Active ingredients: Paracetamol, Codeine (Codeine phosphate)
LONARID 400 mg + 10 mg tablets
LONARID adults 400 mg + 20 mg suppositories
LONARID children 200 mg + 5 mg suppositories
Why is Lonarid used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Other analgesics and antipyretics
This product contains codeine. Codeine belongs to a group of drugs called opioid analgesics that work to relieve pain. It can be used alone or in combination with other pain relievers such as acetaminophen.
THERAPEUTIC INDICATIONS
Adults
Neuralgia, myalgia and arthralgia; toothache and consecutive pains after tooth extractions; headaches of all kinds; ear pain; dysmenorrhea; post-operative and post-traumatic pains
Children over the age of 12
Codeine can be used in children 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 Lonarid should not be used
- Hypersensitivity to the active substances or to any of the excipients.
- Children under 12 years of age (see sections "Therapeutic indications" and "Warnings and precautions")
- Porphyria, severe hepatocellular (Child - Pugh C) and renal insufficiency, severe myocardial damage, acute intoxication from alcohol, sleeping pills, analgesics, psychotropic drugs; in all those states that are accompanied by depression of the breath, in cough with danger of stagnation of the secretion, in chronic constipation, in pulmonary emphysema, in bronchial asthma, in acute asthma attack, in pneumonia.
- Imminent birth, risk of premature birth.
- Intestinal obstruction.
- Paracetamol-based products are contraindicated in patients with manifest insufficiency of glucose-6-phosphate dehydrogenase and in those suffering from severe haemolytic anemia.
- 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 patients known to rapidly metabolize codeine to morphine
- In women during breastfeeding with breast milk
Precautions for use What you need to know before taking Lonarid
During treatment with Lonarid, before taking any other medicine, check that it does not contain paracetamol and codeine, as serious adverse reactions can occur if taken in high doses. Also, before combining any other medicine, contact your doctor. See also "Interactions". Due to the presence of paracetamol, administer with caution in subjects with renal or hepatic insufficiency. High or prolonged doses of the product can cause high-risk liver disease and even serious changes in the kidney and blood. Do not administer for more than three consecutive days without consulting your doctor.
Lonarid should be used after a "careful risk-benefit assessment in cases of opioid dependence, loss of consciousness, hypovolaemic states, head injuries, intracranial injuries or in case of pre-existing increases in intracranial pressure, concomitant administration of inhibitors of MAO, chronic obstructive airway diseases, glucose-6-phosphate-dehydrogenase deficiency, chronic constipation, Gilbert's syndrome.
A dose reduction or prolongation of the dosage interval is required in the following cases: liver function disorders and hepatitis (Child-Pugh AB), chronic alcohol abuse, Gilbert's syndrome (Maulengracht disease), severe renal insufficiency (clearance of creatinine habituation.
The individual patient's reaction to the medicinal product should be monitored at the start of treatment so that any related overdoses can be detected early. This is particularly true for elderly patients and for patients with impaired renal or respiratory function.
During therapy with oral anticoagulants it is recommended to reduce the doses.
Severe acute hypersensitivity reactions (e.g. anaphylactic shock) are very rarely observed. Treatment should be stopped at the first sign of a hypersensitivity reaction following administration of Lonarid. Based on these signs and symptoms it is necessary to intervene with medical measures.
A higher than recommended dosage can damage the liver.
Extensive use of analgesics, especially at high doses, can cause headache which should not be treated with higher doses of the medicine. In such cases, the analgesic should not be continued without a doctor's advice. Abrupt discontinuation of analgesics after prolonged use at high doses may induce withdrawal symptoms (e.g. headache, fatigue, nervousness, muscle aches and vegetative symptoms), which usually resolve within a few days. The resumption of therapy depends on the doctor's opinion, and on the abatement of withdrawal symptoms.
High dosages of this medicinal product should not be taken by patients with hypotension and concomitant hypovolaemia.
Codeine, in fixed association with paracetamol, has a primary addictive potential. Addiction, physical and psychological dependence develop with the prolonged use of high doses. There is cross-habituation with other opiates. Relapses can be expected in a short time in patients with pre-existing opioid dependence (including those in remission). Codeine is considered by addicts to be a heroin substitute. People addicted to alcohol or sedatives also tend to misuse codeine. Codeine, taken in high doses and over a prolonged period of time, can be addictive.
Patients undergoing cholecystectomy should be treated with caution. Contraction of the sphincter of Oddi can cause symptoms similar to those of a myocardial infarction or intensify symptoms in patients with pancreatitis. Preparations containing codeine can only be taken if prescribed by the doctor and under his regular supervision.
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 isn't made or produced in very small quantities, and it won't 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.
Medicines that have been prescribed for personal use should not be given to others.
Interactions Which drugs or foods can modify the effect of Lonarid
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Paracetamol
Patients on chronic treatment with medicinal products that can lead to 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) should use paracetamol with extreme caution and only under strict medical supervision.
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).
The association with other psychotropic drugs requires particular caution and vigilance on the part of the physician, to avoid unexpected undesirable effects from interaction.
Do not administer alcohol during treatment.
Otherwise harmless doses of paracetamol can cause liver damage when taken together with drugs that induce enzyme induction, such as certain hypnotics and antiepileptics (eg glutethymide, phenobarbital, phenytoin, carbamazepine) and rifampicin. The same can happen in the case of potentially hepatotoxic substances and alcohol abuse (see "Overdose").
