Active ingredients: Paracetamol, Codeine (codeine phosphate)
CO-EFFERALGAN 500 mg + 30 mg effervescent tablets
CO-EFFERALGAN 500 mg + 30 mg film-coated tablets
Why is Co-efferalgan used? What is it for?
Pharmacotherapeutic group
CO-EFFERALGAN is a medicine based on paracetamol and codeine.
Codeine belongs to a group of drugs called opioid analgesics, which work to relieve pain. It can be used alone or in combination with other pain relievers such as acetaminophen.
Co-Efferalgan is classified as anilide analgesic and antipyretic drugs (paracetamol, combinations excluding psycholeptics).
Therapeutic indications
Co-Efferalgan can be used in patients over 12 years of age, in the short-term treatment of moderate pain that is not relieved by other pain relievers such as acetaminophen or ibuprofen alone.
Contraindications When Co-efferalgan should not be used
Children under the age of 12.
Related to paracetamol
Hypersensitivity to paracetamol or propacetamol hydrochloride (precursor of paracetamol) or to any of the excipients.
Related to codeine
Hypersensitivity to codeine. In cases of respiratory failure, regardless of the degree, as codeine has a depressant effect on the respiratory centers.
To relieve pain in children and adolescents (0-18 years of age) after removal of the tonsils or adenoids due to obstructive sleep apnea syndrome.
In subjects who rapidly metabolize codeine to morphine.
In women who are breastfeeding.
Limited to the formulation in effervescent tablets
Phenylketonuria.
Due to the presence of sorbitol, this medicine is contraindicated in case of fructose intolerance.
Precautions for use What you need to know before taking Co-efferalgan
Paracetamol should be administered with caution to patients with mild to moderate hepatic insufficiency (including Gilbert's syndrome), severe hepatic insufficiency (Child-Pugh> 9), acute hepatitis, concomitant treatment with drugs that impair liver function, deficiency glucose-6-phosphate dehydrogenase, haemolytic anemia.
Paracetamol should be administered with caution in subjects with renal insufficiency (creatinine clearance ≤ 30 ml / min). In case of allergic reactions the administration should be discontinued.
Use with caution in case of chronic alcoholism, excessive alcohol intake (3 or more alcoholic drinks per day), anorexia, bulimia or cachexia, chronic malnutrition (low reserves of hepatic glutathione), dehydration, hypovolemia.
During treatment with paracetamol, before taking any other drug, check that it does not contain the same active ingredient, as serious adverse reactions can occur if paracetamol is taken in high doses. Also, before combining any other medication, contact your doctor. See also the "Interactions" section.
It is advisable, due to the presence of codeine, not to take alcoholic beverages; codeine can cause increased intracranial hypertension.
In patients who have had their gallbladder removed, codeine can induce acute biliary or pancreatic abdominal pain, usually associated with abnormal laboratory tests, indicative of spasm of the sphincter of Oddi. In the presence of a cough that produces phlegm, codeine may prevent its expectoration.
Codeine is transformed into morphine in the liver by an enzyme. Morphine is the substance that relieves pain. Some people have a variation of this enzyme and this can affect people in different ways. In some people, morphine is not produced or produced in very small quantities, and it will not be enough to relieve pain. Other people produce a high amount of morphine and are highly likely to have serious side effects. If you notice any of the following side effects, you should stop treatment and seek medical attention immediately: slow or shallow breathing, confusion, drowsiness, reduced pupils, nausea or vomiting, constipation, lack of appetite.
Children and adolescents
Use in children and adolescents after surgery
Codeine should not be used to relieve pain in children and adolescents after removal of the tonsils or adenoids due to obstructive sleep apnea syndrome.
Use in children with respiratory problems
Codeine is not recommended for children with respiratory problems, as the symptoms of morphine toxicity may be worse in these children.
In the case of a low-sodium diet, it should be borne in mind that 1 effervescent tablet of COEFFERALGAN contains 380 mg of sodium (equal to 16.5 mEq).
Do not associate with other depressant drugs such as sedatives, tranquilizers and antistamines.
