Codeine


Concise Prescribing Info
Indications/Uses
Listed in Dosage.
Dosage/Direction for Use
Adult : PO Mild to moderate pain 15-60 mg 4 hourly as needed. Max: 360 mg/day. Cough suppressant 15-30 mg 3-4 times/day. Acute diarrhoea 30 mg 3-4 times/day. IM Mild to moderate pain 30-60 mg 6 hourly as needed.
Dosage Details
Intramuscular
Mild to moderate pain
Adult: 30-60 mg 4 hourly as needed.
Child: ≥12 years 0.5-1 mg/kg 6 hourly as needed. Max: 240 mg daily.

Oral
Acute diarrhoea
Adult: 30 mg 3-4 times daily.
Elderly: Dose adjustment may be needed.

Oral
Mild to moderate pain
Adult: Initially, 15-60 mg 4 hourly as needed. Max: 360 mg daily.
Child: ≥12 years 0.5-1 mg/kg 6 hourly as needed. Max: 240 mg daily (60 mg/dose).
Elderly: Dose reduction may be needed.

Oral
Cough suppressant
Adult: 15-30 mg 3-4 times daily.
Elderly: Dose adjustment may be needed.
Special Patient Group
CYP2D6 is the major enzyme responsible for the conversion of codeine to morphine (higher potency). Genetic testing for CYP2D6 is recommended prior to initiation of codeine therapy, especially in young children and lactating mothers. CYP2D6 testing may also be considered in patients who does not respond to codeine therapy (possible poor metabolisers) or who have unexpected adverse effects (possible ultra-rapid metabolisers).

Ultra-rapid metabolisers (carriers of >2 copies of functional alleles e.g. *1/*1xN, *1/*2xN)
Avoid use of codeine due to increased morphine formation which may lead to higher risk of toxicity (e.g. respiratory depression). Analgesics which are not affected by CYP2D6 polymorphism (e.g. morphine, non-opioid analgesics) may be given as alternative. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5-1% in Chinese, Japanese, and Hispanics, 1-10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians, and Arabs.

Extensive metabolisers (carriers of 2 alleles encoding full or reduced function; or 1 full-function allele together with either 1 nonfunctional or 1 reduced-function allele e.g. *1/*1, *1/*2, *2/*2, *1/*41, *1/*4, *2/*5, *1/*10)
No dose adjustment needed.

Intermediate metabolisers (carriers of 1 reduced-function and 1 nonfunctional allele e.g. *4/*10, *5/*41)
No dose adjustment needed. If there is no response, may consider use of alternative analgesics (e.g. morphine, non-opioid analgesics).

Poor metabolisers (individuals not carrying any functional alleles e.g. *4/*4, *4/*5, *5/*5, *4/*6)
Avoid use of codeine due to reduced morphine formation, resulting in lack of efficacy. Analgesics which are not affected by CYP2D6 polymorphism (e.g. morphine, non-opioid analgesics) may be given as alternative.
Renal Impairment
Oral
Mild to moderate pain: Dose adjustment may be needed.

Intramuscular
Mild to moderate pain:
CrCl mL/min  Dosage
 <10  50% of normal dose. 
 10-<20  75% of normal dose.
Hepatic Impairment
Oral
Mild to moderate pain: Severe: Dose reduction or careful titration may be needed.

