Adult: Paracetamol 300 mg and codeine 15 mg tab Paracetamol 300 mg and codeine 30 mg tab
For the management of cases in which alternative treatments are inadequate: 1-2 tabs 4 hourly as needed. Max: 4,000 mg/360 mg per 24 hours.
Paracetamol 300 mg and codeine 60 mg tab
For the management of cases in which alternative treatments are inadequate: 1 tab 4 hourly as needed. Max: 4,000 mg/360 mg per 24 hours.
Paracetamol 120 mg and codeine 12 mg per 5 mL oral solution
For the management of cases in which alternative treatments are inadequate: 15 mL 4 hourly as needed. Max: 4,000 mg/360 mg per 24 hours. Dosage is individualised based on the severity of pain, patient response, opioid tolerance and prior analgesic experience. Use the lowest effective dose for the shortest possible duration. Dosage and treatment recommendations may vary among countries and between individual products (refer to specific product guidelines). Elderly: Initiate at the lower end of the dosing range.
Oral Moderate acute pain
Adult: Paracetamol 500 mg and codeine 8 mg tab Paracetamol 500 mg and codeine 8 mg effervescent tab Paracetamol 500 mg and codeine 8 mg cap
For cases not relieved using other analgesics: 1-2 tabs or caps 4-6 hourly as needed. Max: 8 caps or tabs in 24 hours.
Paracetamol 500 mg and codeine 15 mg tab Paracetamol 500 mg and codeine 15 mg effervescent tab Paracetamol 500 mg and codeine 15 mg cap
For cases not relieved using other analgesics: 2 tabs or caps 4-6 hourly as needed. Max: 8 caps or tabs in 24 hours.
Paracetamol 500 mg and codeine 30 mg per 5 mL oral solution
For cases not relieved using other analgesics: 5-10 mL (500 mg/30 mg to 1,000 mg/60 mg) up to 3-4 times daily; doses must not be given more frequently than 4-6 hourly. Max: 4 doses in 24 hours. Dosage is individualised based on the severity of pain, patient response, opioid tolerance and prior analgesic experience. Use the lowest effective dose for the shortest possible duration. Dosage and treatment recommendations may vary among countries and between individual products (refer to specific product guidelines). Elderly: Initiate at the lower end of the dosing range. Child: Paracetamol 500 mg and codeine 8 mg tab Paracetamol 500 mg and codeine 8 mg effervescent tab Paracetamol 500 mg and codeine 8 mg cap Paracetamol 500 mg and codeine 15 mg tab Paracetamol 500 mg and codeine 15 mg effervescent tab Paracetamol 500 mg and codeine 15 mg cap
For cases not relieved using other analgesics: 12-15 years 1 tab or cap 6 hourly as needed. Max: 4 caps or tabs in 24 hours; ≥16 years 1-2 tabs or caps 6 hourly as needed. Max: 8 caps or tabs in 24 hours.
Paracetamol 500 mg and codeine 30 mg per 5 mL oral solution
For cases not relieved using other analgesics: 12-15 years 5-7.5 mL (500 mg/30 mg to 750 mg/45 mg) up to 3-4 times daily; doses must not be given more frequently than 4-6 hourly; ≥16 years Same as adult dose. Max: 4 doses in 24 hours. Dosage is individualised based on the severity of pain, patient response, opioid tolerance and prior analgesic experience. Use the lowest effective dose for the shortest possible duration. Dosage and treatment recommendations may vary among countries and between individual products (refer to specific product guidelines).
Oral Moderate to severe pain
Adult: Paracetamol 500 mg and codeine 30 mg tab Paracetamol 500 mg and codeine 30 mg effervescent tab Paracetamol 500 mg and codeine 30 mg cap
For cases not relieved using other analgesics: 2 tabs or caps 4-6 hourly as needed. Max: 8 caps or tabs in 24 hours. Dosage is individualised based on the severity of pain, patient response, opioid tolerance and prior analgesic experience. Use the lowest effective dose for the shortest possible duration. Dosage and treatment recommendations may vary among countries and between individual products (refer to specific product guidelines). Elderly: Initiate at the lower end of the dosing range. Child: Paracetamol 500 mg and codeine 30 mg tab Paracetamol 500 mg and codeine 30 mg effervescent tab Paracetamol 500 mg and codeine 30 mg cap
For cases not relieved using other analgesics: 12-15 years 1 tab or cap 6 hourly as needed. Max: 4 caps or tabs in 24 hours; ≥16 years 1-2 tabs or caps 6 hourly as needed. Max: 8 caps or tabs in 24 hours. Dosage is individualised based on the severity of pain, patient response, opioid tolerance and prior analgesic experience. Use the lowest effective dose for the shortest possible duration. Dosage and treatment recommendations may vary among countries and between individual products (refer to specific product guidelines).
