1 Name of Medicine
Paracetamol and codeine phosphate hemihydrate.
2 Qualitative and Quantitative Composition
Each tablet contains paracetamol 500 mg and codeine phosphate hemihydrate 15 mg.
List of excipients with known effects: sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Paracetamol/Codeine GH 500/15 tablets are white to off-white capsule shaped uncoated tablets, plain on one side and breakline on the other side.
4.1 Therapeutic Indications
For the relief of acute moderate pain and fever.
4.2 Dose and Method of Administration
Adults and children over 12 years.
2 tablets every four to six hours as required (maximum 8 tablets in 24 hours).
Use in children under 12 years is contraindicated.4.3 Contraindications
Hypersensitivity to paracetamol or codeine or other ingredients.
It must not be used in patients with known glucose-6-phosphate-dehydrogenase deficiency or severe respiratory disease, acute respiratory disease and respiratory depression, for example acute asthma, acute exacerbations of chronic obstructive pulmonary disease since codeine may exacerbate the condition.
Paracetamol should not be used in patients with a history of intolerance to the drug.
Paracetamol should not be used in patients with severe hepatocellular insufficiency.
Due to codeine's structural similarity to morphine and oxycodone, patients experiencing systemic allergy (generalised rash, shortness of breath) to these drugs should not receive codeine.
Codeine is contraindicated in patients with diarrhoea caused by poisoning, until the toxic substance has been eliminated from the gastrointestinal tract, or diarrhoea associated with pseudomembranous colitis caused by antibiotic administration since codeine may slow the elimination of the toxic material or antibiotic.
Paracetamol should not be used in patients with active alcoholism as chronic excessive alcohol ingestion predisposes patients to paracetamol hepatotoxicity.
Paracetamol/Codeine GH 500/15 is contraindicated during breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).
Paracetamol/Codeine GH 500/15 is contraindicated in patients younger than 12 years of age (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
Paracetamol/Codeine GH 500/15 is contraindicated in patients aged between 12-18 years in whom respiratory function might be compromised, including post tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, due to an increased risk of developing serious and life-threatening adverse reactions (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
Paracetamol/Codeine GH 500/15 is also contraindicated for use in patients who are CYP2D6 ultra-rapid metabolisers (see Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism).
Paracetamol/Codeine GH 500/15 is contraindicated in the event of impending childbirth or in case of risk of premature birth.
4.4 Special Warnings and Precautions for Use
Hepatotoxicity may occur with paracetamol even at therapeutic doses, after short treatment duration and in patients without pre-existing liver dysfunction.
In view of the increased risk of hepatotoxicity, the benefit should be weighed against the risk when administering Paracetamol/Codeine GH 500/15 to patients with viral hepatitis or pre-existing hepatic disease. In such patients, hepatic function determinations may be required at periodic intervals during high dose or long-term therapy.
To avoid the risk of overdose, check that paracetamol is absent from the composition of other medicinal products taken concomitantly.
Codeine should be used with caution in patients with CNS depression or decreased respiratory reserve e.g. in emphysema, kyphoscoliosis, hypoxia, hypercapnia or even severe obesity or cor pulmonale, or chronic obstructive pulmonary disease. Codeine may exacerbate respiratory impairment and CNS depression.
Codeine should be administered with caution in patients with impaired cardiac, hepatic or renal function, hypotension, benign prostatic hyperplasia, urethral stenosis, chronic colitis ulcerative, gallbladder conditions, multiple sclerosis, hypothyroidism, adrenocortical insufficiency (e.g. Addison's disease), shock, myxoedema, acute alcohol intoxication or delirium tremens since codeine may exacerbate the symptoms or increase the risk of respiratory and/or CNS depression.
Codeine should be administered with great caution in patients with head injury, brain tumour or increased intracranial pressure since codeine may increase the risk of respiratory depression and further elevate intracranial pressure. In addition, codeine can produce side effects such as confusion, miosis and vomiting which are important signs in following the clinical course of patients with head injuries.
Extensive use of analgesics to relieve headaches or migraines, especially at high doses, may induce headaches that must not be treated with increased doses of the drug. In such cases the analgesic should not continue to be taken without medical advice.
Monitoring after prolonged use should include blood count, liver function and renal function.
Codeine should only be used after careful risk-benefit assessment in case of:
Opioid dependence.
Chronic constipation.
Conditions with elevated intracranial pressure and head trauma. Codeine can increase the pressure of cerebrospinal fluid and may increase the respiratory depressant effect. Like other narcotics, it causes adverse reactions that can obscure the clinical course of patients with head injury.