For oral use only:
Medicines that slow down gastric emptying, such as propantheline, reduce the absorption rate of paracetamol and delay the onset of its effect. Medicines that accelerate gastric emptying, such as metoclopramide, lead to an increase in the rate of absorption.
The combination of paracetamol with chloramphenicol can prolong the half-life of chloramphenicol, increasing its risk of toxicity.
The clinical relevance of the interactions between paracetamol and warfarin and with coumarin derivatives could not be assessed. Therefore, the prolonged use of paracetamol in patients being treated with oral anticoagulants is advisable only under medical supervision.
The concomitant use of paracetamol and AZT (zidovudine or retrovir) increases the risk of neutropenia induced by the latter. Therefore, Lonarid should be taken together with AZT only under medical supervision.
Intake of probenecid inhibits the binding of paracetamol to glucuronic acid, thereby reducing the clearance of paracetamol by about a factor of 2. Therefore, the dose of paracetamol should be reduced when given in combination with probenecid.
Cholestyramine reduces the absorption of paracetamol.
Codeine
In patients receiving other narcotic analgesics, antipsychotics, anxiolytics or other CNS depressants (including alcohol) concomitantly with codeine, additive CNS depression may occur. The sedative and depressing effect on the respiratory system. can be increased by concomitant administration of alcohol or other CNS depressants such as sedatives, hypnotic or psychotropic agents (phenothiazines, such as chlorpromazine, thioridazine, perphenazine) and antihistamines (eg promethazine, meclozine), antihypertensives and other analgesics. Codeine-induced respiratory depression can be potentiated by tricyclic antidepressants (imipramine, amitriptyline) and opipramol. Since concomitant administration of MAO inhibitors, e.g. tranylcypromine, may lead to potentiation of CNS effects and other undesirable effects of unpredictable severity, this medicinal product should not be taken until two weeks after completion of treatment. with MAO inhibitors.
The effect of analgesics is also enhanced. Concomitant use of partial agonists / opioid antagonists, such as buprenorphine, pentazocine may reduce the effect of the drug.
Cimetidine and other medicinal products that affect liver metabolism may potentiate the effect of Lonarid. During treatment with morphine, an inhibition of its catabolism, resulting in an increase in its plasma concentration, has been observed. An interaction of this type cannot be observed. be excluded for codeine.
Alcohol should be avoided during treatment with this medicine as psychomotor capacity can be significantly reduced (additive effect of the individual components).
Warnings It is important to know that:
Fertility, pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
Pregnancy
Paracetamol
Long experience has shown no evidence of undesirable adverse effects on pregnancy or the health of the fetus or newborn. Prospective data regarding paracetamol overdose during pregnancy did not show any increased risk of malformations. Reproduction studies conducted to investigate the oral use of paracetamol have shown no signs suggesting malformations or foetotoxicity. Under normal conditions of use, paracetamol can be used during pregnancy (ie in all trimesters), after a "careful evaluation of the risk-benefit ratio. During pregnancy, paracetamol should not be taken for prolonged periods, in high doses or in combination with other medicines, as safety has not been confirmed in these cases.
Codeine
The use of Lonarid is contraindicated in cases of preterm birth or risk of premature birth, as codeine phosphate crosses the placental barrier and can produce respiratory depression in newborns.Findings from a case-control study suggest that it may increase the risk of respiratory tract malformations in the offspring of women who used codeine during the first four months of pregnancy. This increase was not statistically significant. Evidence of other malformations is also reported in epidemiological studies conducted in narcotic analgesics, including codeine. Long-term codeine intake may develop opioid dependence in the fetus. Lonarid should only be used in pregnancy if the potential benefit justifies the potential risk to the fetus. If Lonarid is used for an extended period of time during the latter trimester of pregnancy, neonatal withdrawal syndrome may develop.
Feeding time
Do not take codeine while breastfeeding. Codeine and morphine pass into breast milk.
Fertility
Preclinical studies have not indicated direct or indirect harmful effects on fertility index.
Effects on ability to drive and use machines
Undesirable effects such as fatigue, somnolence, syncope, light-headedness, dizziness, sedation, myosis and disturbances in visomotor coordination and visual acuity may occur during treatment with Lonarid. Therefore caution is recommended when driving or driving vehicles. use of machinery. If fatigue, sleepiness, syncope, light-headedness, dizziness, sedation, miosis, and disturbances in visomotor coordination and visual acuity occur, avoid potentially hazardous activities such as driving or operating machinery.
Dosage and method of use How to use Lonarid: Dosage
Unless otherwise advised by the doctor, in adults and children over 12 years the dosage is 1-2 tablets (400 mg + 10 mg) or one suppository for adults (400 mg + 20 mg) up to 3 times a day. say, according to the severity of the case. The drug should not be taken for more than 3 days. If the pain does not improve after 3 days, talk to your doctor for advice. The maximum daily dose of codeine should not exceed 240 mg.
Lonarid should not be taken by children under the age of 12 due to the risk of severe breathing problems.
Overdose What to do if you have taken too much Lonarid
In case of accidental ingestion / intake of an overdose of Lonarid, notify your doctor immediately or go to the nearest hospital.
Elderly, young children, patients with liver disease, chronic alcoholics or patients with chronic nutritional disorders, as well as patients taking concomitant enzyme-inducing medicinal products are subject to an increased risk of intoxication, even with a fatal outcome.