What are the brands available for Paracetamol + Codeine in Hong Kong?
Codeine, an opioid analgesic prodrug, is metabolised in the liver via O-demethylation by CYP2D6 into its active metabolite, morphine. Polymorphisms in the CYP2D6 gene may lead to elevated morphine levels, potentially resulting in toxic systemic concentrations even at low doses or reduced morphine levels, leading to an attenuated analgesic effect. Genetic testing should be considered for both children and adults prior to initiating codeine therapy to identify individuals predisposed to adverse effects.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of December 2020:
Phenotype
Implications
Recommendations
CYP2D6 ultrarapid metaboliser (activity score range of >2.25)
Increased morphine formation, thereby increasing the risk of toxicity.
Avoid the use of codeine. Consider the administration of non-tramadol opioids if opioid use is preferred.
CYP2D6 intermediate metaboliser (activity score 0 < x ≤2.25)
Decreased morphine formation.
No dose adjustment is needed. If there is no response and opioid use is preferred, consider the administration of non-tramadol opioids.
CYP2D6 poor metaboliser (activity score range 0)
Greatly decreased morphine formation, resulting in decreased analgesia.
Avoid the use of codeine. Consider the administration of non-tramadol opioids if opioid use is preferred.
Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline as of November 2018:
Phenotype
Implications
Recommendations
CYP2D6 ultrarapid metaboliser
Increased conversion to morphine thereby increases the risk of adverse effects.
Morphine may be used as an alternative; CYP2D6 metabolises oxycodone to a certain extent (this does not cause any differences in side effects in patients); avoid the use of tramadol.
CYP2D6 intermediate metaboliser
Decreased conversion to morphine, resulting in decreased analgesic effect.
Due to the limited data available, recommendations for dosage adjustment are not possible (refer to international guidelines). Monitor for reduced efficacy. For cases of reduced efficacy, doses may be increased. If the desired effect is not achieved, morphine may be used as an alternative; CYP2D6 metabolises oxycodone to a certain extent (this does not cause any differences in side effects in patients); avoid the use of tramadol. Report for inadequate analgesia if no alternative agent is selected.
CYP2D6 poor metaboliser
Decreased conversion to morphine, resulting in decreased analgesic effect.
Due to the limited data available, recommendations for dosage adjustment are not possible (refer to international guidelines). Morphine may be used as an alternative; CYP2D6 metabolises oxycodone to a certain extent (this does not cause any differences in side effects in patients); avoid the use of tramadol. Report for inadequate analgesia if no alternative agent is selected.
Renal Impairment
Dose reduction may be needed.
Hepatic Impairment
Severe: Contraindicated.
Contraindications
Significant respiratory depression, acute or severe bronchial asthma (in unmonitored setting or lack of resuscitative equipment), suspected or known gastrointestinal obstruction (e.g. paralytic ileus), diarrhoea caused by poisoning or pseudomembranous colitis. CYP2D6 ultrarapid metabolisers. Severe hepatic impairment. Children <12 years; <18 years who have undergone adenoidectomy and/or tonsillectomy. Lactation. Concomitant use or within 14 days after MAOI therapy.
Special Precautions
Patient with hypersensitivity to other phenanthrene-derivative opioid agonists (e.g. hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone); significant COPD or cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, pre-existing respiratory depression; CV disease (e.g. MI), hypovolaemia, hypotension, circulatory shock; delirium tremens, toxic psychosis, mental health conditions (e.g. anxiety disorders, depression, PTSD), current or history of substance abuse; history of seizure disorders; myasthenia gravis, sleep-related disorders (e.g. sleep apnoea); impaired consciousness or coma; head injury, intracranial lesions, elevated ICP; adrenal insufficiency (including Addison's disease); thyroid dysfunction (e.g. hypothyroidism); acute abdominal conditions, intestinal motility disorders, biliary tract dysfunction (including acute pancreatitis); prostatic hyperplasia and/or urinary stricture; G6PD deficiency. Avoid use in children who have risk factors for respiratory depression. Avoid abrupt withdrawal. Not recommended for long-term use. CYP2D6 intermediate and poor metabolisers. Morbidly obese, cachectic or debilitated patients. Renal and mild to moderate hepatic impairment. Children (≥12 years) and elderly. Pregnancy.
