1. Name Of The Medicinal Product
Codipar 15mg/500mg Effervescent Tablets
2. Qualitative And Quantitative Composition
Each tablet contains Codeine Phosphate hemihydrate 15mg.and Paracetamol 500mg,
Excipients: Each tablet also contains 389mg of sorbitol and 379 mg of sodium.
For a full list of excipients, see 6.1.
3. Pharmaceutical Form
Effervescent Tablet
Bevelled, flat, round, white tablet
4. Clinical Particulars
4.1 Therapeutic Indications
For the relief of mild to severe acute pain
4.2 Posology And Method Of Administration
Method of administration: Oral
The tablets should be placed in a glass of water and allowed to be dissolved completely. The resulting solution should be drunk immediately.
Adults: The usual dose is two tablets every four hours as required. The total daily dose should not exceed 4 g paracetamol (8 tablets in a day).
Elderly; As for adults, however a reduced dose may be required (see section 4.4)
Paediatric population: Not recommended in children below the age of 18 years (see section 5.1).
4.3 Contraindications
Hypersensitivity to either paracetamol or codeine, or any of the excipients of Codipar tablets.
Conditions where morphine and opioids are contraindicated e.g., acute asthma, respiratory depression, acute alcoholism, head injuries, raised intra-cranial pressure and following biliary tract surgery; monoamine oxidase inhibitor therapy, concurrent or within 14 days.
Codipar is also contraindicated in severe liver disease and severe renal impairment. The hazards of overdose could be greater in those with alcoholic liver disease.
Use of codeine containing products is contraindicated in mothers who are breastfeeding unless prescribed by a doctor (see section 4.6).
4.4 Special Warnings And Precautions For Use
Care should be observed in administering the product to any patient whose condition may be exacerbated by opioids, including the elderly, who may be sensitive to their central and gastro-intestinal effects, those on concurrent CNS depressant drugs, those with prostatic hypertrophy / urethral stricture and those with inflammatory or obstructive bowel disorders. Care should also be observed if prolonged therapy is contemplated, since side effects are more frequent and may lead to intolerance of the product with regular, long-term use.
Codeine at high doses has the same disadvantages as morphine, including respiratory depression. Drug dependence of the morphine type can be produced by codeine, and the potential for drug abuse with codeine must be considered. Codeine may impair mental or physical abilities required in the performance of potentially hazardous tasks.
Prolonged regular use, except under medical supervision, may lead to physical and psychological dependence (addiction) and result in withdrawal symptoms such as restlessness and irritability, once the drug is stopped.
Care should be taken in patients with liver and kidney disease with suitable dose reductions as appropriate.
Prolonged use except on the doctor's advice may be harmful.
This product should be used only when clearly necessary.
Immediate medical advice should be sought in the event of overdosage, even if the patient feels well, because of the risk of irreversible liver damage.
Patients must be advised not to exceed the recommended dose and not to take other paracetamol containing products concurrently.
The risk-benefit of continued use should be assessed regularly by the prescriber.
Patients must be advised not to take other products containing paracetamol or opiate derivatives when taking Codipar, and to consult their doctor if symptoms persist.
The cough suppressant effect of codeine may be undesirable in patients with some respiratory conditions.
As the effervescent tablet contains 389mg of sorbitol, patients with rare hereditary problems of fructose intolerance should not take this medicine
This medicine contains 379 mg sodium in each tablet. This should be taken into consideration by patients on a controlled sodium (salt) diet.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
The hypotensive effects of antihypertensive agents, including diuretics, may be potentiated by codeine.
The CNS depressant action of Codipar may be enhanced by coadministration with any other drug which has a CNS depressant effect (e.g. anxiolytics, hypnotics, antidepressants, antipsychotics and alcohol). Concomitant use of any drug with a CNS depressant action should be avoided. If combined therapy is necessary, the dose of one or both agents should be reduced.
Concomitant administration of Codipar and MAOIs or tricyclic antidepressants may increase the effect of either the antidepressant or codeine.
Concomitant administration of codeine and anticholinergics may cause paralytic ileus.
Concomitant administration of codeine with an anti-diarrhoeal agent increases the risk of severe constipation, and coadministration with an antimuscarinic drug may cause urinary retention.
The absorption of paracetamol may be enhanced by metoclopramide or domperidone, and absorption may be reduced by cholestyramine.
The metabolism of paracetamol is increased in patients taking enzyme-inducing antiepileptics (carbamazepine, phenytoin, phenobarbital, primidone). Isolated reports describe unexpected hepatotoxicity in patients taking phenobarbital, phenytoin, or carbamazepine after taking paracetamol.
The anticoagulant effect of warfarin and other coumarins may be increased by long term regular daily use of paracetamol, with increased risk of bleeding. Occasional doses of paracetamol do not have a significant effect on these anticoagulants.
Dependence of codeine hypoalgesia on morphine formation via CYP2D6 makes this effect liable to interaction with drugs that are inhibitors of CYP2D6. Examples of potent inhibitors of CYP2D6 are quinidine, some selective serotonin reuptake inhibitors, some neuroleptics and ritornavir.
