Co-Codamol 8/500mg Effervescent Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Longtec 10 mg film-coated, prolonged release tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 9.0 mg of oxycodone as 10 mg of oxycodone hydrochloride. For a full list of excipients see Section 6.1.
This product contains lactose monohydrate (see section 4.3 Contra-indications).
3 PHARMACEUTICAL FORM
Film coated, prolonged release tablet.
White, round, convex tablets marked OC on one side and 10 on the other.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
For the treatment of moderate to severe pain in patients with cancer and post-operative pain. For the treatment of severe pain requiring the use of a strong opioid.
4.2 Posology and method of administration
Longtec tablets must be swallowed whole, and not chewed.
Elderly and adults over 18 years:
Longtec tablets should be taken at 12-hourly intervals. The dosage is dependent on the severity of the pain, and the patient’s previous history of analgesic requirements.
Longtec tablets are not intended for use as a pm analgesic.
Increasing severity of pain will require an increased dosage of Longtec tablets, using the 10 mg, 20 mg, 40 mg or 80 mg tablet strengths, either alone or in combination, to achieve pain relief. The correct dosage for any individual patient is that which controls the pain and is well tolerated for a full 12 hours. Patients should be titrated to pain relief unless unmanageable adverse drug reactions prevent this. If higher doses are necessary, increases should be made where possible, in 25% - 50% increments. The need for escape medication more than twice a day indicates that the dosage of Longtec tablets should be increased.
The usual starting dose for opioid naive patients or patients presenting with severe pain uncontrolled by weaker opioids is 10 mg, 12-hourly. Some patients may benefit from a starting dose of 5 mg to minimise the incidence of side effects. The dose should then be carefully titrated, as frequently as once a day if necessary, to achieve pain relief. For the majority of patients, the maximum dose is 200 mg 12-hourly. However, a few patients may require higher doses. Doses in excess of 1000 mg daily have been recorded.
Patients receiving oral morphine before Longtec tablets should have their daily dose based on the following ratio: 10 mg of oral oxycodone is equivalent to 20 mg of oral morphine. It must be emphasised that this is a guide to the dose of Longtec tablets required. Inter-patient variability requires that each patient is carefully titrated to the appropriate dose.
Controlled pharmacokinetic studies in elderly patients (aged over 65 years) have shown that, compared with younger adults, the clearance of oxycodone is only slightly reduced. No untoward adverse drug reactions were seen based on age, therefore adult doses and dosage intervals are appropriate.
Children under 18 years:
There were no studies in patients below 18 years of age, therefore Longtec tablets should not be used in patients under 18 years.
Adults with mild to moderate renal impairment and mild hepatic impairment:
The plasma concentration in this population may be increased. Therefore dose initiation should follow a conservative approach. Opioid naive patients should be started on Longtec tablets 5 mg or OxyNorm liquid 2.5 mg 6-hourly and titrated to pain relief as described before.
Use in non-malignant pain:
Opioids are not first-line therapy for chronic non-malignant pain, nor are they recommended as the only treatment. Types of chronic pain which have been shown to be alleviated by strong opioids include chronic osteoarthritic pain and intervertebral disc disease. The need for continued treatment in
non-malignant pain should be assessed at regular intervals.
Cessation of Therapy:
When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.
4.3 Contraindications
Hypersensitivity to any of the constituents, respiratory depression, head injury, paralytic ileus, acute abdomen, delayed gastric emptying, chronic obstructive airways disease, cor pulmonale, chronic bronchial asthma, hypercarbia, known oxycodone sensitivity or in any situation where opioids are contraindicated, moderate to severe hepatic impairment, severe renal impairment (creatinine clearance <10ml/min), chronic constipation, concurrent administration of monoamine oxidase inhibitors or within 2 weeks of discontinuation of their use. Not recommended for pre-operative use or for the first 24 hours post-operatively. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Pregnancy.
4.4 Special warnings and precautions for use
The major risk of opioid excess is respiratory depression. As with all narcotics, a reduction in dosage may be advisable in hypothyroidism. Use with caution in patients with raised intracranial pressure, hypotension, hypovolaemia, toxic psychosis, diseases of the biliary tract, inflammatory bowel disorders, prostatic hypertrophy, adrenocortical insufficiency, acute alcoholism, delirium tremens, pancreatitis, chronic renal and hepatic disease, or severe pulmonary disease, and debilitated elderly and infirm patients. Longtec tablets should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, Longtec tablets should be discontinued immediately. As with all opioid preparations, patients who are to undergo cordotomy or other pain relieving surgical procedures should not receive Longtec tablets for 24 hours before surgery. If further treatment with Longtec tablets is then indicated the dosage should be adjusted to the new post-operative requirement.