Intramuscular
Mild to moderate pain: Contraindicated.
Administration
May be taken with or without food.
Contraindications
Acute respiratory depression, comatose states, liver failure, acute or severe bronchial asthma, GI obstruction, paralytic ileus, abdominal distension, acute alcoholism, head injuries, increased intracranial pressure, diarrhoea caused by pseudomembranous colitis or poisoning. CYPD26 ultrarapid metabolisers. Hepatic impairment (IM inj). Children <12 years old; <18 years of age who undergo tonsillectomy and/or adenoidectomy; 12-18 years old who have other risk factors for respiratory depression; <18 years old (when used in the management of cough). Lactation. Concomitant or within 14 days of MAOI use.
Special Precautions
Patient with hypotension, hypothyroidism, prostatic hypertrophy, urethral stricture, adrenocortical insufficiency, acute abdominal conditions, biliary tract dysfunction (e.g. acute pancreatitis), inflammatory or obstructive bowel disorders, shock, convulsive disorders, myasthenia gravis, mental health conditions, toxic psychosis, history of drug abuse or acute alcoholism. Morbidly obese patients. CYP2D6 extensive, intermediate, and poor metabolisers. Renal and hepatic impairment. Children and elderly. Pregnancy.
Adverse Reactions
Significant: CNS depression, hypotension, constipation.
Blood and lymphatic system disorders: Lymphadenopathy, splenomegaly.
Cardiac disorders: Tachycardia, bradycardia, palpitations.
Endocrine disorders: Hyperglycaemia.
Eye disorders: Miosis, blurred or double vision.
Gastrointestinal disorders: Nausea, vomiting, dry mouth, pancreatitis, stomach cramps.
General disorders and administration site conditions: Fever, malaise, tiredness.
Hepatobiliary disorders: Biliary spasm.
Immune system disorders: Maculopapular rash.
Metabolism and nutrition disorders: Anorexia.
Musculoskeletal and connective tissue disorders: Muscular rigidity, uncontrolled muscle movements.
Nervous system disorders: Dizziness, headache, vertigo, raised intracranial pressure, convulsions.
Psychiatric disorders: Confusion, restlessness, mood disorder, mental depression, hallucinations, nightmares.
Renal and urinary disorders: Urinary retention, difficulty in micturition, dysuria.
Reproductive system and breast disorders: Sexual dysfunction, decreased libido.
Respiratory, thoracic and mediastinal disorders: Dyspnoea.
Skin and subcutaneous tissue disorders: Rash, pruritus, urticaria, sweating.
Vascular disorders: Hypotension.
Potentially Fatal: Respiratory depression.
Parenteral/PO: C
Patient Counseling Information
This drug may cause drowsiness or visual disturbances (e.g. blurred or double vision), if affected, do not drive or operate machinery.
MonitoringParameters
Monitor pain relief, blood pressure, heart rate, respiratory and mental status; development of addiction, abuse or misuse.
Overdosage
Symptoms: CNS or respiratory depression, pinpoint-sized pupil, nausea, vomiting, dry mouth, sweating, facial flushing, circulatory failure, muscle rigidity, nightmares, coma or excitement, and in children, convulsions. Management: Symptomatic and supportive treatment including airway clearing and monitoring of vital signs. Activated charcoal may be given within 1 hour of ingestion to reduce absorption. Administer naloxone if clinically significant respiratory or cardiac depression is present.
Drug Interactions
Increased risk of CNS or respiratory depression with benzodiazepines (e.g. anxiolytics, sedatives), anaesthetics, antihistamines, and sodium oxybate. Increased risk of severe constipation with anticholinergics and antidiarrhoeals. Quinidine may impair codeine metabolism. Cimetidine may increase plasma concentration of codeine. Delays the absorption of mexiletine. Antagonises the effect of domperidone, metoclopramide, cisapride.
Potentially Fatal: Severe CNS excitation or depression with MAOIs.
Food Interaction
Enhances the hypotensive, sedative, and respiratory depressive effects of alcohol.
Lab Interference
May interfere with gastric emptying studies and with hepatobiliary imaging using technetium Tc 99m disofenin.
Action
Description: Codeine is a phenantrene derivative opiate agonist which alters the perception of and response to pain by binding to opiate receptors in the CNS, blocking the ascending pain pathways. It also helps suppress cough by direct action in the medulla and appears to exert a drying effect on the respiratory tract mucosa, thus increasing the viscosity of bronchial secretions.
Onset: Analgesia: 0.5-1 hour (oral, immediate-release); 10-30 minutes (inj).
Duration: 4-6 hours.
Pharmacokinetics:
Absorption: Well absorbed from the gastrointestinal tract. Bioavailability: 53%. Time to peak plasma concentration: 1-1.5 hours.
Distribution: Crosses placenta and enters breast milk. Volume of distribution: Approx 3-6 L/kg. Plasma protein binding: Approx 7-25%.
Metabolism: Metabolised in the liver via O-demethylation by CYPD26 to morphine (active), N-demethylation by CYP3A4, and partial conjugation with glucuronic acid.
Excretion: Via urine (approx 90%, 10% as unchanged drug); faeces. Plasma half-life: 3-4 hours (oral/IM).
Storage
Store between 15-30°C. Protect from light.
ATC Classification
R05DA04 - codeine ; Belongs to the class of opium alkaloids and derivatives. Used as cough suppressant.
References
Chang KL, Weitzel K, Schmidt S. Pharmacogenetics: Using Genetic Information to Guide Drug Therapy. Am Fam Physician. 92(7):588-594. Accessed 18/09/2018. PMID: 26447442

Crews KR, Gaedigk A, Dunnenburger HM et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for Cytochrome P450 2D6 Genotype and Codeine Therapy: 2014 Update. CPIC Update. 2014 Apr;95(4):376-382. doi: 10.1038/clpt.2013.254. Accessed 11/09/2018

Dean L. Codeine Therapy and CYP2D6 Genotype. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US). Accessed 11/09/2018. PMID: 28520350

Annotation of CPIC Guideline for codeine and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 11/09/2018.

Annotation of FDA Label for Codeine and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 11/09/2018.

Anon. Codeine Phosphate (Analgesic). AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 07/08/2018.

Anon. Codeine Phosphate (Antitussive). AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 08/08/2018.

Anon. Codeine. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 01/08/2018.

Buckingham R (ed). Codeine. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 01/08/2018.

Clinical Annotation for CYP2D6*1, CYP2D6*10, CYP2D6*17, CYP2D6*1xN, CYP2D6*2, CYP2D6*2xN, CYP2D6*3, CYP2D6*4, CYP2D6*40, CYP2D6*41, CYP2D6*5, CYP2D6*6 Related to Codeine - Efficacy/Toxicity (1A). Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 11/09/2018.

Clinical Pharmacogenetics Implementation Consortium Guidelines for Cytochrome P450 2D6 Genotype and Codeine Therapy: 2014 Update . Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org/. Accessed 11/09/2018.

Codeine Phosphate Injection 60 mg in 1 mL (South Devon Healthcare). MHRA. https://products.mhra.gov.uk/. Accessed 12/09/2018.

Joint Formulary Committee. Codeine Phosphate. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 01/08/2018.

Disclaimer: This information is independently developed by MIMS based on Codeine from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in