Codeine may delay the absorption of mexilitine
4.6 Pregnancy And Lactation
Pregnancy: On the basis of published literature (Danish National Birth Cohort), paracetamol use during any time of pregnancy was associated with a small but statistically significant increased risk of physician-diagnosed asthma or bronchitis among children at 18 months.
Use of codeine during pregnancy may lead to withdrawal symptoms in neonates, and use during labour may cause neonatal respiratory depression.
Codipar is then not recommended during pregnancy.
Lactation: Codeine is excreted in the human milk. The decision to use codeine in nursing women should be based on clinical judgment. If used in such patients, codeine should be administered in the lowest effective dosage for the shortest possible time.
In nursing mothers, who are ultra-rapid metabolisers of codeine, higher than expected serum and breast milk morphine levels can occur. Morphine toxicity in babies can cause excessive somnolence, hypotonia, miosis and difficulty breastfeeding or breathing. In severe cases respiratory depression and death can occur. In severe cases, naloxone may be appropriate to reverse the effects. The lowest effective dose should be used, for the shortest possible time.
Nursing mothers should be informed about carefully monitoring the infant during treatment for any signs and/or symptoms of morphine toxicity such as increased drowsiness or sedation, difficulty breastfeeding, breathing difficulties, miosis and decreased tone, and seeking immediate medical care if such symptoms or signs are noticed. The nursing mother should be informed about monitoring for signs and symptoms of maternal opioid toxicity as well. Should such signs/symptoms be noted in mother or baby, the mother should immediately stop taking all codeine-containing medicines and seek medical advice.
Paracetamol is distributed in human milk, although its concentration is 20% lower than in plasma. For these reasons, Codipar should be avoided during breast-feeding.
4.7 Effects On Ability To Drive And Use Machines
Patients should be advised not to drive or operate machinery if Codipar causes dizziness or sedation. Codeine may cause visual disturbances.
4.8 Undesirable Effects
Reported adverse reactions seem more prominent in ambulatory than non-ambulatory patients and some of these effects may be alleviated if the patient lies down.
The most commonly (>1/100, <1/10) reported reactions are:
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In clinical use of paracetamol-containing products, blood dyscrasias (including thrombocytopenia and agranulocytosis) are reported rarely (>1/10000, <1/1000).
Also, rarely hypersensitivity including skin rash may occur with paracetamol use. _
The frequencies of the following side effects are not known or cannot be estimated from the data available:
Eye disorders: Miosis
Renal and urinary disorders: Urinary retention
Codeine can cause respiratory depression particularly in overdosage and in patients with compromised respiratory function (see Section 4.9).
Liver damage in association with therapeutic use of paracetamol has been documented; most cases have occurred in conjunction with chronic alcohol abuse.
Regular prolonged use of codeine is known to lead to addiction and symptoms of restlessness and irritability may result when treatment is then stopped.
4.9 Overdose
Codeine
Large doses of codeine produce respiratory depression and hypotension, with circulatory failure and deepening coma. Convulsions may occur from respiratory failure. Blood concentrations of codeine ranged from 1.4 to 5.6 mg/l in eight adults whose deaths were attributed primarily to codeine overdosage.
Primary attention should be given to the re-establishment of adequate respiratory exchange through the provision of a patent airway and the institution of controlled ventilation. Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated. Opioid antagonists may be employed. Gastric lavage should be considered. Patients should remain under observation, as per hospital guidelines and on a case per case basis.
Paracetamol
Because of its ready availability, paracetamol is often taken in overdosage. Toxicity is likely if more than 150 mg/kg of paracetamol is ingested. The major complication is acute hepatic necrosis, although without treatment fewer than 10% of unselected patients are at risk of severe liver damage (plasma aminotransferase > 1000 mg/l). About 1% develop fulminant hepatic failure which is usually fatal. Renal failure from acute tubular necrosis is a further uncommon complication which may develop in the absence of hepatic failure. There are no specific early manifestations of severe paracetamol poisoning. Consciousness is not impaired except in the occasional unusually severely poisoned patient with metabolic acidosis, and maximum abnormality of liver function tests is delayed for at least 3 days.
Emergency estimation of the plasma paracetamol concentration is therefore necessary to determine the severity of intoxication and the need for specific therapy with N-acetylcysteine (NAC).
Patients who have ingested more than 150 mg/kg should have gastric lavage performed if they present within an hour of ingestion. Activated charcoal may also be given. A plasma paracetamol level will indicate the likelihood of a patient developing high ALT/AST activities (i.e> 1,000 i.u. /L) and must be measured at least 4 hours after ingestion. Plasma levels measured less than 4 hours post-ingestion cannot be interpreted. Patients with a plasma level above the treatment line require N-acetylcysteine (NAC). A paracetamol normogram should be employed to determine treatment levels.
Patients who present to an Accident and Emergency Department more than 8 hours after ingesting a paracetamol overdose are at greater risk of developing hepatic damage. In cases of severe poisoning, hepatic failure may progress to encephalopathy, coma and death.
