Codeine

Codeine is a prescription opioid analgesic indicated for the relief of mild to moderate severe pain where the use of an opioid analgesic is appropriate.

• Codeine is not available under different brand names.

Adult and pediatric dosages:

Tablets, schedule II

• 15 mg
• 30 mg
• 60 mg

Oral solution, schedule II (pediatric dosing only)

• 30 mg/ml

Injection solution

• 15 mg/ml
• 30 mg/ml

Dosage Considerations -- Should Be Given As Follows:

Adult Dosage Considerations

Pain

• 15-60 mg orally/subcutaneous/intramuscular every 4-6 hours as needed, not to exceed 360 mg/day in opiate naive patients

Dosing considerations

• Patients with prior opioid exposure may require higher initial doses

Pediatric

• 0.5-1 mg/kg orally/subcutaneous/intramuscular every 4-6 hours as needed, not to exceed 60 mg/dose

Dosing considerations

• See warnings and contraindications sections for warnings regarding postoperative use following tonsillectomy and/or adenoidectomy
• The potential toxic dose for children under 6 years: 2 mg/kg

Cough

Adult

• 7.5-20 mg orally every 4-6 hours as needed, not to exceed 120 mg/24 hours

Infants

• Safety and efficacy not established

Children

Children: 2-6 years

• 1-1.5 mg/kg/day divided every 4-6 hours orally/subcutaneous/intramuscular; not to exceed 30 mg/day

6-12 years

• 1-1.5 mg/kg/day divided every 4-6 hours orally/subcutaneous/intramuscular; not to exceed 30 mg/day

Children over the age of 12 should be dosed as adults.

Pediatric Dosage Considerations

• The potential toxic dose for children under 6 years: 2 mg/kg

Side effects of codeine include:

• constipation
• drowsiness
• low blood pressure
• irregular heartbeat
• confusion
• dizziness
• false feeling of well-being
• headache
• lightheadedness
• a general feeling of discomfort (malaise)
• contradictory (paradoxical) central nervous system stimulation
• restlessness
• rash or hives
• loss of appetite
• nausea
• vomiting
• dry mouth
• bladder spasm with decreased urination
• increased liver function tests
• burning at the injection site
• weakness
• blurred vision
• difficulty breathing
• histamine release
• low blood pressure with IV use
• seizures with excessive doses
• respiratory depression

Rare side effects of Codeine include:

• severe allergic (anaphylactoid) reaction

Postmarketing side effects of Codeine reported include:

• severe low blood pressure
• life-threatening respiratory depression
• neonatal opioid withdrawal syndrome
• death related to ultra-rapid metabolizers of codeine
• adrenal insufficiency
• gastrointestinal adverse reactions
• seizures
• the feeling of excitement or happiness
• the feeling of unease or dissatisfaction
• abdominal pain
• itching
• sweating
• serotonin syndrome
• acute allergic reaction
• androgen deficiency

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Severe Interactions of Codeine include:
  • alvimopan
• Codeine has serious interactions with at least 22 different drugs.
• Codeine has moderate interactions with at least 220 different drugs.
• Codeine has minor interactions with at least 23 different drugs.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist. Check with your physician if you have health questions or concerns.

Warnings

Addiction, abuse, and misuse

• Risk of opioid addiction, abuse, and misuse, which can lead to overdose and death; assess each patient's risk before prescribing and monitor all patients regularly for the development of these behaviors or conditions

Life-threatening respiratory depression

• Serious, life-threatening, or fatal respiratory depression may occur
• Monitor for respiratory depression, especially during initiation or following a dose increase

Accidental ingestion

• Accidental ingestion of even 1 dose of codeine, especially by children, can result in a fatal overdose

Neonatal opioid withdrawal syndrome

• Prolonged use of codeine during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts
• If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

Death related to ultra-metabolism of codeine to morphine

• Respiratory depression and death were reported in children who received codeine following tonsillectomy and/or adenoidectomy that were also ultra-rapid metabolizers of codeine due to CYP2D6 polymorphism.

This medication contains codeine. Do not take codeine if you are allergic to codeine or any ingredients contained in this drug.

Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center immediately.

Contraindications

• Hypersensitivity to codeine
• Significant respiratory depression
• Postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy
• Acute or severe bronchial asthma in an unmonitored setting or the absence of resuscitative equipment
• Concurrent use of monoamine oxidase inhibitors (MAOI) or use of MAOI within the last 14 days
• Known or suspected gastrointestinal obstruction, including paralytic ileus

Effects of Drug Abuse

• Risk of opioid addiction, abuse, and misuse, which can lead to overdose and death; assess each patient's risk before prescribing and monitor all patients regularly for the development of these behaviors or conditions

Short-Term Effects

• Risk of life-threatening respiratory depression. Use caution not to drive or operate dangerous machinery until the effects and reactions to the medication are known.
• See also "What Are Side Effects Associated with Using Codeine?”

Long-Term Effects

• Risk of opioid addiction, abuse, and misuse, which can lead to overdose and death; assess each patient's risk before prescribing and monitor all patients regularly for the development of these behaviors or conditions
• Chronic use of opioids may cause reduced fertility in females and males of reproductive potential
• It is not known whether these effects on fertility are reversible
• See also "What Are Side Effects Associated with Using Codeine?”