Impaired consciousness.
Compromised respiratory function (due to emphysema, kyphoscoliosis, severe obesity) and chronic obstructive airway disease.
Patients with known analgesic intolerance or known bronchial asthma must only use Paracetamol/Codeine GH 500/15 after having consulted a physician (hypersensitivity reactions including bronchospasm possible).
Caution is advised in patients with underlying sensitivity to aspirin and/or to non-steroidal anti-inflammatory drugs (NSAIDs).
Severe cutaneous adverse reactions (SCARs).
Life threatening cutaneous reactions Stevens-Johnson syndrome (SJS), and Toxic Epidermal Necrolysis (TEN) have been reported with the use of paracetamol. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. If symptoms or signs of SJS and TEN (e.g. progressive skin rash often with blisters or mucosal lesions) occur, patients should stop paracetamol treatment immediately and seek medical advice.
Paracetamol should be used upon medical advice in patients with:
Mild to moderate hepatocellular insufficiency (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).
Severe renal insufficiency (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).
Chronic alcohol use including recent cessation of alcohol intake.
Low glutathione reserves.
Gilbert's syndrome.
Codeine should be administered with caution in patients with acute abdominal conditions since codeine may obscure the diagnosis or the course of the disease. Codeine should be administered with caution in patients with severe inflammatory bowel disease (risk of toxic megacolon may be increased, especially with repeated dosing). Paracetamol/Codeine GH 500/15 should also be used with caution in patients who have had recent gastrointestinal tract surgery.
Patients who have had a cholecystectomy should be treated with caution. The contraction of the sphincter of Oddi can cause symptoms resembling those of myocardial infarction or intensify the symptoms in patients with pancreatitis.
Codeine should be administered with caution in patients with a history of convulsive disorders (convulsions may be induced or exacerbated by codeine).
Codeine should be administered with caution in patients with prostatic hypertrophy, urethral structure or recent urinary tract surgery since codeine may cause urinary retention.
Codeine should be used with caution in elderly or debilitated patients because of the danger of respiratory or cardiac depression.
Codeine should be administered with caution in patients taking Monoamine Oxidase Inhibitors (MAOIs) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
The concomitant use of opioids with gabapentinoids (gabapentin and pregabalin) increases the risk of respiratory depression, hypotension, profound sedation, coma or death because of additive CNS depressant effect.
CYP2D6 metabolism.
Paracetamol/Codeine GH 500/15 is contraindicated for use in patients who are CYP2D6 ultra-rapid metabolisers.
Codeine is metabolised by the liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect will not be obtained.
However, if the patient is an extensive or ultra-rapid metaboliser, there is an increased risk of developing side effects of opioid toxicity even at commonly prescribed doses. These patients convert codeine into morphine rapidly resulting in higher than expected serum morphine levels. General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation, and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life-threatening and very rarely fatal. Children are particularly susceptible due to their immature airway anatomy. Deaths have been reported in children with rapid metabolism who were given codeine for analgesia post adenotonsillectomy. Morphine can also be ingested by infants through breast milk, causing risk of respiratory depression to infants of rapid metaboliser mothers who take codeine. The prevalence of codeine ultra-rapid metabolism by CYP2D6 in children is not known, but is assumed to be similar to that reported in adults. The prevalence of ultra-rapid metabolisers differs according to racial and ethnic group. It is estimated to be 1% in those of Chinese, Japanese and Hispanic descent, 3% in African Americans and 1%-10% in Caucasians. The highest prevalence (16-28%) occurs in North African, Ethiopian and Arab populations. (Also see Section 4.4 Special Warnings and Precautions for Use, Paediatric use; Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).
Hazardous and harmful use.
Paracetamol/Codeine GH 500/15 contains the opioid codeine and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Paracetamol/Codeine GH 500/15 at recommended doses.
The risk of addiction is increased in patients with a personal or family history of substance abuse (including alcohol and prescription and illicit drugs) or mental illness. The risk also increases the longer the drug is used and with higher doses. Patients should be assessed for their risks for opioid abuse or addiction prior to being prescribed Paracetamol/Codeine GH 500/15.
There have been reports of drug abuse with codeine, including cases in children and adolescents. Caution is particularly recommended for use in children, adolescents, young adults and in patients with a history of drug and/or alcohol abuse. (See Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
All patients receiving opioids should be routinely monitored for signs of misuse and abuse. Opioids are sought by people with addiction and may be subject to diversion. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the safe storage and proper disposal of any unused drug (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal). Caution patients that abuse of oral or transdermal forms of opioids by parenteral administration can result in serious adverse events, which may be fatal.
