Clinical medicine profile
Codeine
Opioid analgesic
- Route
- ORAL / IV / IM / SC / TD / RECTAL
- Schedule
- POM
- ATC
- Not assigned
- PPB status
- registered
Safety essentials
The information most likely to change a prescribing or dispensing decision.
WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF CODEINE SULFATE TABLETS Addiction, Abuse, and Misuse Because the use of Codeine Sulfate Tablets exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.1 ), Dosage and Administration ( 2.1 )] . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Codeine Sulfate Tablets, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Codeine Sulfate Tablets are essential [see Warnings and Precautions ( 5.2 )] . Accidental Ingestion Accidental ingestion of even one dose of Codeine Sulfate Tablets, especially by children, can result in a fatal overdose of codeine [see Warnings and Precautions ( 5.2 )] . Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of Codeine Sulfate Tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [ see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7 )] . Neonatal Opioid Withdrawal Syndrome (NOWS) Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. [see Warnings and Precautions ( 5.4 )] . Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions ( 5.5 )] . Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism [see Warnings and Precautions ( 5.6 )]. Codeine Sulfate Tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications ( 4 )]. Avoid the use of Codeine Sulfate Tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. Interactions with Drugs Affecting Cytochrome P450 Isoenzymes The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Codeine Sulfate Tablets requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. [See Warnings and Precautions ( 5.7 ), Drug Interactions ( 7 )] . WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF CODEINE SULFATE TABLETS See full prescribing information for complete boxed warning. • Codeine Sulfate Tablets exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and reassess regularly for these behaviors and conditions. ( 5.1 ) • Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Codeine Sulfate Tablets are essential. ( 5.2 ) • Accidental ingestion of Codeine Sulfate Tablets, especially by children, can result in a fatal overdose of codeine. ( 5.2 ) • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. ( 5.3 , 7 ) • Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. ( 5.4 ) • Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription. ( 5.5 ) • Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. ( 5.6 ) Codeine Sulfate Tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy ( 4 ). Avoid the use of Codeine Sulfate Tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. • The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Codeine Sulfate Tablets requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. ( 5.7 , 7 )
Contraindications
- 4 CONTRAINDICATIONS Codeine Sulfate Tablets are contraindicated for: • All children younger than 12 years of age [see Warnings and Precautions ( 5.6 )] . • Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions ( 5.6 )] .
- Codeine Sulfate Tablets are also contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions ( 5.2 )]. • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.9 )]. • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions ( 5.10 ), Drug Interactions ( 7 )]. • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.14 )]. • Hypersensitivity to codeine (e.g., anaphylaxis) [see Adverse Reactions ( 6 )] . • Children younger than 12 years of age. • Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy.
- ( 4 ) • Significant respiratory depression.
- ( 4 ) • Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment.
- ( 4 ) • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days.
- ( 4 ) • Known or suspected gastrointestinal obstruction, including paralytic ileus.
- ( 4 ) • Hypersensitivity to codeine.
Precautions
- 5 WARNINGS AND PRECAUTIONS • Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain.
- If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation.
- ( 5.8 ) • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Regularly evaluate closely, particularly during initiation and titration.
- ( 5.9 ) • Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
- ( 5.11 ) • Severe Hypotension : Regularly evaluate during dosage initiation and titration.
- Avoid use of Codeine Sulfate Tablets in patients with circulatory shock.
- ( 5.12 ) • Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression.
- Avoid use of Codeine Sulfate Tablets in patients with impaired consciousness or coma.
- ( 5.13 ) 5.1 Addiction, Abuse, and Misuse Codeine Sulfate Tablets contain codeine, a Schedule II controlled substance.
- As an opioid, Codeine Sulfate Tablets exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 )].
- Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Codeine Sulfate Tablets.
- Addiction can occur at recommended dosages and if the drug is misused or abused.
Dosing matrix
Population and organ-function guidance, shown together for faster comparison.