Symptoms
The overdose symptoms of Lonarid are identical to the overdose symptoms of the two active substances considered separately.
Paracetamol
Symptoms of overdose usually occur in the first 24 hours and are pale, nausea, vomiting, anorexia and abdominal pain. Patients may experience temporary subjective improvement, but mild abdominal pain is indicative that liver damage persists. A single dose of paracetamol of approximately 6 g or more in adults or 140 mg / kg in children causes hepatocellular necrosis. This can lead to complete and irreversible necrosis and consequently to hepatocellular insufficiency, metabolic acidosis and encephalopathy, which in turn can lead to coma and death. Concurrent increases in transaminases (AST, ALT), lactate dehydrogenase and bilirubin and an increase in prothrombin time, occurring 12 to 48 hours after ingestion, have been observed in the liver. Clinical signs of liver injury usually appear after. 2 days and reach a maximum after 4 - 6 days. Acute renal failure, with acute tubular necrosis can develop even in the absence of severe liver damage. Other non-hepatic symptoms, such as myocardial changes and pancreatitis, can also occur after an overdose of paracetamol.
Codeine
Symptoms of a narcotic overdose due to the codeine contained in Lonarid are expected before signs of toxicity due to paracetamol. Severe intoxication carries the risk of respiratory depression and apnea, which could be fatal. Marked miosis with "pinpoint" pupils are also pathognomonic. This may be accompanied by somnolence, extending to stupor and coma, with vomiting, headache, urinary and fecal retention, sometimes including bradycardia and a drop in blood pressure. Seizures occur occasionally, especially in children. The development of apnea can be fatal.
Therapy
Where there is suspicion of paracetamol intoxication, intravenous administration of SH group donor medicines, such as Nacetylcysteine, in the first 10 hours after ingestion is indicated. Although N-acetylcysteine is most effective if taken within this period, it can still provide some degree of protection if given within 48 hours of ingestion at the latest; in that case, it must be taken for longer. They must also be considered. general measures (eg activated charcoal). Additional measures will depend on the severity, nature and course of the symptoms of paracetamol intoxication and standard intensive care protocols should be followed. Serial plasma concentration testing of paracetamol is recommended. of paracetamol can be reduced by dialysis. In case of respiratory depression, maintain adequate ventilation and oxygenation. If appropriate, 0.4-2 mg iv of naloxone (specific opioid antagonist) can be given. response, the dose should be repeated every 2-3 minutes up to a total dose of 10-20 mg. Warning: the duration of action of naloxone (2-3 hours) is shorter than that of many opioids. If you have any questions about the use of Lonarid, ask your doctor or pharmacist.
Side Effects What are the side effects of Lonarid
Like all medicines, Lonarid can cause side effects, although not everybody gets them.
Skin reactions of various types and severities have been reported with the use of paracetamol, including rare cases of allergic-based skin rashes and cases of erythema multiforme, Stevens-Johnson syndrome and epidermal necrolysis. Hypersensitivity reactions such as angioedema have been reported. , laryngeal edema, anaphylactic shock At the first signs of a hypersensitivity reaction the patient should stop treatment with Lonarid and contact the physician immediately.
There is no evidence showing that the magnitude and nature of the side effects are increased by paracetamol and codeine in combination, relative to the individual substances, when the medicine is used correctly. In addition, the following side effects have been reported: thrombocytopenia, leukopenia , anemia, agranulocytosis, impaired liver function and hepatitis, alterations in the kidney (acute renal failure, interstitial nephritis, haematuria, anuria), gastrointestinal reactions and dizziness. In case of overdose, paracetamol can cause hepatic cytolysis which may progress to massive and irreversible necrosis. Like other derivatives of morphine, codeine phosphate if taken for long periods can cause constipation. Use for long periods also involves the risk of addiction. Withdrawal symptoms may be observed upon abrupt discontinuation after continued use. At high doses, codeine possesses most of the side effects of morphine including respiratory depression, light-headedness, dizziness, sedation, nausea and vomiting. Others Undesirable effects due to codeine include: miosis, euphoria, dysphoria, urinary retention Hypersensitivity reactions (itching, urticaria and rarely rash) have also been observed.
The evaluation of undesirable effects is based on the following frequencies:
Very common ≥ 1/10
Common ≥ 1/100, <1/10
Uncommon ≥ 1 / 1,000 to <1/100
Rare ≥ 1 / 10,000, <1 / 1,000
Very rare <1 / 10,000
Not known Frequency cannot be estimated from the available data.
Disorders of the blood and lymphatic system:
- Very rare: Thrombocytopenia, leukopenia.
- Not known: Agranulocytosis, pancytopenia.
Immune system disorders:
- Very rare: Hypersensitivity (including anaphylactic shock, angioedema, decreased blood pressure, dyspnoea, nausea and hyperhidrosis).
Nervous system disorders:
- Very common: Tiredness, headache.
- Common: Somnolence.
- Uncommon: Sleep disturbances.
At high doses or in particularly sensitive patients, visomotor coordination and visual acuity can be affected in a dose-dependent manner. Euphoria and respiratory depression are also possible.
Ear and labyrinth disorders:
- Uncommon: Tinnitus.
Cardiac disorders:
- Common: Blood pressure decreased, syncope.
Respiratory, thoracic and mediastinal disorders:
- Uncommon: Dyspnoea.