Patients should be advised not to share Paracetamol/Codeine GH 500/15 with anyone else.
Respiratory depression.
Serious, life-threatening or fatal respiratory depression can occur with the use of opioids even when used as recommended. It can occur at any time during the use of Paracetamol/Codeine GH 500/15 but the risk is greatest during initiation of therapy or following an increase in dose. Patients should be monitored closely for respiratory depression at these times.
The risk of life-threatening respiratory depression is also higher in elderly, frail, or debilitated patients, in patients with hepatic and renal impairment (see Use in hepatic impairment and Use in renal impairment, below) and in patients with existing impairment of respiratory function (e.g. chronic obstructive pulmonary disease; asthma). Opioids should be used with caution and with close monitoring in these patients. The use of opioids is contraindicated in patients with severe respiratory disease, acute respiratory disease and respiratory depression (see Section 4.3 Contraindications).
The risk of respiratory depression is greater with the use of high doses of opioids, especially high potency and modified release formulations, and in opioid naïve patients. Initiation of opioid treatment should be at the lower end of the dosage recommendations with careful titration of doses to achieve effective pain relief. Careful calculation of equianalgesic doses is required when changing opioids or switching from immediate release to modified release formulations together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response.
Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol.
Concomitant use of opioids and benzodiazepines or other CNS depressants, including alcohol, may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of Paracetamol/Codeine GH 500/15 with CNS depressant medicines, such as other opioid analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti-emetics and other CNS depressants, should be reserved for patients for whom other treatment options are not possible. If a decision is made to prescribe Paracetamol/Codeine GH 500/15 concomitantly with any of the medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible. Patients should be followed closely for signs and symptoms of respiratory depression and sedation. Patients and their caregivers should be made aware of these symptoms. Patients and their caregivers should also be informed of the potential harms of consuming alcohol while taking Paracetamol/Codeine GH 500/15.
Use of opioids in chronic (long-term) non-cancer pain (CNCP).
Opioid analgesics have an established role in the treatment of acute pain, cancer pain and palliative and end-of-life care. Current evidence does not generally support opioid analgesics in improving pain and function for most patients with chronic non-cancer pain. The development of tolerance and physical dependence and risks of adverse effects, including hazardous and harmful use, increase with the length of time a patient takes an opioid. The use of opioids for long-term treatment of CNCP is not recommended.
The use of an opioid to treat CNCP should only be considered after maximised non-pharmacological and non-opioid treatments have been tried and found ineffective, not tolerated or otherwise inadequate to provide sufficient management of pain. Opioids should only be prescribed as a component of comprehensive multidisciplinary and multimodal pain management.
Opioid therapy for CNCP should be initiated as a trial in accordance with clinical guidelines and after a comprehensive biopsychosocial assessment has established a cause for the pain and the appropriateness of opioid therapy for the patient (see Hazardous and harmful use, above). The expected outcome of therapy (pain reduction rather than complete abolition of pain, improved function and quality of life) should be discussed with the patient before commencing opioid treatment, with agreement to discontinue treatment if these objectives are not met.
Owing to the varied response to opioids between individuals, it is recommended that all patients be started at the lowest appropriate dose and titrated to achieve an adequate level of analgesia and functional improvement with minimum adverse reactions. Immediate-release products should not be used to treat chronic pain, but may be used for a short period in opioid-naïve patients to develop a level of tolerance before switching to a modified-release formulation. Careful and regular assessment and monitoring is required to establish the clinical need for ongoing treatment. Discontinue opioid therapy if there is no improvement of pain and/or function during the trial period or if there is any evidence of misuse or abuse. Treatment should only continue if the trial has demonstrated that the pain is opioid responsive and there has been functional improvement. The patient's condition should be reviewed regularly and the dose tapered off slowly if opioid treatment is no longer appropriate (see Ceasing opioids, below).
Tolerance, dependence and withdrawal.
Neuroadaptation of the opioid receptors to repeated administration of opioids can produce tolerance and physical dependence. Tolerance is the need for increasing doses to maintain analgesia. Tolerance may occur to both the desired and undesired effects of the opioid.
Physical dependence, which can occur after several days to weeks of continued opioid usage, results in withdrawal symptoms if the opioid is ceased abruptly or the dose is significantly reduced. Withdrawal symptoms can also occur following the administration of an opioid antagonist (e.g. naloxone) or partial agonist (e.g. buprenorphine). Withdrawal can result in some or all of the following symptoms: dysphoria, restlessness/agitation, lacrimation, rhinorrhoea, yawning, sweating, chills, myalgia, mydriasis, irritability, anxiety, increasing pain, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, increased blood pressure, increased respiratory rate and increased heart rate.