• Codeine Sulfate Tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 ) • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of Codeine Sulfate Tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) • Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. ( 2.1 ) • Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 2.1 , 5.1 ) • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Codeine Sulfate Tablets. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) • Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with Codeine Sulfate Tablets, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. ( 2.2 , 5.1 , 5.2 , 5.3 ) • Initiate treatment with 15 to 60 mg every 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Codeine Sulfate Tablets. ( 2.3 ) • Periodically reassess patients receiving Codeine Sulfate Tablets to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. ( 2.4 ) • Do not rapidly reduce or abruptly discontinue Codeine Sulfate Tablets in a physically-dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.5 , 5.16 ) 2.1 Important Dosage and Administration Instructions • Codeine Sulfate Tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Codeine Sulfate Tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. • Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. • There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.1 )] . • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Codeine Sulfate Tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ( 5 )]. 2.2 Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )]. Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Warnings and Precautions ( 5.2 )] . There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent . 2.3 Initial Dosage Initiating Treatment with Codeine Sulfate Tablets: Initiate treatment with Codeine Sulfate Tablets in a dosing range of 15 to 60 mg every 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Codeine Sulfate Tablets. Adult doses of Codeine Sulfate Tablets higher than 60 mg provide no further efficacy but are associated with greater adverse reactions. The maximum 24-hour dose is 360 mg. Conversion from Other Opioids to Codeine Sulfate Tablets: There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Codeine Sulfate Tablets. It is safer to underestimate a patient’s 24-hour Codeine Sulfate Tablets dosage than to overestimate the 24-hour Codeine Sulfate Tablets dosage and manage an adverse reaction due to overdose. 2.4 Titration and Maintenance of Therapy Individually titrate Codeine Sulfate Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving codeine sulfate to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.1 , 5.16 )] . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Codeine Sulfate Tablets dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions ( 5 )] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.5 Safe Reduction or Discontinuation of Codeine Sulfate Tablets Do not rapidly reduce or abruptly discontinue Codeine Sulfate Tablets in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Codeine Sulfate Tablets, there are a variety of factors that should be considered, including the total daily dose of opioid (including Codeine Sulfate Tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on Codeine Sulfate Tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and 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. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions ( 5.16 ), Drug Abuse and Dependence ( 9.3 )].
8.4 Pediatric Use The safety and effectiveness of Codeine Sulfate Tablets in pediatric patients have not been established. Life-threatening respiratory depression and death have occurred in children who received codeine [see Warnings and Precautions ( 5.6 )] . In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children 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). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of codeine. Because of the risk of life-threatening respiratory depression and death: • Codeine Sulfate Tablets are contraindicated for all children younger than 12 years of age [see Contraindications ( 4 )] . • Codeine Sulfate Tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications ( 4 )] . • Avoid the use of Codeine Sulfate Tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression [see Warnings and Precautions ( 5.6 )].
Prefer fentanyl/methadone expert use over morphine in advanced CKD; reduce doses.
- CrCl 0–120: Confirm renal dosing in product SmPC / primary label.
Reduce dose/frequency; avoid long-acting in decompensated disease.
Use, effects & interactions
Indications
- 1 INDICATIONS AND USAGE Codeine Sulfate Tablets are indicated for the management of mild to moderate pain, where treatment with an opioid is appropriate and for which alternative treatments are inadequate.
- Limitations of Use: • Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy [see Warnings and Precautions ( 5.1 )] , reserve opioid analgesics, including Codeine Sulfate Tablets, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
- Codeine Sulfate Tablets are an opioid agonist, indicated for the management of mild to moderate pain, where treatment with an opioid is appropriate and for which alternative treatments are inadequate.
- ( 1 ) Limitations of Use • Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including Codeine Sulfate Tablets, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
- ( 1 , 5.1 )
Adverse effects
- 6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] • Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )] • Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions ( 5.3 )] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] • Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children [see Warnings and Precautions ( 5.6 )] • Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.8 )] • Adrenal Insufficiency [see Warnings and Precautions ( 5.11 )] • Severe Hypotension [see Warnings and Precautions ( 5.12 )] • Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.14 )] • Seizures [see Warnings and Precautions ( 5.15 )] • Withdrawal [see Warnings and Precautions ( 5.16 )] The following adverse reactions associated with the use of codeine were identified in clinical studies or postmarketing reports.
- Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Serious adverse reactions associated with codeine were respiratory depression and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest.
- The most frequently observed adverse reactions with codeine administration included drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, sweating, and constipation.