Longtec tablets 80 mg should not be used in patients not previously exposed to opioids. This tablet strength may cause fatal respiratory depression when administered to opioid naive patients.
As with all opioid preparations, Longtec tablets should be used with caution following abdominal surgery, as opioids are known to impair intestinal motility, and should not be used until the physician is assured of normal bowel function.
For appropriate patients who suffer with chronic non-malignant pain, opioids should be used as part of a comprehensive treatment programme involving other medications and treatment modalities. A crucial part of the assessment of a patient with chronic non-malignant pain is the patient’s addiction and substance abuse history. Longtec tablets should be used with particular care in patients with a history of alcohol and drug abuse.
If opioid treatment is considered appropriate for the patient, then the main aim of treatment is not to minimise the dose of opioid but rather to achieve a dose which provides adequate pain relief with a minimum of side effects. There must be frequent contact between physician and patient so that dosage adjustments can be made. It is strongly recommended that the physician defines treatment outcomes in accordance with pain management guidelines. The physician and patient can then agree to discontinue treatment if these objectives are not met.
Oxycodone has an abuse liability similar to other strong opioids and should be used with caution in opioid-dependent patients, or if the doctor or pharmacist is concerned about the risk of misuse. Oxycodone may be sought and abused by people with latent or manifest addiction disorders.
As with other opioids, infants who are born to dependent mothers may exhibit withdrawal symptoms and may have respiratory depression at birth.
Longtec tablets must be swallowed whole, and not broken, chewed or crushed. The administration of broken, chewed, or crushed Longtec tablets leads to a rapid release and absorption of a potentially fatal dose of oxycodone (see Section 4.9). Abuse of the tablets by parenteral administration can be expected to result in other serious adverse events, such as local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis, and valvular heart injury, which may be fatal.
4.5 Interaction with other medicinal products and other forms of interaction
Oxycodone, like other opioids, potentiates the effects of tranquillisers, anaesthetics, hypnotics, anti-depressants, sedatives, phenothiazines, neuroleptic drugs, alcohol, other opioids, muscle relaxants and antihypertensives. Monoamine oxidase inhibitors are known to interact with narcotic analgesics, producing CNS excitation or depression with hypertensive or hypotensive crisis. Concurrent administration of quinidine, an inhibitor of cytochrome P450-2D6, resulted in an increase in oxycodone Cmax by 11%, AUC by 13%, and t/2 elim. by 14%. Also an increase in noroxycodone level was observed, (Cmax by 50%; AUC by 85%, and t/ elim. by 42%). The pharmacodynamic effects of oxycodone were not altered. This interaction may be observed for other potent inhibitors of cytochrome P450-2D6 enzyme. Cimetidine and inhibitors of cytochrome P450-3A such as ketoconazole and erythromycin may inhibit the metabolism of oxycodone.
4.6 Pregnancy and lactation
Longtec tablets are not recommended for use in pregnancy nor during labour. Infants born to mothers who have received opioids during pregnancy should be monitored for respiratory depression..
Oxycodone may be secreted in breast milk and may cause respiratory depression in the newborn. Longtec tablets should, therefore, not be used in breast-feeding mothers.
4.7 Effects on ability to drive and use machines
Oxycodone may modify patients’ reactions to a varying extent depending on the dosage and individual susceptibility. Therefore, patients should not drive or operate machinery if affected.
4.8 Undesirable effects
Adverse drug reactions are typical of full opioid agonists. Tolerance and dependence may occur (see Tolerance and Dependence, below). Constipation may be prevented with an appropriate laxative. If nausea and vomiting are troublesome, oxycodone may be combined with an anti-emetic.