When discontinuing Paracetamol/Codeine GH 500/15 in a person who may be physically-dependent, the drug should not be ceased abruptly but withdrawn by tapering the dose gradually (see Ceasing opioids, below).
Accidental ingestion/exposure.
Accidental ingestion or exposure of Paracetamol/Codeine GH 500/15, especially by children, can result in a fatal overdose of codeine. Patients and their caregivers should be given information on safe storage and disposal of unused Paracetamol/Codeine GH 500/15 (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal).
Hyperalgesia.
Hyperalgesia may occur with the use of opioids, particularly at high doses. Hyperalgesia may manifest as an unexplained increase in pain, increased levels of pain with increasing opioid dosages or diffuse sensitivity not associated with the original pain. Hyperalgesia should not be confused with tolerance (see Tolerance, dependence and withdrawal, above). If opioid induced hyperalgesia is suspected, the dose should be reduced and tapered off if possible. A change to a different opioid may be required.
Opioid-induced hyperalgesia or allodynia.
Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain (hyperalgesia), or an increase in sensitivity to pain (allodynia). This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect.
Symptoms of OIH include increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). The pain experienced may be at the same location of the underlying pain or can be more generalised or widespread in nature. These symptoms may suggest the occurrence of OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behaviour.
If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (safety switching the patient to a different opioid moiety).
Ceasing opioids.
Abrupt discontinuation or rapid decreasing of the dose in a person physically dependent on an opioid may result in serious withdrawal symptoms and uncontrolled pain (see Tolerance, dependence and withdrawal, above). Such symptoms may lead the patient to seek other sources of licit or illicit opioids. Opioids should not be ceased abruptly in a patient who is physically dependent but withdrawn by tapering the dose slowly. Factors to take into account when deciding how to discontinue or decrease therapy include the dose and duration of the opioid the patient has been taking, the type of pain being treated and the physical and psychological attributes of the patient. A multimodal approach to pain management should be in place before initiating an opioid analgesic taper. During tapering, patients require regular review and support to manage any increase in pain, psychological distress and withdrawal symptoms.
There are no standard tapering schedules suitable for all patients and an individualised plan is necessary. In general, tapering should involve a dose reduction of no more than 10 percent to 25 percent every 2 to 4 weeks. If the patient is experiencing increased pain or serious withdrawal symptoms, it may be necessary to go back to the previous dose until stable before proceeding with a more gradual taper.
When ceasing opioids in a patient who has a suspected opioid use disorder, the need for medication assisted treatment and/or referral to a specialist should be considered.
Use in hepatic impairment.
Paracetamol/Codeine GH 500/15 should be administered with caution to patients with hepatic dysfunction, viral hepatitis, and to patients taking other drugs which affect the liver.
Use in renal impairment.
Paracetamol/Codeine GH 500/15 should be administered with caution to patients with renal dysfunction.
Use in the elderly.
Elderly people may be more sensitive to the effects of this medicinal product, especially respiratory depression. The elderly are more likely to have hypertrophy, prostatic obstruction and age-related renal impairment and may be more susceptible to the undesirable effects due to opioid-induced urinary retention and the respiratory effects of opioid analgesics. Dose reduction may be required.
Paediatric use.
This product is contraindicated for use in children:
younger than 12 years;
aged between 12-18 years in whom respiratory function might be compromised, including post tonsillectomy and/or adenoidectomy for obstructive sleep apnoea. Respiratory depression and death have occurred in some children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolisers of codeine due to a CYP2D6 polymorphism (see Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism).
Effects on laboratory tests.
Plasma amylase and lipase activity.
Codeine may cause increased biliary tract pressure, thus increasing plasma amylase and/or lipase concentrations.
Gastric emptying studies.
Gastric emptying is delayed by codeine so gastric emptying studies will not be valid.
Uric acid and blood glucose.
Intake of paracetamol may affect the laboratory determination of uric acid by phosphotungstic acid and of blood glucose by glucose oxidase-peroxidase.4.5 Interactions with Other Medicines and Other Forms of Interactions
Salicylates and NSAIDs.
Prolonged concurrent use of paracetamol and salicylates or non-steroidal anti-inflammatory drugs may increase the risk of adverse renal effects.
Coumarins.
Paracetamol may increase the risk of bleeding in patients taking warfarin and other antivitamin K. Patients should be monitored for appropriate coagulation and bleeding complications.