- Very rare: Bronchospasm (analgesic asthma syndrome).
- Not known: Pulmonary edema (at high doses, especially in patients with previous impaired lung function).
Gastrointestinal disorders:
- Very common: Constipation, vomiting (initially), nausea.
- Uncommon: Dry mouth.
Hepatobiliary disorders:
- Rare: Increased transaminases.
Skin and subcutaneous tissue disorders:
- Uncommon: Erythema, allergic dermatitis, urticaria, pruritus.
- Rare: Hypersensitivity including Stevens-Johnson syndrome.
- Not known: Drug eruption.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please inform your doctor or pharmacist.
Expiry and Retention
Expiry: see the expiry date printed on the package. Warning: do not use the medicine after the expiry date shown on the package.
The expiry date indicated refers to the product in intact packaging, correctly stored.
Tablets: Store at a temperature not exceeding 25 ° C. Suppositories: store at a temperature not exceeding 30 ° C.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.
KEEP THIS MEDICINAL PRODUCT OUT OF THE SIGHT AND REACH OF CHILDREN
Composition and pharmaceutical form
COMPOSITION
LONARID 400 mg + 10 mg tablets
one tablet contains: active ingredients: paracetamol 400 mg, codeine phosphate 10 mg.
Excipients: anhydrous colloidal silica; carmellose sodium; microcrystalline cellulose; cornstarch; ethylcellulose; magnesium stearate.
LONARID adults 400 mg + 20 mg suppositories
one suppository contains: active ingredients: paracetamol 400 mg, codeine phosphate 20 mg.
Excipients: soy lecithin; triglycerides of fatty acids.
LONARID children 200 mg + 5 mg suppositories
one suppository contains: active ingredients: paracetamol 200 mg, codeine phosphate 5 mg.
Excipients: soy lecithin; triglycerides of fatty acids.
PHARMACEUTICAL FORM AND CONTENT
20 tablets.
6 adult suppositories.
6 suppositories for children.
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
LONARID
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
LONARID 400 mg + 10 mg tablets:
one tablet contains:
Active ingredients: paracetamol 400 mg, codeine phosphate 10 mg
LONARID adults 400 mg + 20 mg suppositories:
a suppository contains:
Active ingredients: paracetamol 400 mg, codeine phosphate 20 mg
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablets
Suppositories
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Adults
Neuralgia, myalgia and arthralgia; toothache and consecutive pains after tooth extractions; headaches of all kinds; ear pain; dysmenorrhea; post-operative and post-traumatic pains.
Children over the age of 12
Codeine 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 acetaminophen or ibuprofen (alone).
04.2 Posology and method of administration
Unless otherwise advised by the doctor, in adults and children over 12 years the dosage is 1-2 tablets (400 mg + 10 mg) or one suppository for adults (400 mg + 20 mg) up to 3 times a day. say, according to the severity of the case.
The maximum daily dose of codeine should not exceed 240 mg.
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.
Pediatric population
Children under the age of 12
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).
04.3 Contraindications
• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
• Children below 12 years of age (see sections 4.2 and 4.4).
• Porphyria, severe hepatocellular (Child - Pugh C) and renal insufficiency, severe myocardial damage, acute intoxication from alcohol, sleeping pills, analgesics, psychotropic drugs; in all those states that are accompanied by depression of the breath, in cough with danger of stagnation of the secretion, in chronic constipation, in pulmonary emphysema, in bronchial asthma, in acute asthma attack, in pneumonia.
• Imminent birth, risk of premature birth.
• Intestinal obstruction.
• Paracetamol-based products are contraindicated in patients with manifest insufficiency of glucose-6-phosphate dehydrogenase and in those suffering from severe haemolytic anemia.
• In all pediatric patients (0-18 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 who are breastfeeding (see section 4.6).
• In patients known to be CYP2D6 ultra-rapid metabolisers.
04.4 Special warnings and appropriate precautions for use
During treatment with Lonarid, before taking any other medicine, check that it does not contain paracetamol and codeine, as serious adverse reactions can occur if taken in high doses. Instruct the patient to contact their doctor before combining any other medicines. See section 4.5.
Due to the presence of paracetamol, administer with caution in subjects with renal or hepatic insufficiency. High or prolonged doses of the product can cause high-risk liver disease and even serious changes in the kidney and blood.
Do not administer for more than three consecutive days without consulting your doctor.
Lonarid should be used after a "careful risk-benefit assessment in cases of opioid dependence, loss of consciousness, hypovolaemic states, head injuries, intracranial injuries or in case of pre-existing increases in intracranial pressure, concomitant administration of inhibitors of MAO, chronic obstructive airway diseases, glucose-6-phosphate-dehydrogenase deficiency, chronic constipation, Gilbert's syndrome.
A dose reduction or prolongation of the dosage interval is required in the following cases: liver function disorders and hepatitis (Child-Pugh AB), chronic alcohol abuse, Gilbert's syndrome (Meulengracht disease), severe renal insufficiency (clearance of creatinine
Due to the presence of codeine, the product can be addictive.
CYP2D6 metabolism
Codeine is metabolised by the hepatic enzyme CYP2D6 to morphine, its active metabolite.
If a patient has a deficiency or a complete lack of 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 a strong or ultrafast metabolizer, there is an increased risk of developing side effects of opioid toxicity even at commonly prescribed doses. These patients rapidly convert codeine to morphine, 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.