Common (incidence of 1%) and uncommon (incidence of 1%) adverse drug reactions are listed in the table below.
|
Body System |
Common |
Uncommon |
|
Gastrointestinal |
Constipation |
Biliary spasm |
|
Nausea |
Dysphagia | |
|
Vomiting |
Eructation | |
|
Dry mouth |
Flatulence | |
|
Anorexia |
Gastrointestinal disorders | |
|
Dyspepsia |
Ileus | |
|
Abdominal pain |
Taste perversion | |
|
Diarrhoea |
Gastritis Hiccups | |
|
Central Nervous System |
Headache |
Vertigo |
|
Confusion |
Hallucinations | |
|
Asthenia |
Hypertonia | |
|
Faintness |
Disorientation | |
|
Dizziness |
Mood changes | |
|
Sedation |
Restlessness | |
|
Anxiety |
Agitation | |
|
Abnormal dreams |
Depression | |
|
Nervousness |
Tremor | |
|
Insomnia |
Withdrawal syndrome | |
|
Thought abnormalities |
Amnesia | |
|
Drowsiness |
Hypoaesthesia | |
|
Twitching |
Hypotonia Malaise |
|
Paraesthesia Speech disorder Euphoria Dysphoria Seizure Vision abnormalities | ||
|
Genitourinary |
Urinary retention Ureteric spasm Impotence Amenorrhoea Decreased libido | |
|
Cardiovascular |
Orthostatic hypotension |
Palpitations Supraventricular tachycardia Hypotension Syncope Vasodilation |
|
Metabolic and Nutritional |
Dehydration Oedema Peripheral oedema Thirst | |
|
Respiratory |
Bronchospasm |
Overdose may produce |
|
Dyspnoea Decreased cough reflex |
respiratory depression | |
|
Dermatological |
Rash |
Dry skin |
|
Pruritus |
Exfoliative dermatitis Urticaria | |
|
General |
Sweating |
Facial flushing |
|
Chills |
Miosis Muscular rigidity Allergic reaction |
Fever
Anaphylaxis
Tolerance and Dependence :
The patient may develop tolerance to the drug with chronic use and require progressively higher doses to maintain pain control. Prolonged use of Longtec tablets may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy. When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. The opioid abstinence or withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia and mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, or increased blood pressure, respiratory rate or heart rate.
The development of psychological dependence (addiction) to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of psychological dependence (addiction) in chronic pain patients.
Longtec tablets should be used with particular care in patients with a history of alcohol and drug abuse.
4.9 Overdose
Signs of oxycodone toxicity and overdosage are pin-point pupils, respiratory depression and hypotension. Circulatory failure and somnolence progressing to stupor or deepening coma, skeletal muscle flaccidity, bradycardia and death may occur in more severe cases.
Treatment of oxycodone overdosage: primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation.
In the case of massive overdosage, administer naloxone intravenously (0.4 to 2 mg for an adult an 0.01 mg/kg body weight for children) if the patient is in a coma or respiratory depression is present. Repeat the dose at 2 minute intervals if there is no response. If repeated doses are required then an infusion of 60% of the initial dose per hour is a useful starting point. A solution of 10 mg made up in 50 ml dextrose will produce 200 micrograms/ml for infusion using an IV pump (dose adjusted to the clinical response). Infusions are not a substitute for frequent review of the patient’s clinical state. Intramuscular naloxone is an alternative in the event that IV access is not possible. As the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established. Naloxone is a competitive antagonist and large doses (4 mg) may be required in seriously poisoned patients.
For less severe overdosage, administer naloxone 0.2 mg intravenously followed by increments of 0.1 mg every 2 minutes if required.
Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone overdosage. Naloxone should be administered cautiously to persons who are known, or suspected, to be physically dependent on oxycodone. In such cases, an abrupt or complete reversal of opioid effects may precipitate pain and an acute withdrawal syndrome.
Additional/other considerations:
• Consider activated charcoal (50 g for adults, 10-15 g for children), if a substantial amount has been ingested within 1 hour, provided the airway can be protected. It may be reasonable to assume that late administration of activated charcoal may be beneficial for prolonged release preparations; however there is no evidence to support this.
• Longtec tablets will continue to release and add to the oxycodone load for up to 12 hours after administration and the management of oxycodone overdosage should be modified accordingly. Gastric contents may therefore need to be emptied as this can be useful in removing unabsorbed drug, particularly when a prolonged release formulation has been taken.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Natural opium alkaloids ATC code: N02A A05
Oxycodone is a full opioid agonist with no antagonist properties. It has an affinity for kappa, mu and delta opiate receptors in the brain and spinal cord. Oxycodone is similar to morphine in its action. The therapeutic effect is mainly analgesic, anxiolytic and sedative.
5.2 Pharmacokinetic properties
Compared with morphine, which has an absolute bioavailability of approximately 30%, oxycodone has a high absolute bioavailability of up to 87% following oral administration. Oxycodone has an elimination half-life of approximately 3 hours and is metabolised principally to noroxycodone and oxymorphone. Oxymorphone has some analgesic activity, but is present in the plasma in low concentrations and is not considered to contribute to oxycodone’s pharmacological effect.