Chloramphenicol.
Paracetamol may slow down the excretion of chloramphenicol, entailing the risk of increased toxicity.
Diflunisal.
Diflunisal may increase the plasma concentrations of paracetamol by 50%.
Anticholinergics.
Concomitant use of codeine and anticholinergic agents may increase the risk of severe constipation and/or urinary retention. Drugs, which decrease gastric emptying may decrease the absorption of paracetamol.
Cholestyramine.
Cholestyramine reduces the absorption of paracetamol if given within one hour of paracetamol administration.
Chelating resin.
Chelating resin can decrease the intestinal absorption of paracetamol and potentially decrease its efficacy if taken simultaneously. In general, there must be an interval of more than 2 hours between taking the resin and taking paracetamol, if possible.
Propantheline.
Decreases gastric emptying which may decrease the absorption of paracetamol.
Alcohol.
Codeine may potentiate the effects of alcohol. The concomitant use of alcohol and opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. Concomitant use with alcohol is not recommended (see Section 4.4 Special Warnings and Precautions for Use).
Flucloxacillin.
Co-administration of flucloxacillin with paracetamol may lead to metabolic acidosis, particularly in patients presenting risk factors of glutathione depletion, such as sepsis, malnutrition or chronic alcoholism.
Metoclopramide.
Codeine may antagonise the effects of metoclopramide on gastrointestinal motility. Paracetamol absorption is increased by drugs, which increase gastric emptying.
Domperidone.
The absorption rate of paracetamol may be increased by domperidone.
Opioid analgesics.
Concurrent use of codeine and other opioid agonists is usually inappropriate as additive CNS depression, respiratory depressant and hypotensive effects may occur. Narcotic analgesics may decrease gastric emptying and therefore decrease the absorption of paracetamol.
Morphinic agonists-antagonists.
Concomitant use of codeine with a partial agonist (e.g. buprenorphine) or antagonist (e.g. naltrexone) can precipitate or delay codeine effects.
Tranquillisers, sedatives, hypnotics, general anaesthetics and CNS depressants.
Codeine may potentiate the effects of these drugs. Concomitant use of tranquillisers or sedatives may enhance the potential respiratory depressant effects of codeine. The concomitant use of benzodiazepines and opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. Limit dosage and duration of concomitant use of benzodiazepines and opioids (see Section 4.4 Special Warnings and Precautions for Use).
Hepatotoxic drugs and liver microsomal enzyme inducers.
The risk of paracetamol toxicity may be increased in patients receiving other potentially hepatotoxic drugs or drugs that induce liver microsomal enzymes, such as antiepileptics (such as phenobarbital, phenytoin, carbamazepine, topiramate), barbiturates, rifampicin and alcohol.
Zidovudine.
When used concurrently with zidovudine, an increased tendency for neutropenia or hepatotoxicity may develop. Combination of Paracetamol/Codeine GH 500/15 and zidovudine should be avoided. If chronic paracetamol and zidovudine are to be given concurrently, monitor white blood cell count and liver function tests, especially in malnourished patients.
Antiperistaltic antidiarrhoeals (including kaolin, pectin, loperamide).
Concurrent use of these agents with codeine may increase the risk of severe constipation and CNS depression.
Monoamine oxidase inhibitors.
Non-selective MAOI's intensify the effects of opioid drugs, which can cause anxiety, confusion and significant respiratory depression and other side effects of unpredictable severity. Severe and sometimes fatal reactions have occurred in patients concurrently administered MAO inhibitors and pethidine. Codeine should not be given to patients taking non-selective MAOI's or within two weeks of stopping such treatment. As it is unknown whether there is an interaction between the selective MAOI's (Reversible Inhibitors of Monoamine Oxidase A) and codeine, caution is advised with this drug combination.
Tricyclic antidepressants.
A codeine-induced respiratory depression can be potentiated by tricyclic antidepressants.
Antihypertensives.
Hypotensive effects of antihypertensive agents may be potentiated when used concurrently with codeine and lead to orthostatic hypotension.
Neuromuscular blocking agents.
Codeine may enhance the effects of neuromuscular blocking agents resulting in increased respiratory depression.
Patients receiving other narcotic analgesics, antitussives, antihypertensives, antihistamines, antipsychotics, antianxiety agents or other CNS depressants (including gabapentinoids, cannabis, centrally-active anti-emetics, alcohol) concomitantly with this codeine-containing medicine may exhibit additive CNS depression (see Section 4.4 Special Warnings and Precautions for Use).
CYP2D6 inhibitors.
