patients with unstable angina, and patients after myocardial infarction. The hemodynamic responses to valsalva-like maneuvers due to straining may have adverse cardiovascular consequences in patients with critical coronary artery disease.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported (see Dental Health Professional Considerations)
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Dental Comment
It is recommended that codeine not be used as the sole entity for analgesia because of moderate efficacy along with relatively high incidence of nausea, sedation, and constipation. In addition, codeine has some narcotic addiction liability. Codeine in combination with acetaminophen or aspirin is recommended. Maximum effective analgesic dose of codeine is 60 mg (1 grain). Beyond 60 mg increases respiratory depression only. Sodium thiosulfate is an effective chemical antidote for codeine poisoning.
Mental Health: Effects on Mental Status
Drowsiness is common; may cause euphoria, confusion, insomnia, hallucinations, or depression
Mental Health: Effects on Psychiatric Treatment
Concurrent use with psychotropics may produce additive toxicity; concurrent use with fluoxetine or paroxetine may result in loss of pain control
Nursing: Physical Assessment/Monitoring
Monitor for effectiveness of pain relief and CNS status prior to treatment and periodically throughout. May cause physical and/or psychological dependence. For inpatients, implement safety measures to prevent falls. Assess patient's physical and/or psychological dependence. Discontinue slowly after prolonged use.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Powder, for prescription compounding, as phosphate: USP: 100% (10 g, 25 g)
Tablet, oral, as phosphate: 30 mg [DSC], 60 mg [DSC]
Tablet, oral, as sulfate: 15 mg, 30 mg, 60 mg
Extemporaneously Prepared
A 3 mg/mL oral suspension may be made with codeine phosphate powder, USP. Add 600 mg of powder to a 400 mL beaker. Add 2.5 mL of Sterile Water for Irrigation, USP, and stir to dissolve the powder. Mix for 10 minutes while adding Ora-Sweet® to make 200 mL; transfer to a calibrated bottle. Stable 98 days at room temperature.
Dentinger PJ and Swenson CF, "Stability of Codeine Phosphate in an Extemporaneously Compounded Syrup," Am J Health Syst Pharm, 2007, 64(24):2569-73.
References
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Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007, p 18, 135.
Bolser DC, “Cough Suppressant and Pharmacologic Protussive Therapy: ACCP Evidence-Based Clinical Practice Guidelines,” Chest, 2006, 129(1 Suppl):238-48.
Cardan E, “Fatal Case of Codeine Poisoning,” Lancet, 1981, 1(8233):1313.
de Groot AC and Conemans J, “Allergic Urticarial Rash From Oral Codeine,” Contact Dermatitis, 1986, 14(4):209-14.
Desjardins PJ, Cooper SA, Gallegos TL, et al, “The Relative Analgesic Efficacy of Propiram Fumarate, Codeine, Aspirin, and Placebo in Postimpaction Dental Pain,” J Clin Pharmacol, 1984, 24(1):35-42.
“Drugs for Pain,” Med Lett Drugs Ther, 2000, 42(1085):73-8.
Ferrell BA, “Pain Management in Elderly People,” J Am Geriatr Soc, 1991, 39(1):64-73.
Forbes JA, Keller CK, Smith JW, et al, “Analgesic Effect of Naproxen Sodium, Codeine, a Naproxen-Codeine Combination and Aspirin on the Postoperative Pain of Oral Surgery,” Pharmacotherapy, 1986, 6(5):211-8.
Irwin RS, Boulet LP, Cloutier MM, et al, “Managing Cough as a Defense Mechanism and as a Symptom: A Consensus Panel Report of the American College of Chest Physicians,” Chest, 198, 114(2):133-81.
Ivey HH and Kattwinkel J, “Danger of Actifed-C,” Pediatrics, 1976, 57(1):164-5.
Jacobi J, Fraser GL, Coursin DB, et al, “Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult,” Crit Care Med, 2002, 30(1):119-41. Available at http://www.sccm.org/pdf/sedatives.pdf. Accessed August 2, 2003.
Kaiko RF, Wallenstein SL, Rogers AG, et al, “Narcotics in the Elderly,” Med Clin North Am, 1982, 66(5):1079-89.
Khan K and Chang J, “Neonatal Abstinence Syndrome Due to Codeine,” Arch Dis Child Fetal Neonatal Ed, 1997; 76(1): F59-60.
Koren G, Caims J, Chitayat D, et al, “Pharmacogenetics of Morphine Poisoning in a Breastfed Neonate of a Codeine-Prescribed Mother,” Lancet, 2006, 368(9536):704.
Mokhlesi B, Leikin JB, Murray P, et al, “Adult Toxicology in Critical Care: Part II: Specific Poisonings,” Chest, 2003, 123(3):897-922.
“Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain,” 6th ed, Glenview, IL: American Pain Society, 2008.
Reynolds EW, Riel-Romero RM, and Bada HS, “Neonatal Abstinence Syndrome and Cerebral Infarction Following Maternal Codeine Use During Pregnancy,” Clin Pediatr, 2007, 46(7):639-45.
Smith SM, Schroeder K, and Fahey T, “Over-the-Counter (OTC) Medications for Acute Cough in Children and Adults in Ambulatory Settings (Review),” Cochrane Database Syst Rev, 2010, 9:1-33.
Spigset O and Hagg S, “Analgesics and Breast-Feeding: Safety Considerations,” Paediatr Drugs, 2000, 2(3):223-38.
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International Brand Names
Lexi-Comp.com
Last full review/revision November 2011
Content last modified November 2011
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