Interactions Which drugs or foods can modify the effect of Co-efferalgan
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Paracetamol can increase the chance of side effects if given at the same time as other drugs. The administration of paracetamol can interfere with the determination of uric acid (by the method of phosphotungstic acid) and with that of blood glucose (by the method of glucose oxidase-peroxidase).
During therapy with oral anticoagulants it is recommended to reduce the doses. Patients being treated with rifampicin, cimetidine or antiepileptic drugs such as glutethimide, phenobarbital, carbamazepine should use paracetamol with extreme caution and only under strict medical supervision.
Patients being treated with phenytoin should avoid taking high and / or chronic doses of paracetamol.
A dose reduction of paracetamol should be considered when administered concomitantly with probenecid.
The effects of opium alkaloids can be enhanced by other depressant drugs such as sedatives, tranquilizers and antihistamines.
CO-EFFERALGAN is contraindicated in combination with:
- Morphine agonists and antagonists (buprenorphine, nalbuphine, pentazocine).
In function of the reduced analgesic effect due to the competitive blocking of receptors, with the risk of onset of rejection syndrome.
- Alcohol Alcohol increases the sedative effect of morphine analgesics. Reduced alertness can make it dangerous to drive and use machines.
- Naltrexone There is a risk of reduced analgesic effect. The dosage of morphine derivatives should be increased if necessary.
The combination of CO-EFFERALGAN with:
- Other morphine agonist analgesics (alfentanil, dextromoramide, dextropropoxyphene, fentanyl, dihydrocodeine, hydromorphone, morphine, oxycodone, pethidine, phenoperidine, remifentanil, sufentanil, tramadol), morphine-like antitussive drugs, morphine dextrine-like drugs (suppressor metorphine), morphine dextrin-like drugs, nipinoscorphine cough (codeine, etymorphine), benzodiazepines, barbiturates, methadone.
Increased risk of respiratory depression which can be fatal in case of overdose.
- Other sedative drugs: morphine derivatives (analgesics, cough suppressants and replacement treatments) neuroleptics, barbiturates, benzodiazepines, anxiolytics other than benzodiazepines (meprobramate), hypnotics, sedative antidepressants (amitriptyline, doxepine, mirtazapine, mianserin), trimipramate Sedative H1, centrally acting anti-hypertensive drugs, baclofen and thalidomide. Increased central depressive action. The altered state of alertness can make it dangerous to drive or use machines.
Warnings It is important to know that:
High or prolonged doses of the product can cause high-risk liver disease and alterations, even serious ones, in the kidney and blood (paracetamol) or cause addiction (codeine). Do not administer during chronic treatment with drugs that can determine the induction of hepatic monooxygenases or in case of exposure to substances that can have this effect (paracetamol). The product can cause drowsiness and vehicle drivers and people who use machinery.
Pregnancy
Epidemiological data on the use of therapeutic doses of oral paracetamol indicate that no undesirable effects occur in pregnant women or on the health of the fetus or newborns. Reproductive studies with paracetamol have shown no malformation or foetotoxic effects. Paracetamol must, however, , to be used during pregnancy only after a "careful evaluation of the risk / benefit ratio.
In pregnant patients, the recommended posology and duration of treatment should be strictly observed.
With regard to the presence of codeine, if the drug is taken at the end of pregnancy, its morphine mimetic characteristics must be taken into consideration (theoretical risk of respiratory depression in newborns in case of high doses taken before birth, risk of withdrawal syndrome in case of chronic administration at the end of pregnancy).
In clinical practice, although an increased risk of cardiac malformations has been demonstrated in some sample cases, most epidemiological studies exclude the risk of malformations. Studies in animals have shown a teratogenic effect.
Feeding time
The medicine should not be taken by women who are breastfeeding. Codeine and morphine pass into breast milk.
Dosage and method of use How to use Co-efferalgan: Dosage
1-2 tablets depending on the degree of pain 1-3 times a day at intervals of at least 4 hours. In case of severe renal insufficiency the interval between two administrations should be at least 8 hours.