Blood should be taken for a plasma level, but the NAC infusion should be started as soon as possible if more than 150 mg/kg was taken. The NAC infusion should not be delayed while awaiting the result of the plasma paracetamol level. Administration of the antidote should be stopped if the plasma level is subsequently found to be below the treatment line. General supportive measures must be available.
At the end of the NAC infusion, blood should be taken to check the INR and creatinine concentration. If the investigations are abnormal, a further infusion of NAC (at 16 hour dose), to be continued until recovery or death, should be considered.
In the range of concentrations associated with overdosage, paracetamol may give a false positive result for plasma salicylate in tests based on the direct colour reaction with ferric ions. In the same circumstances it may induce spuriously high results for blood dextrose estimated with the YSI and Yellow Springs Model 23AM dextrose analyzers. Conversely, it may cause falsely low results for dextrose when the dextrose peroxidase/dextrose-6-phosphate dehydrogenase method is used
Liver damage following overdosage is relatively uncommon in young children.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Anilides, Paracetamol combinations
ATC Code: NO2B E51
Paracetamol is an analgesic which acts peripherally, probably by blocking impulse generation at the bradykinin sensitive chemo-receptors which evoke pain. Paracetamol is a weak, reversible, isoform-nonspecific cyclooxygenase inhibitor at dosages of 1 g daily. The inhibitory effect of paracetamol on cyclooxygenase-1 is limited, and the drug does not inhibit platelet function. Animal studies have indicated that paracetamol strongly inhibits prostaglandin synthetase in the brain (which may account for its antipyretic and analgesic effects) but that it has little effect on peripheral tissue prostaglandins (which are involved in inflammatory reactions).
Codeine is a centrally acting analgesic. Codeine exerts its effect through ยต opioid receptors, although codeine has an exceptionally low affinity or these receptors, and its analgesic effect is due to its conversion to morphine. However, its antitussive actions may involve distinct receptors that bind codeine itself.
The conversion of codeine to morphine is effected by the CYP2D6. Well-characterised genetic polymorphism in CYP2D6 lead to the inability to covert codeine to morphine, thus making codeine ineffective as an analgesic for about 10% of the Caucasian population.
The fixed combination of paracetamol and codeine has been shown to be effective in acute nociceptive pain. However, data in chronic pain, cancer pain and neuropathic pain are lacking.
5.2 Pharmacokinetic Properties
Paracetamol is rapidly and completely absorbed after oral administration, with peak plasma concentrations occurring between 15 min and 2 h after ingestion. Paracetamol is distributed throughout most body tissues, with an apparent volume of distribution of approximately 1 L/kg of body weight. Concentrations in whole blood are up to 20% higher and in breast milk about 20% lower. Paracetamol crosses the placenta. Paracetamol is extensively metabolised in the liver and the total body clearance is about 5 ml/min/1/kg. Some 2-5% of a therapeutic dose of paracetamol is excreted unchanged in the urine.
Codeine is absorbed rapidly following oral administration; peak plasma concentrations occur in about 1 h and the plasma half-life is about 3.5 h. The volume of distribution is approximately 3.6 l/kg. The total body clearance of codeine is approximately 0.85 l/min. Codeine crosses the placenta and is present in the milk of lactating mothers.
Codeine is metabolised in the liver by O-demethylation to form morphine (codeine is in fact a pro-drug to morphine), and other metabolites. After an oral dose, about 86% is excreted in the urine in 24 h as free drug and metabolites, mostly in the form of metabolites. Some of a dose of codeine is excreted in the bile and trace amounts are found in the faeces. Unchanged drug accounts for 6-8% of the dose in urine in 24 h.
The bioavailabilities of paracetamol and codeine, when given as the combination, are similar to those when they are given separately.
5.3 Preclinical Safety Data
There are no findings of relevance to the prescriber other than those already mentioned elsewhere in the SPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium Hydrogen carbonate
Sodium carbonate anhydrous
Citric acid anhydrous
Sorbitol Neosorb P60 W
Povidone K30
Sodium Saccharin
Macrogol 6000
Grapefruit flavour
6.2 Incompatibilities
Not applicable
6.3 Shelf Life
2 years
6.4 Special Precautions For Storage
Do not store above 25°C
6.5 Nature And Contents Of Container
Strips of Aluminium / polyethylene foils
Each strip contains 4 tablets individually packed in cardboard containers.of 100 tablets.
6.6 Special Precautions For Disposal And Other Handling
The tablets should be placed in a glass of water and allowed to be dissolved completely. The resulting solution should be drunk immediately.
No special requirements for disposal
7. Marketing Authorisation Holder
Goldshield Pharmaceuticals Ltd
NLA Tower 12-16 Addiscombe Road
Croydon CR0 0XT
United Kingdom
8. Marketing Authorisation Number(S)
PL 12762/0405
9. Date Of First Authorisation/Renewal Of The Authorisation
16/08/2010
10. Date Of Revision Of The Text
07/02/2011
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