Prevalence estimates of ultra-rapid metabolisers in different populations are summarized below:
The individual patient's reaction to the medicinal product should be monitored at the start of treatment so that any related overdoses can be detected early. This is particularly true for elderly patients and for patients with impaired renal or respiratory function.
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 no evidence that these children were strong or ultra-rapid metabolisers in their ability to metabolise codeine to morphine.
Children with impaired respiratory function
Codeine is not recommended for use in children in whom respiratory function may be impaired, including 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.
During therapy with oral anticoagulants it is recommended to reduce the doses.
Severe acute hypersensitivity reactions (e.g. anaphylactic shock) are very rarely observed. Treatment should be stopped at the first sign of a hypersensitivity reaction following administration of Lonarid. Based on these signs and symptoms it is necessary to intervene with medical measures.
A higher than recommended dosage can damage the liver.
Extensive use of analgesics, especially at high doses, can cause headache which should not be treated with higher doses of the medicine. In such cases, the analgesic should not be continued without a doctor's advice.
Abrupt discontinuation of analgesics after prolonged use at high doses may induce withdrawal symptoms (e.g. headache, fatigue, nervousness, muscle aches and vegetative symptoms), which usually resolve within a few days.
The resumption of therapy depends on the doctor's opinion and on the abatement of withdrawal symptoms.
High dosages of this medicinal product should not be taken by patients with hypotension and concomitant hypovolaemia.
Codeine, in fixed association with paracetamol, has a primary addictive potential.
Addiction, physical and psychological dependence develop with the prolonged use of high doses. There is cross-habituation with other opiates. Relapses can be expected in a short time in patients with pre-existing opioid dependence (including those in remission).
Codeine is considered by addicts to be a heroin substitute. People addicted to alcohol or sedatives also tend to misuse codeine. Codeine, taken in high doses and over a prolonged period of time, can be addictive.
Patients undergoing cholecystectomy should be treated with caution. Contraction of the sphincter of Oddi can cause symptoms similar to those of a myocardial infarction or intensify symptoms in patients with pancreatitis.
Preparations containing codeine can only be taken if prescribed by the doctor and under his regular supervision.
Medicines that have been prescribed for personal use should not be given to others.
04.5 Interactions with other medicinal products and other forms of interaction
Paracetamol
Use with extreme caution and under strict control during chronic treatment with medicines 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).
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).
The association with other psychotropic drugs requires particular caution and vigilance on the part of the physician, to avoid unexpected undesirable effects from interaction. Do not administer alcohol during treatment.
Otherwise harmless doses of paracetamol can cause liver damage when taken together with drugs that induce enzyme induction, such as certain hypnotics and antiepileptics (e.g. glutethymide, phenobarbital, phenytoin, carbamazepine) and rifampicin. The same can happen in the case of potentially hepatotoxic substances and alcohol abuse (see section 4.9).
For oral use only:
Medicines that slow down gastric emptying, such as propantheline, reduce the absorption rate of paracetamol and delay the onset of its effect. Medicines that accelerate gastric emptying, such as metoclopramide, lead to an increase in the rate of absorption.
The combination of paracetamol with chloramphenicol can prolong the half-life of chloramphenicol, increasing its risk of toxicity.
The clinical relevance of the interactions between paracetamol and warfarin and with coumarin derivatives could not be assessed. Therefore, the prolonged use of paracetamol in patients being treated with oral anticoagulants is advisable only under medical supervision.
The concomitant use of paracetamol and AZT (zidovudine or retrovir) increases the risk of neutropenia induced by the latter. Therefore, Lonarid should be taken together with AZT only under medical supervision.
Intake of probenecid inhibits the binding of paracetamol to glucuronic acid, thereby reducing the clearance of paracetamol by about a factor of 2. Therefore, the dose of paracetamol should be reduced when given in combination with probenecid.
Cholestyramine reduces the absorption of paracetamol.
Codeine
In patients receiving other narcotic analgesics, antipsychotics, anxiolytics, or other CNS depressants (including alcohol) concomitantly with codeine, additive CNS depression may occur.
The sedative and depressing effect on the respiratory level can be increased by the concomitant administration of alcohol or other CNS depressants such as sedatives, hypnotic or psychotropic agents (phenothiazines, such as chlorpromazine, thioridazine, perphenazine) , and antihistamines (eg, promethazine, meclozine), antihypertensives and other analgesics.
Codeine-induced respiratory depression can be potentiated by tricyclic antidepressants (imipramine, amitriptyline) and opipramol.
Since concomitant administration of MAO inhibitors, for example, tranylcypromine, may lead to potentiation of central nervous system effects and other undesirable effects of unpredictable severity, this medicinal product should not be taken until two weeks after completion of the drug. treatment with MAO inhibitors.
The effect of analgesics is also enhanced. Concomitant use of partial agonists / opioid antagonists, such as buprenorphine, pentazocine may reduce the effect of the drug.
Cimetidine and other medicinal products that affect liver metabolism may potentiate the effect of Lonarid. During treatment with morphine, an inhibition of its catabolism, resulting in an increase in its plasma concentration, has been observed. An interaction of this type cannot be observed. be excluded for codeine.
Alcohol should be avoided during treatment with this medicine as psychomotor capacity can be significantly reduced (additive effect of the individual components).
04.6 Pregnancy and lactation
Pregnancy
Paracetamol
Long experience has shown no evidence of undesirable adverse effects on pregnancy or the health of the fetus or newborn.