- Other adverse reactions included allergic reactions, euphoria, dysphoria, abdominal pain, and pruritis.
- Other less frequently observed adverse reactions expected from opioid analgesics, including Codeine Sulfate Tablets, 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 Serotonin Syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
- Adrenal Insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
- Anaphylaxis : Anaphylaxis has been reported with ingredients contained in Codeine Sulfate Tablets.
- Androgen Deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology ( 12.2 )] .
- Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.8 )] .
- Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids.
- Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).
- Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions ( 5.14 )] .
- Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021.
Drug interactions
Open multi-drug checker ↗- WHO ladder still useful framework.
- For cancer pain use around-the-clock + breakthrough.
- Naloxone for overdose.
- Document functional goals
- review long-term opioid benefit regularly.
Mechanism & disposition
12.
Read complete mechanism
12.1 Mechanism of Action Codeine sulfate is an opioid agonist relatively selective for the mu-opioid receptor, but with a much weaker affinity than morphine. The analgesic properties of codeine have been speculated to come from its conversion to morphine, although the exact mechanism of analgesic action remains unknown.
Minutes (IV) to hour (oral)
Hours (agent-dependent)
ORAL / IV / IM / SC / TD / RECTAL
Codeine is absorbed from the gastrointestinal tract with maximum plasma concentration occurring 60 minutes post administration. Administration of 15 mg of codeine sulfate every four hours for 5 days resulted in steady-state concentrations of codeine, morphine, morphine-3-glucuron...
Codeine has been reported to have an apparent volume of distribution of approximately 3 to 6 L/kg, indicating extensive distribution of the drug into tissues. Codeine has low plasma protein binding with about 7% to 25% of codeine bound to plasma proteins.
About 70% to 80% of the administered dose of codeine is metabolized by conjugation with glucuronic acid to codeine-6-glucuronide (C6G) and via O -demethylation to morphine (about 5% to 10%) and N -demethylation to norcodeine (about 10%) respectively. UDP-glucuronosyltransferase (...
Codeine is metabolized by conjugation to codeine-6-glucuronide (70% to 80%), by O -demethylation to morphine (5% to 10%), and by N -demethylation to norcodeine (~10%). Approximately 90% of the total dose of codeine is excreted through the kidneys. The plasma half-lives of codeine...
Pregnancy, lactation & diet
8.1 Pregnancy Risk Summary: Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.4 )] . Available data with Codeine Sulfate Tablets are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, codeine administration during organogenesis has been shown to produce delayed ossification in the offspring of mice at 1.4 times maximum recommended human dose (MRHD) of 360 mg/day, embryolethal and fetotoxic effects in the offspring of rats and hamsters at approximately 2 to 3 times the MRHD, and cranial malformations/cranioschisis in the offspring of hamsters between 2 and 8 times the MRHD [ see Data ]. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations: Fetal/Neonatal Adverse Reactions: Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.4 )] . Labor or Delivery: Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. Codeine Sulfate Tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Codeine Sulfate Tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data: Animal Data: Studies on the reproductive and developmental effects of codeine have been reported in the published literature in hamsters, rats, mice and rabbits. In a study in which pregnant hamsters were administered 150 mg/kg twice daily of codeine (oral; approximately 7 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m 2 basis) during organogenesis cranial malformations (i.e., meningoencephalocele) in several fetuses were reported; as well as the observation of increases in the percentage of resorptions per litter. Doses of 50 and 150 mg/kg, bid resulted in fetotoxicity as demonstrated by decreased fetal body weight. In an earlier study in hamsters, single oral doses of 73 to 360 mg/kg level on Gestation Day 8 (oral; approximately 2 to 8 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m 2 basis), reportedly produced cranioschisis in all of the fetuses examined. In studies in rats, doses at the 120 mg/kg level (oral; approximately 3 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m 2 basis) during organogenesis, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation. In pregnant mice, a single 100 mg/kg dose (subcutaneous; approximately 1.4 times the recommended daily dose of 360 mg/day for adults on a mg/mg 2 basis) administered between Gestation Day 7 and 12 reportedly resulted in delayed ossification in the offspring. No teratogenic effects were observed in rabbits administered up to 30 mg/kg (approximately 2 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m 2 basis) of codeine during organogenesis. Codeine (30 mg/kg) administered subcutaneously to pregnant rats during pregnancy and for 25 days after delivery increased neonatal mortality at birth. This dose is 0.8 times the maximum recommended human dose of 360 mg/day on a body surface area comparison.