Elderly: The starting dose should be halved according to the recommended dosage for adults and may subsequently be increased according to tolerance and requirements.
Co-Efferalgan should not be taken by children under the age of 12 due to the risk of severe breathing problems.
The medicine should not be taken for more than 3 days. If the pain does not improve after 3 days, speak to your doctor for advice.
The effervescent tablets should be dissolved in a glass of water, according to the directions.
Overdose What to do if you have taken an overdose of Co-efferalgan
Methods of intervention in case of overdose
Paracetamol
There is a risk of intoxication, especially in patients with liver disease, in cases of chronic alcoholism, in patients with chronic malnutrition, and in patients receiving enzyme inducers. In these cases, overdose can be fatal.
Symptoms generally appear within the first 24 hours and include: nausea, vomiting, anorexia, paleness, malaise and diaphoresis.
Overdose with acute ingestion of 7.5 g or more of paracetamol in adults and 140 mg / kg body weight in children causes hepatic cytolysis which can progress to complete and irreversible necrosis, resulting in hepatocellular failure, metabolic acidosis and encephalopathy, which can lead to coma and death. At the same time, increased levels of hepatic transaminases (AST, ALT), lactic dehydrogenase and bilirubin are observed, together with a decrease in the prothrombin value, which may occur 12 to 48 hours after administration. Clinical symptoms of liver damage usually manifest themselves after one or two days, and reach their maximum after 3 - 4 days.
Emergency measures:
- Immediate hospitalization.
- Before starting treatment, take a blood sample to determine plasma paracetamol levels as soon as possible, but not earlier than 4 hours after the overdose. - Rapid elimination of paracetamol by gastric lavage.
- Treatment following an overdose includes the administration of the antidote, Nacetylcysteine (NAC), intravenously or orally, if possible, within 8 hours of ingestion. NAC may, however, provide some degree of protection. even after 16 hours.
- Symptomatic treatment.
Liver tests should be performed at the start of treatment, which will be repeated every 24 hours. In most cases, liver transaminases return to normal within a week or two with full recovery of liver function. In very severe cases, however. , liver transplantation may be required.
Codeine
Signs in adults: acute depression of the respiratory centers (cyanosis, impaired respiratory function), drowsiness, rash, itching, vomiting, ataxia, pulmonary edema (rare).
Signs in children (toxic dose: 2 mg / kg as a single dose): impaired respiratory function, respiratory arrest, miosis, convulsions, histamine release signals: facial redness and swelling, hives, collapse, urinary retention.
Emergency measures
- Assisted ventilation.
- Administration of naloxone.
Side Effects What are the side effects of Co-efferalgan
Skin reactions of various types and severities have been reported with the use of paracetamol including cases of erythema multiforme, Stevens-Johnson syndrome and epidermal necrolysis.
Hypersensitivity reactions such as angioedema, larynx edema, anaphylactic shock have been reported. In addition, the following undesirable effects have been reported: thrombocytopenia, leukopenia, anemia, agranulocytosis, liver function abnormalities and hepatitis, kidney disorders (acute renal failure, interstitial nephritis, haematuria, anuria), gastrointestinal reactions and dizziness.
In case of overdose, paracetamol can cause hepatic cytolysis which can evolve towards massive and irreversible necrosis.
The table below lists the adverse reactions, some of which already mentioned above, associated with the administration of paracetamol, resulting from subsequent surveillance.
At therapeutic doses, codeine-related undesirable effects are comparable to those of other opioids, although they are rarer and more modest.
It is possible the occurrence of:
- constipation, nausea, vomiting
- sedation, euphoria, dysphoria
- miosis, urinary retention
- hypersensitivity reactions (itching, hives and rash)
- drowsiness, dizziness
- bronchospasm, respiratory depression
- acute biliary or pancreatic abdominal pain syndrome, suggesting spasm of the sphincter of Oddi, which occurs particularly in patients who have had their gallbladder removed.
At higher than therapeutic dosages: there is a risk of addiction and withdrawal syndrome following a "sudden interruption of dosing which can be observed in both patients and infants born to codeine-dependent mothers."