Prospective data regarding paracetamol overdose during pregnancy did not show any increased risk of malformations. Reproduction studies conducted to investigate the oral use of paracetamol have shown no signs suggesting malformations or foetotoxicity. Under normal conditions of use, paracetamol can be used during pregnancy (ie in all trimesters), after a "careful evaluation of the risk-benefit ratio (see section 5.3).
During pregnancy, paracetamol should not be taken for prolonged periods, in high doses or in combination with other medicines, as safety has not been confirmed in these cases.
Codeine
The use of Lonarid is contraindicated in case of preterm birth or risk of premature birth, as codeine phosphate crosses the placental barrier, can produce respiratory depression in newborns.
Findings from a case-control study suggest that it may increase the risk of respiratory tract malformations in the offspring of women who used codeine during the first four months of pregnancy. This increase was not statistically significant. Evidence of other malformations is also reported in epidemiological studies conducted in narcotic analgesics, including codeine.
Long-term use of codeine can develop opioid dependence in the fetus.
Lonarid should only be used in pregnancy if the potential benefit justifies the potential risks to the fetus. If Lonarid is used for an extended period of time during the last trimester of pregnancy, neonatal withdrawal syndrome may develop.
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 metaboliser of CYP2D6, higher levels of the active metabolite, morphine, may be present in breast milk and in very rare cases, may cause symptoms of opioid toxicity in the newborn, which can be fatal.
Fertility
Preclinical studies have not indicated direct or indirect harmful effects on fertility index (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
In any case, patients should be warned that they may experience undesirable effects such as fatigue, somnolence, syncope, light-headedness, dizziness, sedation, myosis and disturbances in visomotor coordination and visual acuity during treatment with Lonarid. Therefore, Caution should be advised when driving vehicles or using machines.
If the patient experiences fatigue, drowsiness, syncope, light-headedness, dizziness, sedation, miosis, and disturbances in visomotor coordination and visual acuity, he should avoid potentially hazardous activities such as driving or operating machinery.
04.8 Undesirable effects
Skin reactions of various types and severities have been reported with the use of paracetamol, including rare cases of allergic-based rashes and cases of erythema multiforme, Stevens-Johnson syndrome and epidermal necrolysis.
Hypersensitivity reactions such as angioedema, larynx edema, anaphylactic shock have been reported. At the first signs of a hypersensitivity reaction the patient should stop treatment with Lonarid and contact the doctor immediately.
There is no evidence to show that the magnitude and nature of the side effects are increased by paracetamol and codeine in combination, relative to the individual substances, when the medicine is used correctly. In addition, the following side 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.
In case of overdose, paracetamol can cause hepatic cytolysis which can evolve towards massive and irreversible necrosis.
Like other morphine derivatives, codeine phosphate when taken for long periods can cause constipation.
Long-term use also carries the risk of addiction. Withdrawal symptoms may be observed upon abrupt cessation after continued use.
At high doses, codeine possesses most of the side effects of morphine including respiratory depression, light-headedness, dizziness, sedation, nausea and vomiting. Other side effects due to codeine include: miosis, euphoria, dysphoria, urinary retention. Hypersensitivity reactions (itching, hives and rarely rash) have also been observed.
The evaluation of undesirable effects is based on the following frequencies:
Very common ≥ 1/10
Common ≥ 1/100,
Uncommon ≥ 1 / 1,000,
Rare ≥ 1 / 10,000,
Very rare
Not known Frequency cannot be estimated from the available data.
Disorders of the blood and lymphatic system:
• Very rare: Thrombocytopenia, leukopenia
• Not known: Agranulocytosis, pancytopenia.
Disorders of the immune system:
• Very rare: Hypersensitivity (including anaphylactic shock, angioedema, decreased blood pressure, dyspnoea, nausea and hyperhidrosis).
Nervous system disorders:
• Very common: Tiredness, headache
• Common: Somnolence
• Uncommon: Sleep disturbances.
At high doses or in particularly sensitive patients, visomotor coordination and visual acuity can be affected in a dose-dependent manner.
Euphoria and respiratory depression are also possible.
Ear and labyrinth disorders:
• Uncommon: Tinnitus.
Cardiac pathologies:
• Common: Reduced blood pressure, syncope.
Respiratory, thoracic and mediastinal disorders:
• Uncommon: Dyspnea
• Very rare: Bronchospasm (analgesic asthma syndrome)
• Not known: Pulmonary edema (at high doses, especially in patients with previous impaired lung function).
Gastrointestinal disorders:
• Very common: Constipation, vomiting (initially), nausea
• Uncommon: Dry mouth.
Hepatobiliary disorders:
• Rare: Increased transaminases.
Skin and subcutaneous tissue disorders:
• Uncommon: Erythema, allergic dermatitis, urticaria, pruritus
• Rare: Hypersensitivity including Stevens-Johnson syndrome
• Not known: Drug eruption.
04.9 Overdose
Elderly, young children, patients with liver disease, chronic alcoholics or patients with chronic nutritional disorders, as well as patients taking concomitant enzyme-inducing medicinal products, are subject to an increased risk of intoxication, even with a fatal outcome.
Symptoms
The overdose symptoms of Lonarid are identical to the overdose symptoms of the two active substances considered separately.