Adverse Reactions
Significant: CNS depression, constipation, obstructive bowel disease (chronic use), hypersensitivity and anaphylactic reactions, opioid-induced hyperalgesia; severe hypotension including syncope and orthostatic hypotension; secondary hypogonadism (long-term use) which may lead to mood disorders and osteoporosis; constriction of sphincter of Oddi, exaggerated ICP elevation, seizure exacerbation. Blood and lymphatic system disorders: Agranulocytosis, thrombocytopenia. Cardiac disorders: Bradycardia, palpitations. Eye disorders: Miosis, blurred or double vision. Gastrointestinal disorders: Nausea, vomiting, abdominal pain, dyspepsia, dry mouth. Nervous system disorders: Dizziness, drowsiness, headache. Psychiatric disorders: Agitation, confusion, dysphoria, euphoria, hallucinations. Renal and urinary disorders: Urinary retention. Respiratory, thoracic and mediastinal disorders: Dyspnoea. Skin and subcutaneous tissue disorders: Skin rash, urticaria, pruritus, hyperhidrosis. Vascular disorders: Flushing. Potentially Fatal: Respiratory depression; opioid addiction, abuse and misuse; neonatal opioid withdrawal syndrome (prolonged use during pregnancy); acute liver failure (in paracetamol doses >4,000 mg daily) resulting in liver transplant. Rarely, serious skin reactions such as acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN).
This drug may cause dizziness, sedation and changes in vision (e.g. blurred vision), if affected, do not drive or operate machinery.
Monitoring Parameters
Monitor pain relief, bowel function, blood pressure, heart rate and respiratory or mental status. Assess for signs and symptoms of substance abuse, misuse or addiction; hypogonadism or hypoadrenalism.
Overdosage
Paracetamol: Abdominal pain, anorexia, nausea, vomiting, diaphoresis, pallor, abnormalities of glucose metabolism, metabolic acidosis; liver damage may manifest 12-48 hours after the ingestion; acute renal failure with acute tubular necrosis, haematuria and proteinuria (may develop even in the absence of severe hepatic failure); cardiac arrhythmias and pancreatitis. In severe cases, hepatic failure may lead to disseminated intravascular coagulation, encephalopathy, hypoglycaemia and haemorrhage. Codeine: Nausea, vomiting, constricted or pinpoint pupils, marked mydriasis with hypoxia, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, pulmonary oedema, bradycardia, hypotension, hypoglycaemia, atypical snoring, partial or complete airway obstruction, bradycardia, tachycardia, convulsions and respiratory depression. Management: Symptomatic and supportive treatment. Re-establish adequate respiratory exchange. Employ the use of vasopressor agents and oxygen as needed. Empty the stomach to remove any unabsorbed drug. Administer activated charcoal if it is within 1 hour of the overdose. Obtain plasma paracetamol concentration at 4 hours or later following ingestion. Administration of acetylcysteine may be applicable for up to 24 hours after ingestion (most effective if given within 8 hours); if needed, IV administration of acetylcysteine may be given. Alternatively, oral methionine may be given. Administer naloxone if clinically significant respiratory or circulatory depression is present. Perform advanced life-support techniques for arrhythmias and cardiac arrest.
Drug Interactions
Paracetamol: Increased risk of high anion gap metabolic acidosis with flucloxacillin. Concomitant use of other potentially hepatotoxic drugs or drugs that induce liver microsomal enzymes (e.g. carbamazepine, phenobarbital, phenytoin, topiramate, rifampicin) may increase the risk of paracetamol toxicity. Reduced absorption with colestyramine. Increased absorption with metoclopramide and domperidone. Prolonged use of paracetamol may enhance the anticoagulant effect of warfarin and other coumarins.
