Lekadol long

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LECADOL LONG (LEKADOL LONG)

Composition:

Active substances: ibuprofen, paracetamol;

One film-coated tablet contains 200.00 mg of ibuprofen and 500.00 mg of paracetamol;

Excipients: corn starch, crospovidone (E 1202), colloidal anhydrous silicon dioxide (E 551), povidone (E 1201), pregelatinized starch, talc (E 553b), stearic acid; coating: polyvinyl alcohol (E 1203), talc (E 553b), macrogol 3350 (E 1521), titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, oval-shaped tablet, film-coated.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives. Combinations with ibuprofen.

ATC code M01A E51.

Pharmacological Properties.

Pharmacodynamics.

The pharmacological action of ibuprofen and paracetamol differs in site and mechanism of action, but is synergistic, enhancing analgesic and antipyretic effects compared to either substance used alone.

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID), a derivative of propionic acid, which has demonstrated efficacy in inhibiting the synthesis of prostaglandins—mediators of pain and inflammation. Prostaglandins increase the sensitivity of nociceptive afferent nerve endings to mediators such as bradykinin. Thus, ibuprofen exerts its analgesic effect through peripheral inhibition of the cyclooxygenase-2 (COX-2) isoenzyme, resulting in reduced sensitization of peripheral nociceptive nerve endings. It has also been shown that ibuprofen inhibits leukocyte migration into inflamed tissues. Ibuprofen exerts a pronounced effect in the spinal cord, partly through COX inhibition. The antipyretic effect of ibuprofen is due to central inhibition of prostaglandins in the hypothalamus. Therefore, ibuprofen provides analgesic, antipyretic, and anti-inflammatory actions. Additionally, ibuprofen reversibly inhibits platelet aggregation. In humans, ibuprofen reduces inflammatory pain, swelling, and fever.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when both agents are administered concomitantly. Some pharmacodynamic studies have shown that administration of single doses of ibuprofen 400 mg within 8 hours before or within 30 minutes after immediate-release acetylsalicylic acid (81 mg) resulted in reduced effects of aspirin (acetylsalicylic acid) on thromboxane production or platelet aggregation. Although it is uncertain whether these data can be extrapolated to clinical settings, it cannot be ruled out that regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. With occasional, non-systematic use of ibuprofen, such a clinically significant interaction is considered unlikely.

The mechanism of action of paracetamol is not fully elucidated; however, there is strong evidence for central analgesic effects on the central nervous system. Biochemical studies indicate inhibition of COX-2 isoenzyme activity in the central nervous system. Paracetamol may also stimulate descending serotonergic (5-hydroxytryptamine) pathways, which inhibit pain signal transmission in the spinal cord. Evidence suggests that paracetamol is a very weak inhibitor of COX-1 and COX-2 isoenzymes at the peripheral level.

The clinical efficacy of ibuprofen and paracetamol has been demonstrated in headache, dental pain, dysmenorrhea, and fever; furthermore, efficacy has been shown in patients with pain and fever associated with colds and influenza, as well as in pain models such as sore throat, muscular pain, soft tissue injury, and back pain.

This medicinal product is particularly suitable for the treatment of pain requiring stronger analgesia than provided by ibuprofen 400 mg or paracetamol 1000 mg alone.

Studies using this combination in models of acute pain (postoperative dental pain) and chronic knee pain have demonstrated high efficacy of the combination for acute pain (93.2%) and chronic pain (60.2%). This medicinal product has a rapid onset of action, with noticeable pain relief occurring on average within 18.3 minutes. Significant pain reduction occurs on average within 44.6 minutes. The analgesic effect of this drug is significantly longer (9.1 hours) than that of paracetamol 500 mg (4 hours) or 1000 mg (5 hours).

Pharmacokinetics.

Ibuprofen is rapidly absorbed from the gastrointestinal tract and highly bound to plasma proteins. Ibuprofen accumulates in synovial fluid. Ibuprofen is detectable in plasma within 5 minutes and reaches peak plasma concentrations within 1–2 hours after fasting administration. When administered with food, peak plasma concentrations of ibuprofen are reduced and delayed by an average of 25 minutes, but the overall extent of absorption remains equivalent.

Ibuprofen is metabolized in the liver into two primary metabolites, which are excreted almost entirely via the kidneys either unchanged or as conjugates, with minimal unchanged ibuprofen. Elimination of the drug via the kidneys is complete and rapid. The elimination half-life is approximately 2 hours.

In some studies, ibuprofen has been detected in breast milk at very low concentrations.