Paracetamol
Symptoms of overdose usually occur in the first 24 hours and are pale, nausea, vomiting, anorexia and abdominal pain. Patients may experience temporary subjective improvement, but mild abdominal pain is indicative that liver damage persists.
A single dose of paracetamol of approximately 6 g or more in adults or 140 mg / kg in children causes hepatocellular necrosis.
This can lead to complete and irreversible necrosis and consequently to hepatocellular insufficiency, metabolic acidosis and encephalopathy, which in turn can lead to coma and death. Concurrent increases in transaminases (AST, ALT), lactate dehydrogenase and bilirubin and an increase in prothrombin time, occurring 12 to 48 hours after ingestion, have been observed in the liver.
Clinical signs of liver damage usually appear after 2 days and peak after 4 - 6 days.
Acute renal failure, with acute tubular necrosis can develop even in the absence of severe liver damage. Other non-hepatic symptoms, such as myocardial changes and pancreatitis, can also occur after an overdose of paracetamol.
Codeine
Symptoms of a narcotic overdose due to the codeine contained in Lonarid are expected before signs of toxicity due to paracetamol. Severe intoxication carries the risk of respiratory depression and apnea, which could be fatal.
Marked miosis with "pinpoint" pupils are also pathognomonic. This may be accompanied by somnolence, extending to stupor and coma, with vomiting, headache, urinary and fecal retention, sometimes including bradycardia and a drop in blood pressure. Seizures occur occasionally, especially in children. The development of apnea can be fatal.
Therapy
Where there is suspicion of paracetamol intoxication, intravenous administration of SH group donor medicines, such as N-acetylcysteine, in the first 10 hours after ingestion is indicated. Although N-acetylcysteine is most effective if taken within this period, it can still provide some degree of protection if administered within 48 hours of ingestion at the latest, in which case it should be taken for longer.
General measures (e.g. activated carbon) must also be considered.
Further measures will depend on the severity, nature and course of the paracetamol intoxication symptoms and standard intensive care protocols should be followed.
Serial testing of paracetamol plasma concentration is recommended. The plasma concentration of paracetamol can be reduced by dialysis.
In case of respiratory depression, maintain adequate ventilation and oxygenation. If appropriate, 0.4-2 mg i.v. can be administered. of naloxone (specific opioid antagonist). If there is no response, the dose should be repeated every 2-3 minutes up to a total dose of 10-20 mg.
Warning: the duration of action of naloxone (2-3 hours) is shorter than that of many opiates.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: other analgesics and antipyretics. ATC code: N02BE51
Paracetamol
Paracetamol has analgesic and antipyretic action, together with a weak anti-inflammatory effect. Its mechanism of action is not fully known. It strongly inhibits the synthesis of prostaglandins at the central level, but only weakly the synthesis of prostaglandins at the peripheral level. It also inhibits the effect of endogenous pyrogens on the temperature regulation center in the hypothalamus.
Codeine
Codeine is a weak centrally acting analgesic. Codeine exerts its effect via opioid receptors, although codeine 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.
Association
Lonarid is well tolerated and is an effective analgesic. It synergistically combines two active ingredients with different properties, all aimed at relieving pain. Therefore it simultaneously exerts an analgesic and anti-inflammatory effect. A characteristic of Lonarid is its rapid onset of action, after 10 - 20 minutes, and a duration of action of 4 - 6 hours.
The combination of codeine and paracetamol was compared with various analgesics and with placebo in clinical trials. In all cases observed, the fixed combination was statistically significantly superior to placebo. Some studies have produced evidence indicating that analgesic efficacy of the combination, including the case in which the dosage of the individual active ingredients is increased, is higher than that of the individual substances, provided that the risks are acceptable.
05.2 "Pharmacokinetic properties
Paracetamol
Absorption and distribution:
After oral administration, paracetamol is rapidly and almost completely absorbed from the small intestine; the plasma peak is reached approximately 0.5-2 hours after ingestion. After rectal administration, the absorption of paracetamol is less and slower than after oral administration, the absolute bioavailability is approximately 30% -40% and the plasma peak occurs at 1.5-2 hours. The drug is distributed rapidly and evenly in the tissues and crosses the blood brain barrier. The absolute bioavailability after oral administration varies between 63% and 89%, indicating a first pass effect of approximately 20% -40%. Fasting accelerates absorption but does not affect bioavailability. At therapeutic doses, protein binding is low (approximately 15% -21%).
Metabolism:
Paracetamol is extensively metabolised in the liver; the main metabolic pathway leads to the formation of glucuronide (about 60%) and sulphate (about 35%). At higher than therapeutic doses, the secondary metabolic pathway saturates rapidly. A small amount is metabolized by cytochrome P450 isoenzymes (mainly CYP2E1), leading to the formation of a toxic metabolite: N-acetyl-p-benzoquinonimine (NAPQI) which is normally and rapidly detoxified by conjugation with hepatic glutathione (GSH) and excreted. as conjugates of mercaptopurine and cysteine. Following a massive overdose, however, NAPQI levels are increased.
Elimination:
The inactive conjugates of glucuronic acid and sulfuric acid are completely excreted in the urine within 24 hours. Less than 5% of the drug taken is excreted unchanged. Total clearance is approximately 350 mL / min. The plasma half-life is 1.5-3 hours at therapeutic doses. In young children the half-life is prolonged and sulphate-conjugation is the dominant metabolic pathway. The plasma half-life of paracetamol is also prolonged in the case of chronic liver disease and in patients with severely reduced renal function.