Compliance with the instructions contained in this leaflet reduces the risk of undesirable effects.
It is important to inform the doctor or pharmacist of any undesirable effects, even those not described in the package leaflet.
Expiry and Retention
Expiry: see the expiry date indicated on the package. The expiry date indicated refers to the product in intact packaging, correctly stored. Warning: do not use the medicine after the expiry date indicated on the package. Special precautions for storage Protect from moisture and heat.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
KEEP THE MEDICINAL PRODUCT OUT OF THE REACH AND SIGHT OF CHILDREN
Composition
Film-coated tablets
Each tablet contains: Active ingredients: paracetamol 500 mg, codeine phosphate 30 mg. Excipients: povidone, microcrystalline cellulose, croscarmellose sodium, magnesium stearate. Filming agent: hypromellose (E464), titanium dioxide (E171), propylene glycol.
Effervescent tablets
Each effervescent tablet contains: Active ingredients: paracetamol 500 mg, codeine phosphate 30 mg. Excipients: sodium bicarbonate, sodium carbonate, citric acid, sorbitol, sodium benzoate, sodium docusate, polyvinylpyrrolidone, aspartame, grapefruit natural flavor.
Pharmaceutical form and packaging
Film-coated tablets - Box of 16 tablets
Effervescent tablets - Box of 16 effervescent tablets
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
CO-EFFERALGAN
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
CO-EFFERALGAN 500 mg + 30 mg film-coated tablets
each tablet contains:
active ingredients: paracetamol 500 mg, codeine phosphate 30 mg.
CO-EFFERALGAN 500 mg + 30 mg effervescent tablets
each effervescent tablet:
active ingredients: paracetamol 500 mg, codeine phosphate 30 mg.
For excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablets and effervescent tablets for oral use.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Co-Efferalgan is indicated in patients over 12 years of age for the treatment of acute moderate pain that is not adequately controlled by other analgesics such as paracetamol or ibuprofen used alone.
04.2 Posology and method of administration
1-2 tablets depending on the extent of the pain 1-3 times a day at intervals of at least 4 hours.
In case of severe renal insufficiency the interval between two administrations must be at least 8 hours.
Elderly: The starting dose should be halved according to the recommended dosage for adults and may subsequently be increased according to tolerance and requirements.
Children below 12 years of age: Codeine should not be used in children below 12 years of age due to the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see sections 4.3 and 4.4).
The duration of treatment should be limited to 3 days, and if effective pain relief is not achieved the patient / caregiver should be advised to seek medical advice.
The effervescent tablets should be dissolved in a glass of water, according to the directions.
04.3 Contraindications
Children under the age of 12.
Related to paracetamol
Hypersensitivity to paracetamol or propacetamol hydrochloride (precursor of paracetamol) or to any of the excipients.
Related to codeine
Hypersensitivity to codeine.
In cases of respiratory failure, regardless of the degree, as codeine has a depressant effect on the respiratory centers.
In all pediatric patients (up to 18 years of age) undergoing tonsillectomy and / or adenoidectomy for obstructive sleep apnea syndrome, due to an increased risk of developing serious and life-threatening adverse reactions ( see section 4.4).
In women during breastfeeding (see section 4.6).
In patients known to be CYP2D6 ultra-rapid metabolisers.
Limited to the formulation in effervescent tablets
Phenylketonuria.
Due to the presence of sorbitol, this medicine is contraindicated in case of fructose intolerance.
04.4 Special warnings and appropriate precautions for use
Paracetamol should be administered with caution to patients with mild to moderate hepatic insufficiency (including Gilbert's syndrome), severe hepatic insufficiency (Child-Pugh> 9), acute hepatitis, concomitant treatment with drugs that impair liver function, deficiency of glucose-6-phosphate-dehydrogenase, haemolytic anemia.
Do not administer during chronic treatment with drugs that can determine the induction of hepatic monooxygenases or in case of exposure to substances that can have this effect (paracetamol) (see 4.5).