The release of oxycodone from Longtec tablets is biphasic with an initial relatively fast release providing an early onset of analgesia followed by a more controlled release which determines the 12 hour duration of action. The mean apparent elimination half-life of oxycodone is 4.5 hours, which leads to steady-state being achieved in about one day.
Release of oxycodone from Longtec tablets is independent of pH.
Longtec tablets have an oral bioavailability comparable with conventional oral oxycodone, but the former achieve maximal plasma concentrations at about 3 hours rather than about 1 to 1.5 hours. Peak and trough concentrations of oxycodone from Longtec tablets 10 mg administered 12-hourly are equivalent to those achieved from conventional oxycodone 5 mg administered 6-hourly.
Longtec tablets 10 mg, 20 mg, 40 mg and 80 mg are bioequivalent in terms of both rate and extent of absorption. Ingestion of a standard high-fat meal does not alter the peak oxycodone concentration or the extent of oxycodone absorption from Longtec tablets.
Elderly
The AUC in elderly subjects is 15% greater when compared with young subjects.
Gender
Female subjects have, on average, plasma oxycodone concentrations up to 25% higher than males on a body weight adjusted basis. The reason for this difference is unknown.
Patients with renal impairment
Preliminary data from a study of patients with mild to moderate renal dysfunction show peak plasma oxycodone and noroxycodone concentrations approximately 50% and 20% higher, respectively and AUC values for oxycodone, noroxycodone and oxymorphone approximately 60%, 60% and 40% higher than normal subjects, respectively. There was an increase in t./2 of elimination for oxycodone of only 1 hour.
Patients with mild to moderate hepatic impairment
Patients with mild to moderate hepatic dysfunction showed peak plasma oxycodone and noroxycodone concentrations approximately 50% and 20% higher, respectively, than normal subjects. AUC values were approximately 95% and 75% higher, respectively. Oxymorphone peak plasma concentrations and AUC values were lower by 15% to 50%. The t/ elimination for oxycodone increased by 2.3 hours.
5.3 Preclinical safety data
Oxycodone was not mutagenic in the following assays: Ames Salmonella and E. Coli test with and without metabolic activation at doses of up to 5000 pg, chromosomal aberration test in human lymphocytes (in the absence of metabolic activation and with activation after 48 hours of exposure) at doses of up to 1500 pg/ml, and in the in vivo bone marrow micronucleus assay in mice (at plasma levels of up to 48 pg/ml). Mutagenic results occurred in the presence of metabolic activation in the human chromosomal aberration test (at greater than or equal to 1250 |lg/ml) at 24 but not 48 hours of exposure and in the mouse lymphoma assay at doses of 50 pg/ml or greater with metabolic activation and at 400 pg/ml or greater without metabolic activation. The data from these tests indicate that the genotoxic risk to humans may be considered low.
Studies of oxycodone in animals to evaluate its carcinogenic potential have not been conducted owing to the length of clinical experience with the drug substance.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate Povidone K30
Ammoniomethacrylate co-polymer
Sorbic acid
Triacetin
Stearyl alcohol
Talc
Magnesium stearate
Film coat (Opadry white Y-5-18024A
Hypromellose (E464)
Hydroxypropylcellulose Titanium Dioxide (E171)
Macrogol 400
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Three years.
Do not store above 25°C
6.5 Nature and contents of container
1) Polypropylene containers with polyethylene lids (containing 28, 56 or 112 tablets).
2) PVC blister packs with aluminium foil backing (containing 28, 56 or 112 tablets).
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
None.
4.2 Posology and method of administration
For oral administration only. The tablets should be dissolved in at least half a tumbler of water before taking.
Adults and children over 12 years
One to two tablets dissolved in water every 4 to 6 hours as required, to a maximum of 8 tablets daily.
Elderly
There is no current evidence for the alteration of the adult dose except where there is impaired hepatic function when dosage reduction may be necessary.
Do not take more than 3 days continuously without medical review
4.3 Contraindications
Conditions where morphine and opioids are contra-indicated e.g. acute alcoholism and where risk of paralytic ileus, acute respiratory depression, raised intracranial pressure or head injury (affects pupillary responses vital for neurological assessment).
Sensitivity to codeine or paracetamol or any of the constituents of the tablets.