Codeine
Absorption and distribution:
Codeine phosphate is rapidly absorbed after oral administration with a bioavailability of 40-70%. The maximum plasma peak is reached after 60 minutes. About 25-30% of the codeine administered binds to plasma proteins.
Metabolism:
Codeine is metabolised in the liver by the CYP2D6 isoenzyme to morphine, norcodeine and normomorphine.
Elimination:
The elimination of codeine phosphate and its metabolites occurs mainly via the kidney (85-90%), primarily conjugated with glucuronic acid and is considered complete after 48 hours. The percentages of the dose (free and conjugated) found in urine consist of approximately 10% morphine, 10% norcodeine, 50-70% codeine and less than 5% normorphine. The plasma half-life is about 2-4 hours.
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 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.
There is no report that the combination of paracetamol and codeine phosphate modifies the pharmacokinetic parameters of the substances.
Also a pharmacokinetic research on volunteers, performed on this combination and compared to the single substances, showed that no modification of the evaluated pharmacokinetic parameters (AUC, Cmax, tmax, t½ el.) Occurs, both after oral and rectal administration.
05.3 Preclinical safety data
There are no toxicity studies with the paracetamol and codeine phosphate combination. Since the individual components exhibit different mechanisms of pharmacological activity and follow different metabolic pathways, synergistic toxicity from the combination cannot be expected.
Paracetamol
Acute oral toxicity (LD50) in rodents and non-rodents ranges between 400 and 2000 mg / kg for paracetamol. Used according to the recommended dosage, paracetamol is considered a safe medicine. Acute paracetamol intoxication (hepatotoxicity) has been observed in humans. The lethal dose of paracetamol is approximately 10 g.
The most serious toxic effects in both animals and humans consisted of liver damage with centrilobular necrosis and less frequently, renal damage (proximal tubular necrosis). The extent of hepatic necrosis increases with dose and is closely related to the increase in serum transaminase activity.
The main metabolic pathway of paracetamol leads to the formation of glucuronides (slow, high capacity) and conjugate sulfate (fast, low capacity). The minor metabolic pathway leads to the formation of a highly reactive metabolite NAPQI (N-acetyl-p-benzoquinonimine) which is normally blocked and inactivated by conjugation with hepatic glutathione (GSH).
Following a hepatotoxic dose, glutathione availability is reduced and the toxic metabolite covalently binds to essential proteins and enzymes causing cell damage and necrosis.
The toxic effect of paracetamol can be counteracted by administering donors of SH radical groups such as glutathione precursors.
In addition to acute toxicity, chronic paracetamol overdose and also the use of subtoxic doses of paracetamol for several weeks has been associated with chronic active hepatitis. Although hepatotoxicity is the most common toxic effect of paracetamol in animals and humans, chronic kidney damage including proximal tubular necrosis and interstitial nephritis has also been observed.
The results of genotoxicity and carcinogenicity studies performed in rats and mice were mixed.
Paracetamol is classified by the International Agency for Research on Cancer (IARC) as non-genotoxic and non-carcinogenic based on biological studies performed in rats and mice according to the National Toxicology Program (NTP).
Paracetamol crosses the placenta. Paracetamol is reported as non-teratogenic to animals and humans. There are no data on paracetamol-induced changes in fertility and pre / postnatal development in laboratory animals and humans.
Codeine
The acute toxicity (LD50) of codeine phosphate in the various species ranges between 100 and 427 mg / kg.
Acute codeine intoxication has been observed in humans. The lethal dose of codeine is between 500 mg and 1 g.
Several studies and research on genotoxicity have been carried out which confirmed that codeine does not have clastogenic activity. According to the published literature, codeine is not carcinogenic in mice and rats.
The teratogenic potential of codeine observed in some animal studies is not supported by others. Studies on the potential for developmental toxicity of codeine in mice and hamsters were performed. The NOAEL ("No Observable Adverse Effect Level") values were 10 mg / kg / day (in the hamster) and 75 mg / kg / day (in the mouse), 11 times the maximum therapeutic daily oral dose for humans. A decrease in mean fetal weight was observed without, however, structural malformations.
Similar conclusions were drawn from the results of a previous study in rabbits and rats.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Tablets: anhydrous colloidal silica; carmellose sodium; microcrystalline cellulose; cornstarch; ethylcellulose; magnesium stearate.
Adult suppositories: soy lecithin; triglycerides of fatty acids.
06.2 Incompatibility
Not relevant
06.3 Period of validity
Tablets: 18 months
Suppositories: 4 years.
06.4 Special precautions for storage
Tablets: Store at a temperature not exceeding 25 ° C.
Suppositories: store at a temperature not exceeding 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
LONARID 400 mg + 10 mg tablets: 20 tablets, opacified Al / PVC-PVDC blister
LONARID adults 400 mg + 20 mg suppositories: 6 suppositories, polythene aluminum tape
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
BOEHRINGER INGELHEIM ITALIA S.p.A.
Via Lorenzini, 8
20139 Milan
08.0 MARKETING AUTHORIZATION NUMBER
LONARID 400 mg + 10 mg tablets AIC n. 020204095
LONARID adults 400 mg + 20 mg suppositories AIC n. 020204107
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
25.06.1990 / 31.05.2010
10.0 DATE OF REVISION OF THE TEXT
AIFA determination of 25 February 2014