Paracetamol should be administered with caution in subjects with renal insufficiency (creatinine clearance ≤ 30 ml / min).
Use with caution in case of chronic alcoholism, excessive alcohol intake (3 or more alcoholic drinks per day), anorexia, bulimia or cachexia, chronic malnutrition (low reserves of hepatic glutathione), dehydration, hypovolemia.
During treatment with paracetamol, before taking any other drug, check that it does not contain the same active ingredient, as serious adverse reactions can occur if paracetamol is taken in high doses.
Instruct the patient to contact the physician before associating any other medication. See also "Interactions".
High or prolonged doses of the product can cause high-risk liver disease and alterations, even serious ones, in the kidney and blood (paracetamol) or cause addiction (codeine).
In case of allergic reactions the administration should be discontinued.
It is advisable, due to the presence of codeine, not to drink alcoholic beverages; codeine can cause increased intracranial hypertension.
In patients who have had their gallbladder removed, codeine may induce acute biliary or pancreatic abdominal pain, usually associated with abnormal laboratory tests, indicative of sphincter of Oddi spasm.
If you have a cough that produces phlegm, codeine can prevent it from expectorating.
In the case of a low-sodium diet, it must be borne in mind that 1 effervescent tablet of CO-EFFERALGAN contains 380 mg of sodium (equal to 16.5 mEq).
CYP2D6 metabolism
Codeine is metabolised by the hepatic enzyme CYP2D6 to morphine, its active metabolite.
If a patient has a deficiency or completely lacks this enzyme, a sufficient analgesic effect will not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency.
However, if the patient is an extended or ultrafast metabolizer, there is an increased risk of developing side effects of opioid toxicity even at commonly prescribed doses. These patients convert codeine to morphine rapidly, resulting in an increase in the expected serum levels of morphine.
General symptoms of opioid toxicity include confusion, sleepiness, shallow breathing, miotic pupil, nausea, vomiting, constipation, and lack of appetite. In severe cases, this can include symptoms of respiratory and circulatory depression, which can be life-threatening and very rarely fatal.
Treatment of morphine overdose is described in section 4.9.
Prevalence estimates of ultra-rapid metabolisers in different populations are summarized below:
The risk of intoxication is higher in ultra-rapid metabolisers with impaired renal function (see also section 5.2).
A case of morphine intoxication at therapeutic doses of codeine in an ultra-rapid metabolizer has been reported.
A fatal case of morphine intoxication has also been reported in a breastfed infant whose mother was an ultra-rapid metaboliser treated with codeine at therapeutic doses (see also section 4.6).
Post-operative use in children
There have been reports in the literature where codeine, given to children after tonsillectomy and / or adenoidectomy for obstructive sleep apnea, has induced rare, but life-threatening, adverse events including death (see also paragraph 4.3).
All children received doses of codeine that were within the appropriate dose range; however, there was evidence that these children were ultra-rapid or extensive metabolisers in their ability to metabolize codeine to morphine.
Children with impaired respiratory function
Codeine is not recommended for use in children in whom respiratory function may be impaired, which includes neuromuscular disorders, severe heart or respiratory conditions, upper respiratory or lung infections, multiple trauma, or extensive surgical procedures. These factors can worsen symptoms of morphine toxicity.
04.5 Interactions with other medicinal products and other forms of interaction
Paracetamol can increase the chance of side effects if given at the same time as other drugs.
The administration of paracetamol can interfere with the determination of uric acid (by the method of phosphotungstic acid) and with that of blood glucose (by the method of glucose-oxidase-peroxidase).
During therapy with oral anticoagulants it is recommended to reduce the doses.
Monooxygenase inducing drugs
Use with extreme caution and under strict control during chronic treatment with drugs that can determine the induction of hepatic monooxygenases or in case of exposure to substances that can have this effect (for example rifampicin, cimetidine, antiepileptics such as glutethimide, phenobarbital, carbamazepine) .