Other paracetamol containing medication should be avoided when taking co-codamol effervescent tablets. These tablets contain sodium and should be avoided by patients on a low sodium diet. The tablets contain aspartame and so should not be taken by patients with phenylketonuria.
Care should be taken when prescribing these tablets to patients with liver or renal impairment.
The hazards of paracetamol overdose are greater in those with noncirrhotic alcoholic liver disease.
The label will state:
Front of Pack
• Can cause addiction
• For three days use only
Back of Pack
• For the short term treatment of acute moderate pain when other painkillers have not worked. Do not take less than four hours after taking other painkillers.
• For the treatment of pain, including muscular and rheumatic pains, headache, migraine, neuralgia, toothache and period pains.
• If you need to take this medicine continuously for more than three days you should see your doctor or pharmacist
• This medicine contains codeine which can cause addiction if you take it continuously for more than three days. If you take this medicine for headaches for more than three days it can make them worse
The leaflet will state:
Headlines section (to be prominently displayed)
• This medicine can only be used for the short term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone.
• You should only take this product for a maximum of three days at a time. If you need to take it for longer than three days you should see your doctor or pharmacist for advice.
• This medicine contains codeine which can cause addiction if you take it continuously for more than three days. This can give you withdrawal symptoms from the medicine when you stop taking it.
• If you take this medicine for headaches for more than three days it can
make them worse.
Section 1: What the medicine is for
• Co-codamol 8/500 is for the short term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone. It is used to relieve muscular and rheumatic pains, headache, migraine, neuralgia (severe burning or stabbing pain following the line of a nerve), toothache and period pains.
Section 2: Before taking
• This medicine contains codeine which can cause addiction if you take it continuously for more than three days. This can give you withdrawal symptoms from the medicine when you stop taking it.
• If you take a painkiller for headaches for more than three days it can make them worse.
Section 3: Dosage
• Do not take for more than 3 days. If you need to use this medicine for more than three days you must speak to your doctor or pharmacist.
• This medicine contains codeine and can cause addiction if you take it continuously for more than three days. When you stop taking it you may get withdrawal symptoms. You should talk to your doctor or pharmacist if you think you are suffering from withdrawal symptoms.
Section 4: Side effects
• Some people may have side-effects when taking this medicine. If you have any unwanted side-effects you should seek advice from your doctor, pharmacist or other healthcare professional. Also you can help to make sure that medicines remain as safe as possible by reporting any unwanted side-effects via the internet at www.yellowcard.gov.uk; alternatively you can call Freephone 0808 100 3352 (available between 10am-2pm Monday
- Friday) or fill in a paper form available from your local pharmacy.
How do I know if I am addicted?
If you take the medicine according to the instructions on the pack it is unlikely that you will become addicted to the medicine. However, if the following apply to you it is important that you talk to your doctor:
- You need to take the medicine for longer periods of time.
- You need to take more than the recommended dose.
- When you stop taking the medicine you feel very unwell but you feel better if you start taking the medicine again.
Codeine is partially metabolised by CYP2D6. If a patient has a deficiency or is completely lacking this enzyme they will not obtain adequate analgesic effects. Estimates indicate that up to 7% of the caucasian population may have this deficiency. However, if the patient is an ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at low doses. General symptoms of opioid toxicity include nausea, vomiting, constipation, lack of appetite and somnolence. In severe cases this may include symptoms of
circulatory and respiratory depression. Estimates indicate that up to 1 to 2% of the Caucasian population may be ultra-rapid metabolisers.
The leaflet will state in the “Pregnancy and breast-feeding” subsection of section 2 “Before taking your medicine”:
Usually it is safe to take Co-codamol 8/500 while breast feeding as the level of codeine in breast milk are too low to cause your baby any problems.
However, some women who are at increased risk of developing side effects at any dose may have higher levels of codeine in their breast milk. If any of the following side effects develop in you or your baby stop taking this medicine and seek immediate medical advice; feeling sick, vomiting, constipation, decreased or lack of appetite, feeling tired or sleeping for longer than normal, and shallow or slow breathing.
4.5 Interaction with other medicinal products and other forms of interaction
Avoid taking co-codamol effervescent tablets with CNS depressants or other paracetamol containing products. The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine. Opioid analgesics such as codeine antagonise the effects of domperidone or metoclopramide on gastrointestinal activity.
Co-administration with colestyramine may reduce absorption. Patients on anticoagulants may take occasional doses of co-codamol effervescent but the anticoagulant effect of warfarin and coumarins may be enhanced by regular administration of paracetamol.