• Pregnancy : May cause fetal harm. ( 8.1 ) • Lactation : Breastfeeding not recommended. ( 8.2 ) 8.1 Pregnancy Risk Summary: Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.4 )] . Available data with Codeine Sulfate Tablets are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, codeine administration during organogenesis has been shown to produce delayed ossification in the offspring of mice at 1.4 times maximum recommended human dose (MRHD) of 360 mg/day, embryolethal and fetotoxic effects in the offspring of rats and hamsters at approximately 2 to 3 times the MRHD, and cranial malformations/cranioschisis in the offspring of hamsters between 2 and 8 times the MRHD [ see Data ]. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations: Fetal/Neonatal Adverse Reactions: Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.4 )] . Labor or Delivery: Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. Codeine Sulfate Tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Codeine Sulfate Tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data: Animal Data: Studies on the reproductive and developmental effects of codeine have been reported in the published literature in hamsters, rats, mice and rabbits. In a study in which pregnant hamsters were administered 150 mg/kg twice daily of codeine (oral; approximately 7 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m 2 basis) during organogenesis cranial malformations (i.e., meningoencephalocele) in several fetuses were reported; as well as the observation of increases in the percentage of resorptions per litter. Doses of 50 and 150 mg/kg, bid resulted in fetotoxicity as demonstrated by decreased fetal body weight. In an earlier study in hamsters, single oral doses of 73 to 360 mg/kg level on Gestation Day 8 (oral; approximately 2 to 8 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m 2 basis), reportedly produced cranioschisis in all of the fetuses examined. In studies in rats, doses at the 120 mg/kg level (oral; approximately 3 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m 2 basis) during organogenesis, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation. In pregnant mice, a single 100 mg/kg dose (subcutaneous; approximately 1.4 times the recommended daily dose of 360 mg/day for adults on a mg/mg 2 basis) administered between Gestation Day 7 and 12 reportedly resulted in delayed ossification in the offspring. No teratogenic effects were observed in rabbits administered up to 30 mg/kg (approximately 2 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m 2 basis) of codeine during organogenesis. Codeine (30 mg/kg) administered subcutaneously to pregnant rats during pregnancy and for 25 days after delivery increased neonatal mortality at birth. This dose is 0.8 times the maximum recommended human dose of 360 mg/day on a body surface area comparison. 8.2 Lactation Risk Summary: Codeine and its active metabolite, morphine, are present in human milk. There are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to codeine via breast milk. Women who are ultra-rapid metabolizers of codeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. There is no information on the effects of codeine on milk production. Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Codeine Sulfate Tablets [see Warnings and Precautions ( 5.4 )] . Clinical Considerations: If infants are exposed to Codeine Sulfate Tablets through breast milk, they should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped. 8.3 Females and Males of Reproductive Potential Infertility: Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6 )] . 8.4 Pediatric Use The safety and effectiveness of Codeine Sulfate Tablets in pediatric patients have not been established. Life-threatening respiratory depression and death have occurred in children who received codeine [see Warnings and Precautions ( 5.6 )] . In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children 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). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of codeine. Because of the risk of life-threatening respiratory depression and death: • Codeine Sulfate Tablets are contraindicated for all children younger than 12 years of age [see Contraindications ( 4 )] . • Codeine Sulfate Tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications ( 4 )] . • Avoid the use of Codeine Sulfate Tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression [see Warnings and Precautions ( 5.6 )]. 8.5 Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to codeine. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Codeine Sulfate Tablets slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.9 )] . Codeine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function. 8.6 Hepatic Impairment No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of codeine in this patient population are unknown. Start these patients with a lower than normal dosage of Codeine Sulfate Tablets or with longer dosing intervals and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension. 8.7 Renal Impairment Codeine pharmacokinetics may be altered in patients with renal failure. Clearance may be decreased and the metabolites may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Start these patients with a lower than normal dosage of Codeine Sulfate Tablets or with longer dosing intervals and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension.
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