Codeine is metabolized by the liver enzyme CYP2D6 to its active metabolite morphine. Medicines that inhibit CYP2D6 activity may reduce the analgesic effect of codeine. Patients taking codeine and moderate to strong CYP2D6 inhibitors (such as quinidine, fluoxetine, paroxetine, bupropion, cinacalcet, methadone) should be adequately monitored for reduced efficacy and withdrawal signs and symptoms. If necessary, an adjustment of the treatment should be considered.
CYP3A4 inducers.
Medicines that induce CYP3A4 activity may reduce the analgesic effect of codeine. Patients taking codeine and CYP3A4 inducers (such as rifampin) should be adequately monitored for reduced efficacy and withdrawal signs and symptoms. If necessary, an adjustment of the treatment should be considered.
Gabapentinoids and opioids.
The concomitant use of opioids with gabapentinoids (gabapentin and pregabalin) increases the risk of respiratory depression, hypotension, profound sedation, coma or death because of additive CNS depressant effect.4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
See Section 5.3 Preclinical Safety Data, Carcinogenicity.
(Category A)
Paracetamol crosses the placenta, however problems in humans have not been documented. Opioid analgesics cross the placenta. Regular use during pregnancy may cause physical dependence in the foetus, leading to withdrawal symptoms in the neonate. Administration of codeine during labour may cause respiratory depression in the newborn infant. Codeine may cause respiratory depression and withdrawal syndrome in neonates born to mothers who use codeine during the third trimester of pregnancy. As a precautionary measure, use of Paracetamol/Codeine GH 500/15 should be avoided during the third trimester of pregnancy and during labour.
Paracetamol/Codeine GH 500/15 is contraindicated during breast-feeding (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism) due to risk of respiratory depression in the infant. Paracetamol is excreted in breast milk but neither paracetamol nor its metabolites were detected in the urine of nursing infants after 650 mg maternal dose. If Paracetamol/Codeine GH 500/15 is administered to a nursing mother, alternative arrangements should be made for feeding the infant.
Analgesic doses excreted in breast milk are generally low. However, infants of breastfeeding mothers taking codeine may have an increased risk of morphine overdose if the mother is an ultrarapid metaboliser of codeine. Codeine is excreted into human breast milk. Codeine is partially metabolised by cytochrome P4502D6 (CYP2D6) into morphine, which is excreted into breast milk. If nursing mothers are CYP2D6 ultra-rapid metabolisers, higher levels of morphine may be present in their breast milk. This may result in symptoms of opioid toxicity in both mother and the breastfed infant. Life-threatening adverse events or neonatal death may occur even at therapeutic doses (see Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism).
Therefore, Paracetamol/Codeine GH 500/15 is contraindicated for use during breastfeeding. However, in circumstances where a breastfeeding mother requires codeine therapy, breastfeeding should be suspended, and alternative arrangements should be made for feeding the infant for any period during codeine treatment. Breast feeding mothers should be told how to recognise signs of high morphine levels in themselves and their babies. For example, in a mother, symptoms include extreme sleepiness and trouble caring for the baby. In the baby, symptoms include signs of increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Medical advice should be sought immediately.4.7 Effects on Ability to Drive and Use Machines
Paracetamol/Codeine GH 500/15 may cause drowsiness, disturbances of visuomotor coordination and visual acuity and/or dizziness. Due to the preparation's sedative action, impairment of the mental and/or physical abilities required for the performance of potentially hazardous activities may occur. Hence, children engaging in bike riding and other hazardous activities should be supervised to avoid potential harm.
Patients should not drive, operate machinery or drink alcohol whilst taking this medication.
4.8 Adverse Effects (Undesirable Effects)
Reports of adverse reactions are rare. Although the following reactions have been reported when paracetamol and codeine have been administered:
Haematologic.
Less frequent to rare: agranulocytosis, anaemia, thrombocytopenia.
Genitourinary.
Less frequent to rare: renal failure, uraemia, urinary retention or hesitance.
Hypersensitive.
Less frequent to rare: skin rashes and other allergic reactions, histamine release (hypotension, flushing of the face, tachycardia, breathlessness).
Gastrointestinal.
Common: constipation, nausea, vomiting.
Neurological.
Common: drowsiness, dizziness.
Less frequent to rare: euphoria, dysphoria, at higher doses codeine may cause respiratory depression.
Hepatic.
Very rare: pancreatitis.
Metabolism and nutrition system disorders.
Not known: pyroglutamic acidosis, in patients with pre-disposing factors for glutathione depletion.