4.6 Pregnancy and lactation
Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use.
Opioid analgesics may depress neonatal respiration and cause withdrawal effects in neonates of dependent mothers. There is a risk of gastric stasis and of inhalation pneumonia in mothers during labour.
Lactation
At normal therapeutic doses codeine and its active metabolites may be present in breast milk at very low doses and is unlikely to adversely affect the breast fed infant.
However, if the patient is an ultra-rapid metaboliser of CYP2D6, higher levels of the active metabolites may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant.
If symptoms of opioid toxicity develop in either the mother or the infant, then all codeine containing medicines should be stopped and alternative non-opioid analgesics prescribed. In severe cases consideration should be given to prescribing naloxone to reverse these effects.
4.7 Effects on ability to drive and use machines
Patients should be warned not to drive or operate machinery if they become dizzy or sedated while taking co-codamol effervescent tablets.
4.8 Undesirable effects
Co-codamol effervescent tablets are generally well tolerated but hypersensitivity reactions including skin rashes may occur. Rare cases of anaphylaxis, angioedema, urticaria, pruritus and fixed drug eruption have been reported with medications containing paracetamol and/or codeine. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to Co-codamol.
Codeine may sometimes cause typical opioid effects such as vomiting, constipation, nausea, light-headedness, dizziness, confusion, drowsiness and urinary retention. The frequency and severity of these effects are determined by dosage, duration of treatment and individual sensitivity. There have been rare reports of acute pancreatitis in patients taking codeine or codeine/paracetamol combinations.
• Regular prolonged use of codeine is known to lead to addiction and tolerance. Symptoms of restlessness and irritability may result when treatment is then stopped.
• Prolonged use of a painkiller for headaches can make them worse.
Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation 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 via Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
4.9 Overdose
Paracetamol
Liver damage is possible in adults who have taken 10g or more of paracetamol. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).
Risk factors
If the patient
a. Is on long term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St John’s Wort or other drugs that induce liver enzymes.
or
b. Regularly consumes ethanol in excess of recommended amounts. or
c. Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.
Symptoms
Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.
Management
Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines, see BNF overdose section.
Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit.
Codeine
Nausea and vomiting are prominent symptoms of codeine toxicity, with circulatory and respiratory depression in severe overdose.
The effects in overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs.
Symptoms
Central nervous system depression, including respiratory depression, may develop but is unlikely to be severe unless other sedative agents have been coingested, including alcohol, or the overdose is very large. The pupils may be pin-point in size; nausea and vomiting are common. Hypotension and tachycardia are possible but unlikely.
Management
This should include general symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. Consider activated charcoal if an adult presents within one hour of ingestion of more than 350 mg or a child more than 5 mg/kg.
Give naloxone if coma or respiratory depression is present. Naloxone is a competitive antagonist and has a short half-life so large and repeated doses may be required in a seriously poisoned patient. Observe for at least four hours after ingestion, or eight hours if a sustained release preparation has been taken.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Paracetamol has antipyretic and analgesic actions with little anti-inflammatory effect. Codeine is an analgesic related to morphine but with only mild sedative effects.
5.2 Pharmacokinetic properties
Paracetamol is rapidly and well absorbed from the intestinal tract after it has left the stomach. Plasma protein binding is low and paracetamol is metabolised in the liver and mainly excreted in the urine as glucuronide and sulphate conjugates. The elimination half-life is 1-3 hours.
Codeine is absorbed from the gastro-intestinal tract and peak plasma-codeine concentrations are found in about one hour. It is metabolised by O- and N-demethylation in the liver to morphine, norcodeine, and other metabolites including normorphine and hydrocodone. Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid. The elimination half-life has been reported to be between 3 and 4 hours.
5.3 Preclinical safety data
None stated
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium hydrogen carbonate, citric acid, sodium carbonate, povidone, simeticone, sodium saccharin, aspartame, polysorbate 80.
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
Special precautions for storage
6.4
Do not store above 25°C. Store in a dry place and protect from light.
6.5 Nature and contents of container
4 layer paper/PE/aluminium/PE blisters.
Pack sizes: 7, 10, 14, 20, 28, 30 and 32 tablets.
6.6 Special precautions for disposal
None
7 MARKETING AUTHORISATION HOLDER
Neolab Limited 57 High Street Odiham Hants RG29 1LF
8 MARKETING AUTHORISATION NUMBER(S)
08137/0135
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 02/07/2015
10
DATE OF REVISION OF THE TEXT
30/11/2016