Cautions

• Codeine sulfate tablets contain codeine, a schedule II controlled substance; as an opioid, codeine sulfate tablets exposes users to risks of addiction, abuse, and misuse; addiction can occur at recommended dosages and if drug is misused or abused; assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing codeine sulfate tablets, and monitor; risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (major depression); potential for these risks should not prevent proper management of pain in any given patient; patients at increased risk may be prescribed opioids such as codeine sulfate tablets, but use in such patients necessitates intensive counseling about risks and proper use of codeine sulfate along with intensive monitoring for signs of addiction, abuse, and misuse; prescribe the drug in smallest appropriate quantity and advise patient on proper disposal of unused drug
• Therapy may cause severely low blood pressure including low blood pressure when standing and fainting in ambulatory patients; there is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain central nervous system depressant drugs (phenothiazines or general anesthetics); monitor patients for signs of low blood pressure after initiating or altering dosage; in patients with circulatory shock, therapy may cause dilation of blood vessels that can further reduce cardiac output and blood pressure; avoid therapy in patients with circulatory shock
• In patients who may be susceptible to intracranial effects of CO2 retention (those with evidence of increased intracranial pressure or brain tumors), therapy may reduce respiratory drive, and resultant CO2 retention can further increase intracranial pressure; monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy; opioids may obscure clinical course in a patient with a head injury; avoid the use in patients with impaired consciousness or coma
• Avoid use in patients with known or suspected abdominal obstructions, including paralytic ileus; may cause spasm of the sphincter of Oddi; opioids may cause increases in serum amylase; monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms
• Therapy may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures; monitor patients with a history of seizure disorders for worsened seizure control during therapy
• Avoid the use of mixed agonist/antagonist (pentazocine, nalbuphine, and butorphanol) or partial agonist (buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic; mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms; when discontinuing therapy in a physically-dependent patient, gradually taper dosage; do not abruptly discontinue therapy in these patients
• Warn patients not to drive or operate dangerous machinery
• While serious, life-threatening, or fatal respiratory depression can occur at any time during therapy, the risk is greatest during initiation of therapy or following dosage increase; monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases; accidental ingestion of even one dose, especially by children, can result in respiratory depression and death due to overdose of codeine
• Deaths have occurred in nursing infants exposed to high levels of morphine in breast milk because mothers were ultra-rapid metabolizers of codeine
• Profound sedation, respiratory depression, coma, and death may result from simultaneous administration with benzodiazepines or other central nervous system depressants (non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, or alcohol); because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate
• Use in patients with acute or severe bronchial asthma in an unmonitored setting or absence of resuscitative equipment is contraindicated; patients with significant chronic obstructive pulmonary disease or cor pulmonale, and with substantially decreased respiratory reserve, oxygen deficiency, hypercapnia, or pre-existing respiratory depression are at increased risk of the decreased respiratory drive including apnea, even at recommended dosages
• Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients; monitor closely
• Monoamine oxidase inhibitors (MAOIs) may potentiate effects of morphine, codeine's active metabolite, including respiratory depression, coma, and confusion; therapy should not be administered within 14 days of taking MAOIs
• Cases of adrenal insufficiency reported with opioid use, more often following greater than one month of use; symptoms may include nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, and low blood pressure; if adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids; wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers; other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency
• Chronic use of opioids may cause reduced fertility in females and males of reproductive potential
• It is not known whether these effects on fertility are reversible
• 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 concomitant disease or other drug therapy; because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and may be useful to monitor renal function
• Codeine pharmacokinetics may be altered in patients with renal failure; clearance may be decreased and metabolites may accumulate much higher plasma levels in patients with renal failure as compared to patients with normal renal function; start with a lower than normal dosage or with longer dosing intervals and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension Use caution in cardiac arrhythmias, drug abuse/dependence, emotional lability, gallbladder disease, head injury, hepatic impairment, hypothyroidism, increased ICP, prostatic hypertrophy, renal impairment, seizures with epilepsy, urethral stricture, urinary tract surgery
• Do NOT give intravenously (IV), because of severe adverse reactions
• Risk of life-threatening side effects in nursing infants, especially if the mother is an ultra-rapid metabolizer of codeine
• Postoperative pain in children
• Prescribe alternate analgesia for postoperative pain control in children undergoing tonsillectomy and/or adenoidectomy
• Deaths have occurred in children with obstructive sleep apnea who received codeine for postoperative pain following tonsillectomy and/or adenoidectomy
• Codeine is converted to morphine by the liver; these children had evidence of being ultra-rapid metabolizers (via CYP2D6) of codeine, which is an inherited (genetic) ability that causes codeine to be converted rapidly into life-threatening or fatal amounts of morphine

Pregnancy and Lactation with Codeine

• Prolonged use of codeine or opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth; observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly; opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates; an opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate; codeine sulfate is not recommended for use in pregnant women during or immediately before labor when other analgesic techniques are more appropriate; opioid analgesics can prolong labor through actions which temporarily reduce strength, duration, and frequency of uterine contractions
• Codeine is secreted into human milk; in women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent; some women are ultra-rapid metabolizers of codeine; these women achieve higher-than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants that can potentially lead to serious adverse reactions, including death, in nursing infants
• Developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for therapy and any potential adverse effects on the breastfed infant from therapy or the underlying maternal condition