Paracetamol has also been associated with dyspepsia, sweating, erythema, urticaria, anaphylactic shock, angioneurotic oedema, leukopenia, neutropenia and pancytopenia. Bronchospasms may be triggered in patients having a tendency of analgesic asthma. Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalised exanthematous pustulosis, fixed drug eruption (see Section 4.4 Special Warnings and Precautions for Use), cytolytic hepatitis, which may lead to acute hepatic failure, have also been reported.
Haemolytic anaemia in particular in patients with underlying glucose 6-phosphate-dehydrogenase deficiency has been reported. Kounis syndrome and bronchospasm have also been reported.
Codeine has also been associated with confusional state, dysphoria, seizure, headache, somnolence, sedation, miosis, tinnitus, dry mouth, pruritus, fatigue, hypotension. Visuomotor coordination and visual acuity may be adversely affected in a dose-dependent manner at higher doses or in particular sensitive patients. Long term use also entails the risk of drug dependence.
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.4.9 Overdose
Elderly persons, small children, patients with liver disorders, chronic alcohol consumption or chronic malnutrition, as well as patients concomitantly treated with enzyme-inducing drugs are at an increased risk of intoxication, including fatal outcome.
Symptoms.
Toxic symptoms include vomiting, abdominal pain, hypotension, sweating, central stimulation with exhilaration and convulsions in children, drowsiness, respiratory depression, cyanosis and coma. Nausea, vomiting, anorexia, pallor and abdominal pain generally appear during the first 24 hours of overdosage with paracetamol. Overdosage with paracetamol may cause hepatic cytolysis which can lead to hepatocellular insufficiency, gastrointestinal bleeding, metabolic acidosis, encephalopathy, disseminated intravascular coagulation, coma and death. Increased levels of hepatic transaminases, lactate dehydrogenase and bilirubin with a reduction in prothrombin level can appear 12 to 48 hours after acute overdosage. It can also lead to pancreatitis, acute renal failure and pancytopenia. The most serious adverse effect of acute overdosage of paracetamol is a dose dependent, potentially fatal hepatic necrosis.
In adults, hepatotoxicity may occur after ingestion of a single dose of 10 to 15 g (30 tablets) of paracetamol; a dose of 25 g (50 tablets) or more is potentially fatal.
Symptoms during the first two days of acute poisoning by paracetamol do not reflect the potential seriousness of the intoxication. Major manifestations of liver failure, such as jaundice, hypoglycaemia and metabolic acidosis, may take at least three days to develop.
In an evaluation of codeine intoxication in children, symptoms seen included: sedation, rash, miosis, vomiting, itching, ataxia and swelling of the skin. Respiratory failure may occur.
The ingestion of very high doses of codeine can cause initial excitation, anxiety, insomnia followed by drowsiness in certain cases, areflexia progressing to stupor or coma, headache, miosis, alterations in blood pressure, arrhythmias, dry mouth, hypersensitivity reactions, cold clammy skin, bradycardia, tachycardia, convulsions, gastrointestinal disorders, nausea, vomiting and respiratory depression.
Severe intoxication can lead to apnoea, circulatory collapse, cardiac arrest and death.
Treatment.
Despite lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention.
Consists primarily of management of paracetamol toxicity; naloxone is the treatment of choice for codeine intoxication. In cases of overdosage, methods of reducing the absorption of ingested drug are important. Prompt administration of 50 g activated charcoal and 500 mL iced mannitol 20% by mouth may reduce absorption.
Determinations of the plasma concentration of paracetamol are recommended.
Plasma concentration of paracetamol should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable).
Where paracetamol intoxication is suspected, intravenous administration of SH group donators such as acetylcysteine within the first 10 hours after ingestion is indicated. Although acetylcysteine is most effective if initiated within this period, it can still offer some degree of protection if given as late as 48 hours after ingestion; in this case it is taken for longer.
If the history suggests that 15 g paracetamol or more has been ingested, administer one of the following antidotes:
Acetylcysteine 20% i.v.
Administer 20% acetylcysteine (Parvolex, David Bull) immediately without waiting for positive urine test or plasma level results: initial dose 150 mg/kg over 15 minutes, followed by continuous infusion of 50 mg/kg in 500 mL 5% glucose over 4 hours and 100 mg/kg in 1 L 5% glucose over 16 hours; or
Oral methionine.
2.5 g immediately followed by three further doses of 2.5 g at four hourly intervals. For a 3-year-old child, 1 g methionine 4-hourly for four doses has been used.
If more than ten hours have elapsed since the overdosage was taken, the antidote may be ineffective.
Relating to codeine component.