Codeine: May increase the serum concentration of the active metabolites of codeine with CYP3A4 inhibitors (e.g. erythromycin, ketoconazole, ritonavir). May decrease the serum concentration of the active metabolites of codeine with CYP3A4 inducer (e.g. rifampicin, carbamazepine, phenytoin). Concomitant use with CYP2D6 inhibitors (e.g. amiodarone, quinidine) may diminish the therapeutic effect of codeine. Increased risk of severe constipation with anticholinergics and antidiarrhoeal drugs. May enhance the effect of neuromuscular blocking drugs. Potentially Fatal: Codeine: Increased risk of profound sedation, hypotension, respiratory depression and coma with benzodiazepines or other CNS depressants. Concomitant use with MAOIs may increase the risk of respiratory depression, confusion and coma. Increased risk of serotonin syndrome with serotonergic drugs such as SSRIs, SNRIs, TCAs, triptans, 5-HT3 receptor antagonists, certain muscle relaxants (e.g. metaxalone) and MAOIs.
Food Interaction
Paracetamol: May increase the risk of hepatotoxicity with alcohol.
Codeine: Increased risk of profound sedation, respiratory depression and coma with alcohol.
Lab Interference
Paracetamol: May result in false-positive urinary 5-hydroxyindoleacetic acid.
Codeine: May interfere with gastric emptying studies. May increase biliary tract pressure, leading to elevated plasma amylase or lipase levels
Action
Description: Mechanism of Action: Paracetamol is a synthetic, non-opiate para-aminophenol derivative that exhibits analgesic and antipyretic properties with weak anti-inflammatory activity. The exact mechanism of its analgesic effect remains unclear but may involve the activation of descending serotonergic inhibitory pathways in the CNS and interactions with other nociceptive systems. Additionally, its antipyretic effect is mediated by inhibiting the hypothalamic heat-regulating centre.
Codeine, a phenanthrene derivative, is an opioid agonist. It binds to μ-opioid receptors in the CNS, leading to inhibition of ascending pain pathways and alteration of both the perception of and response to pain. Synonym(s): Paracetamol: Acetaminophen. Onset: Paracetamol: <1 hour.
Codeine: 0.5-1 hour. Duration: Paracetamol: 4-6 hours (analgesia).
Codeine: 4-6 hours. Pharmacokinetics: Absorption: Paracetamol: Readily absorbed from the gastrointestinal tract, mainly in the small intestine with minimal absorption from the stomach. Time to peak plasma concentration: 10-60 minutes.
Codeine: Well absorbed from the gastrointestinal tract. Bioavailability: 53%. Time to peak plasma concentration: 1 hour. Distribution: Crosses the placenta and enters breast milk.
Paracetamol: Uniformly and rapidly distributed into most body tissues except fat. Plasma protein binding: 10-25%.
Codeine: Volume of distribution: Approx 3-6 L/kg. Plasma protein binding: Approx 7-25%. Metabolism: Paracetamol: Metabolised mainly in the liver into sulfate and glucuronide conjugates, while a small amount is metabolised by CYP2E1 to a minor hydroxylated metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which is conjugated rapidly by glutathione and inactivated to non-toxic cysteine and mercapturic acid conjugates. Undergoes first-pass metabolism.
Codeine: Metabolised in the liver via glucuronidation by UGT2B7 and UGT2B4 into codeine-6-glucuronide, via O-demethylation by CYP2D6 into morphine, and via N-demethylation by CYP3A4 into norcodeine. Morphine (active metabolite) is further metabolised via glucuronidation into morphine-3-glucuronide and morphine-6-glucuronide (active metabolite). Excretion: Paracetamol: Mainly via urine (60-80% as glucuronide metabolites; 20-30% as sulfate metabolites; approx 8% as cysteine and mercapturic acid metabolites; <5% as unchanged drug). Elimination half-life: Approx 1-3 hours.
Codeine: Via urine (approx 90%; approx 10% as unchanged drug); faeces. Elimination half-life: Approx 3 hours.
Chemical Structure
Paracetamol Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 1983, Acetaminophen. https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen. Accessed Sept. 25, 2024.
Codeine Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 5284371, Codeine. https://pubchem.ncbi.nlm.nih.gov/compound/Codeine. Accessed Mar. 25, 2024.
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