Phenytoin
Concomitant administration of phenytoin may result in decreased efficacy of paracetamol and an increased risk of hepatotoxicity. Patients being treated with phenytoin should avoid high and / or chronic doses of paracetamol. Patients should be monitored for evidence of hepatotoxicity.
Probenecid
Probenecid causes an at least two-fold reduction in paracetamol clearance through inhibition of its conjugation with glucuronic acid. A dose reduction of paracetamol should be considered when administered concomitantly with probenecid.
Salicylamide
Salicylamide may prolong the elimination half-life (t½) of paracetamol.
The effects of opium alkaloids can be enhanced by other depressant drugs such as sedatives, tranquilizers and antihistamines.
CO-EFFERALGAN is contraindicated in combination with:
• Morphine agonists and antagonists (buprenorphine, nalbuphine, pentazocine)
In function of the reduced analgesic effect due to the competitive blocking of receptors, with the risk of onset of rejection syndrome.
• Alcohol
Alcohol increases the sedative effect of morphine analgesics.
Reduced alertness can make it dangerous to drive and use machines.
• Naltrexone
There is a risk of reduced analgesic effect. The dosage of morphine derivatives should be increased if necessary.
The combination of CO-EFFERALGAN with:
• Other morphine agonist analgesics (alfentanil, dextromoramide, dextropropoxyphene, fentanyl, dihydrocodeine, hydromorphone, morphine, oxycodone, pethidine, phenoperidine, remifentanil, sufentanil, tramadol), morphine-like antitussive drugs, morphine dextrin metorphine, follicle suppressor drugs cough (codeine, etymorphine) benzodiazepines, barbiturates, methadone
Increased risk of respiratory depression which can be fatal in case of overdose.
• Other sedative drugs: morphine derivatives (analgesics, cough suppressants and replacement treatments), neuroleptics, barbiturates, benzodiazepines, anxiolytics other than benzodiazepines (meprobramate), hypnotics, sedative antidepressants (amitriptyline, doxepine, mirtazapine, mianserin, trimester) ), sedative H1 antihistamines, centrally acting anti-hypertensive drugs, baclofen and thalidomide. Increased central depressive action. The altered state of alertness can make it dangerous to drive or use machines.
04.6 Pregnancy and lactation
Clinical experience with the use of paracetamol during pregnancy and lactation is limited.
Pregnancy
Epidemiological data on the use of therapeutic doses of oral paracetamol indicate that no undesirable effects occur in pregnant women or on the health of the fetus or newborns. Reproductive studies with paracetamol have shown no malformation or foetotoxic effects. Paracetamol must, however, , to be used during pregnancy only after a "careful evaluation of the risk / benefit ratio.
In pregnant patients, the recommended posology and duration of treatment should be strictly observed.
With regard to the presence of codeine, if the drug is taken at the end of pregnancy, its morphine mimetic characteristics must be taken into consideration (theoretical risk of respiratory depression in newborns in case of high doses taken before birth, risk of withdrawal syndrome in case of chronic administration at the end of pregnancy).
In clinical practice, although an increased risk of cardiac malformations has been demonstrated in some sample cases, most epidemiological studies exclude the risk of malformations.
Studies in animals have shown a teratogenic effect.
Feeding time
Codeine should not be used during breastfeeding (see section 4.3).
At normal therapeutic doses, codeine and its active metabolite may be present in breast milk at very low doses, and are unlikely to adversely affect the infant. However, if the patient is an ultra-rapid metabolizer of CYP2D6, higher levels of the active metabolite morphine may be present in breast milk, and in very rare cases they can cause symptoms of opioid toxicity in the newborn, which can be fatal.
A case of morphine intoxication was reported in a breastfed infant whose mother was an ultra-rapid metabolizer treated with codeine at therapeutic doses.
04.7 Effects on ability to drive and use machines
The product may cause drowsiness and vehicle drivers and people using machinery should be warned of this.
04.8 Undesirable effects
Skin reactions of various types and severities have been reported with the use of paracetamol including cases of erythema multiforme, Stevens-Johnson syndrome and epidermal necrolysis.