In general, treatment should be symptomatic: re-establish adequate respiratory exchange by ensuring a clear airway and using mechanical ventilation. When treatment for paracetamol toxicity has been initiated the opioid antagonist naloxone hydrochloride is an antidote to respiratory depression; naloxone 400 microgram may be administered SC, IM or IV; IV may be repeated at intervals of 2 to 3 minutes if necessary. Assisted respiration may be required.
Further measures will depend on the severity, nature and course of clinical symptoms of intoxication and should follow standard intensive care protocols.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action.
Analgesic and antipyretic.
Paracetamol's analgesic mechanism of action has not been fully elucidated but may involve blocking impulse generation at the bradykinin sensitive chemoreceptors that evoke pain.
The antipyretic effect of paracetamol rises from its ability to block the action of prostaglandin synthetase and so prevent the synthesis of prostaglandins in response to the pyrogen stimulus in the region of the anterior hypothalamus.
Codeine acts centrally. It produces analgesia by dulling the response to painful stimuli at several loci in the central nervous system. This causes an alteration in the sensation and affective response of pain.
There is evidence to suggest that a combination of paracetamol with codeine is superior in analgesic action to either drug administered alone.
Clinical trials.
No data available.
5.2 Pharmacokinetic Properties
Absorption.
After oral administration, paracetamol is absorbed rapidly and completely from the small intestine; peak plasma levels occur 30 to 120 minutes after administration. Food intake delays paracetamol absorption. Codeine has about one-sixth of morphine's analgesic activity. It is well absorbed from the gastrointestinal tract and does not interfere with paracetamol absorption.
Distribution.
Paracetamol is uniformly distributed throughout most body fluids; the apparent volume of distribution is 1 to 1.2 L/kg.
Paracetamol can cross the placenta and is excreted in milk. Plasma protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations.
Metabolism.
Paracetamol is metabolised by the hepatic microsomal enzyme system. In adults, at therapeutic doses, paracetamol is mainly conjugated with glucuronide (45 to 55%) or sulfate (20 to 30%). A minor proportion (less than 20%) is metabolised to catechol derivatives and mercapturic acid compounds via oxidation. Paracetamol is metabolised differently by infants and children compared to adults, the sulfate conjugate being predominant.
Patients who metabolise drugs poorly via CYP2D6 are likely to obtain reduced benefit from codeine due to reduced formation of the active metabolite.
Excretion.
Paracetamol is excreted in the urine mainly as the glucuronide and sulfate conjugates. Less than 5% is excreted as unchanged paracetamol, with 85 to 90% of the administered dose eliminated in the urine within 24 hours of ingestion. The elimination half-life varies from one to four hours.
Codeine is metabolised in the liver to morphine and norcodeine which, with codeine, are excreted in the urine, partly as conjugates with glucuronic acid. Excretion is almost complete within 24 hours.
5.3 Preclinical Safety Data
Genotoxicity.
No data available.
Carcinogenicity.
Toxicity studies in animals have shown that high doses of paracetamol cause testicular atrophy and inhibition of spermatogenesis; the relevance of this finding to use in humans is not known.6 Pharmaceutical Particulars
6.1 List of Excipients
Potato starch, lactose monohydrate, povidone, docusate sodium, colloidal anhydrous silica, magnesium stearate.
6.2 Incompatibilities
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store below 30°C.
6.5 Nature and Contents of Container
The products are presented in blister packs (PVC/PVDC/Al) of 10 tablets, 12 tablets, 20 tablets, 24 tablets, 30 tablets, 36 tablets and 40 tablets.
Not all pack sizes may be marketed in Australia.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.
6.7 Physicochemical Properties
Codeine phosphate hemihydrate is a white or almost white, crystalline powder or small, colourless crystals. It is freely soluble in water, slightly soluble or very slightly soluble in ethanol (96%). Codeine phosphate is an analgesic.
Paracetamol is a white or almost white crystalline powder. It is sparingly soluble in water, freely soluble in alcohol, very slightly soluble in methylene chloride. Paracetamol is an analgesic and antipyretic.
Chemical structure.
Paracetamol.
Molecular Formula: C8H9NO2.
Molecular Weight: 151.2.
Codeine phosphate hemihydrate.
Molecular Formula: C18H21NO3, H3PO4, ½ H2O.
Molecular Weight: 406.4.
CAS number.
Paracetamol: 103-90-2.
Codeine phosphate: 41444-62-6.7 Medicine Schedule (Poisons Standard)
Schedule 4 - Prescription Only Medicine.
Summary Table of Changes