Hypersensitivity reactions such as angioedema, larynx edema, anaphylactic shock have been reported. In addition, the following undesirable effects have been reported: thrombocytopenia, leukopenia, anemia, agranulocytosis, liver function abnormalities and hepatitis, kidney changes (acute renal failure, interstitial nephritis, haematuria, anuria), gastrointestinal reactions and dizziness.
The table below lists the adverse reactions, some of which have already been mentioned above, associated with the administration of paracetamol, resulting from post-marketing surveillance. The frequency of adverse reactions listed below is not known.
In case of overdose, paracetamol can cause hepatic cytolysis which can evolve towards massive and irreversible necrosis.
At therapeutic doses, codeine-related undesirable effects are comparable to those of other opioids, although they are rarer and more modest.
It is possible the occurrence of:
• constipation, nausea, vomiting
• sedation, euphoria, dysphoria
• miosis, urinary retention
• hypersensitivity reactions (itching, hives and rash)
- sleepiness, dizziness
• bronchospasm, respiratory depression
• acute biliary or pancreatic abdominal pain syndrome, suggesting spasm of the sphincter of Oddi, which occurs particularly in patients who have had their gallbladder removed.
At higher than therapeutic dosages: there is a risk of addiction and withdrawal syndrome following a "sudden interruption of dosing which can be observed in both patients and infants born to codeine-dependent mothers."
The risk of pancreatitis was highlighted in the paracetamol and codeine combinations.
04.9 Overdose
Paracetamol
There is a risk of intoxication, especially in patients with liver disease, in cases of chronic alcoholism, in patients with chronic malnutrition, and in patients receiving enzyme inducers. In these cases, overdose can be fatal.
Symptoms generally appear within the first 24 hours and include: nausea, vomiting, anorexia, paleness, malaise and diaphoresis. Overdose with acute ingestion of 7.5 g or more of paracetamol in adults and 140 mg / kg body weight in children causes hepatic cytolysis which can progress to complete and irreversible necrosis, resulting in hepatocellular failure, metabolic acidosis and encephalopathy, which can lead to coma and death. At the same time, increased levels of hepatic transaminases (AST, ALT), lactic dehydrogenase and bilirubin are observed, together with a decrease in the prothrombin value, which may occur 12 to 48 hours after administration. Clinical symptoms of liver damage usually manifest themselves after one or two days, and reach their maximum after 3 to 4 days.
Emergency measures:
• Immediate hospitalization.
• Before starting treatment, take a blood sample to determine plasma paracetamol levels as soon as possible, but not earlier than 4 hours after the overdose.
• Rapid elimination of paracetamol by gastric lavage.
• Treatment following an overdose includes the administration of the antidote, N-acetylcysteine (NAC), intravenously or orally, if possible, within 8 hours of ingestion. NAC may, however, give some degree of protection even after 16 hours.
• Symptomatic treatment.
Liver tests should be performed at the start of treatment, which will be repeated every 24 hours. In most cases, liver transaminases return to normal within a week or two with full recovery of liver function. In very severe cases, however. , liver transplantation may be required.
Codeine
Signs in adults:
Acute depression of the respiratory centers (cyanosis, reduced respiratory function), somnolence, rash, vomiting, pruritus, ataxia, pulmonary edema (rare).
Signs in children (toxic dose: 2 mg / kg as a single dose):
Reduced respiratory function, respiratory arrest, miosis, convulsions, histamine release signals: facial redness and swelling, hives, collapse, urinary retention.
Emergency measures:
• Assisted ventilation.
• Administration of naloxone.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: analgesics, natural opium alkaloids.
ATC code: N02AA59.
Co-Efferalgan is a pharmaceutical specialty based on paracetamol and codeine, classified among anilide analgesic and antipyretic drugs (paracetamol, associations excluding psycholeptics; atc: N02BE51), indicated in the symptomatic treatment of painful affections.
The paracetamol occupies a prominent place among analgesics-antipyretics.Furthermore, being a non-salicylic drug, it is well tolerated in the stomach, and can therefore be advantageously used in case of intolerance to salicylates.
There codeine, a natural opium alkaloid, is a weak centrally acting analgesic. Codeine exerts its effect through the µ opioid receptors, although it has a low affinity for these receptors, and its analgesic effect is due to its conversion to morphine. Codeine, particularly in combination with other analgesics such as acetaminophen, has been shown to be effective in acute nociceptive pain.
The association paracetamol-codeine it has a greater analgesic effect than the single components and longer lasting.
05.2 Pharmacokinetic properties
The paracetamol it is rapidly and almost totally absorbed from the gastrointestinal tract, with rapid diffusion in organic liquids and weak binding to plasma proteins; it has a half-life of approximately 2 hours. At the hepatic level it is metabolized and eliminated via the urine in the form of glucuronide conjugates (60-80%), sulfur conjugates (20-30%) and as such only in small part (less than 5%). A small percentage (about 4%) by cytochrome P 450 gives rise to a metabolite which is conjugated by glutathione; the amount of this metabolite increases in case of overdose intoxication. There codeine it is rapidly absorbed from the intestine, with a half-life of approximately 3 hours; in the liver it is transformed into inactive glucuronide conjugates and excreted in the urine. There codeine crosses the placental barrier.
Special patient groups
Slow and ultra-rapid metabolisers of the CYP2D6 enzyme
Codeine is metabolised primarily via glucuroconjugation, but through a minor metabolic pathway, such as O-demethylation, it is converted to morphine. This metabolic transformation is catalyzed by the CYP2D6 enzyme. About 7% of the population of Caucasian origin has a deficiency of the CYP2D6 enzyme due to genetic variation. These subjects are called poor metabolisers and may not benefit from the expected therapeutic effect as they are unable to transform codeine into its active metabolite morphine.
Conversely, about 5.5% of the population in Western Europe is made up of ultra-rapid metabolisers. These subjects have one or more duplicates of the CYP2D6 gene and therefore may have higher concentrations of morphine in the blood resulting in an increased risk of adverse reactions (see also sections 4.4 and 4.6).
The existence of ultra-rapid metabolisers should be considered with particular attention in the case of patients with renal insufficiency in whom an increase in the concentration of the active metabolite morphine-6-glucuronide may occur.
The genetic variation related to the CYP2D6 enzyme can be ascertained by the genetic typing test.
05.3 Preclinical safety data
The paracetamol administered to common laboratory animals and by various routes (oral, i.p., subcutaneous), it proved to be devoid of ulcerogenic properties, even after prolonged administration. It was also found devoid of embryotoxic and teratogenic effects and was well tolerated even in specific carcinogenesis studies. Its toxicological profile is not enhanced by association with codeine.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Film-coated tablets
povidone, microcrystalline cellulose, croscarmellose sodium, magnesium stearate. Filming agent: hypromellose (E464), titanium dioxide (E171), propylene glycol.
Effervescent tablets
sodium bicarbonate, sodium carbonate, citric acid, sorbitol, sodium benzoate, sodium docusate, povidone, aspartame, grapefruit natural flavor.
06.2 Incompatibility
No specific incompatibilities are known.
06.3 Period of validity
Film-coated tablets and effervescent tablets: 3 years.
06.4 Special precautions for storage
Protect from moisture and heat.
06.5 Nature of the immediate packaging and contents of the package
Aluminum / polythene blister
Pack of 16 film-coated tablets
Pack of 16 effervescent tablets
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Bristol-Myers Squibb S.a.r.l. - Rueil Malmaison (France), represented in Italy by: BRISTOL-MYERS SQUIBB S.r.l. Via Virgilio Maroso, 50 - Rome
08.0 MARKETING AUTHORIZATION NUMBER
CO-EFFERALGAN 500 mg + 30 mg film-coated tablets: 16 tablets A.I.C. N ° 027989033
CO-EFFERALGAN 500 mg + 30 mg effervescent tablets: 16 effervescent tablets A.I.C. N ° 027989019.
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 18 June 1993
Last renewal date: 1 July 2008
10.0 DATE OF REVISION OF THE TEXT
March 2015