Paracetamol is rapidly absorbed from the gastrointestinal tract. At therapeutic concentrations, plasma protein binding is low, although it is dose-dependent. Paracetamol is detectable in plasma within 5 minutes and reaches peak plasma concentrations within 0.5–0.67 hours after fasting administration. When administered with food, peak plasma concentrations of paracetamol are reduced and delayed by an average of 25 minutes, but the overall extent of absorption remains equivalent.

Paracetamol is metabolized in the liver and excreted in urine primarily as glucuronide and sulfate conjugates, with approximately 10% as glutathione conjugates. Less than 5% of paracetamol is excreted unchanged. A hydroxylated metabolite, formed in very small amounts in the liver by mixed-function oxidases and normally detoxified by conjugation with hepatic glutathione, may accumulate in cases of paracetamol overdose and cause hepatotoxicity.

The elimination half-life is approximately 3 hours.

No significant differences in the pharmacokinetic profiles of paracetamol and ibuprofen have been observed in elderly patients. The bioavailability and pharmacokinetic profiles of ibuprofen and paracetamol in this medicinal product are not altered following single or repeated doses of this combination.

The formulation of this medicinal product has been developed using a technology designed to ensure simultaneous release of ibuprofen and paracetamol, thereby potentiating the effects of each active ingredient.

Clinical characteristics.

Indications.

For symptomatic treatment of back and muscular pain, rheumatic pain, pain in mild forms of arthritis, headache including migraine, toothache, dysmenorrhea, symptoms of cold, flu and fever. This medicinal product is particularly suitable for the treatment of pain requiring stronger analgesic effect than that provided by ibuprofen or paracetamol used separately.

Contraindications.

This medicinal product is contraindicated:

• in patients with hypersensitivity to ibuprofen, paracetamol or any of the excipients;
• in patients with a history of hypersensitivity reactions (e.g. bronchospasm, angioedema, bronchial asthma, rhinitis or urticaria) after taking ibuprofen, aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs);
• in active peptic ulcer or gastrointestinal bleeding, or in patients with a history of recurrent peptic ulcer or bleeding (two or more documented episodes of ulceration or bleeding);
• in patients with a history of gastrointestinal bleeding or perforation related to previous NSAID therapy;
• in patients with coagulation disorders;
• in patients with severe hepatic, severe renal or severe heart failure (NYHA class IV);
• during concomitant use with other medicinal products containing paracetamol;
• during concomitant use with other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, and aspirin at doses exceeding 75 mg once daily;
• during the third trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

This medicinal product, like other paracetamol-containing medicinal products, is contraindicated with concomitant use of other medicinal products containing paracetamol due to increased risk of serious adverse reactions.

This medicinal product, like other NSAIDs, should not be used in combination with the following medicinal products:

Aspirin (acetylsalicylic acid). Increased risk of adverse reactions, except when aspirin (dose not exceeding 75 mg per day) has been prescribed by a physician.

Experimental data indicate that concomitant use of ibuprofen may inhibit the effect of low-dose acetylsalicylic acid (aspirin) on platelet aggregation. It is possible that regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. With occasional (non-regular) use of ibuprofen, such clinically significant effects are considered unlikely.

Other NSAIDs (including selective COX-2 inhibitors). Increased frequency of adverse effects.

This medicinal product, like other NSAIDs, should be used with caution in combination with the following medicinal products:

Anticoagulants. NSAIDs may enhance the therapeutic effect of anticoagulants such as warfarin. The anticoagulant effect of warfarin and other coumarins may be potentiated by prolonged regular daily use of paracetamol, increasing the risk of bleeding.

Antihypertensives (angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists) and diuretics. NSAIDs may attenuate the effect of these agents. In some patients with impaired renal function (e.g. dehydrated patients or elderly patients with reduced renal function), concomitant use of ACE inhibitors or angiotensin II receptor antagonists and drugs that inhibit cyclooxygenase synthesis may lead to further deterioration of renal function, including potentially reversible acute renal failure. These interactions should be considered when prescribing coxibs together with ACE inhibitors or angiotensin II receptor antagonists. Therefore, such combinations should be prescribed with caution, especially in elderly patients. Adequate hydration should be ensured and monitoring of renal function should be considered at the start of treatment and periodically thereafter. Diuretics increase the risk of nephrotoxicity when used concomitantly with NSAIDs.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs). Increased risk of gastrointestinal bleeding.

Cardiac glycosides. NSAIDs may increase plasma levels of glycosides, may exacerbate cardiac dysfunction, and reduce glomerular filtration rate.

Cyclosporine. Increased nephrotoxicity.

Corticosteroids may promote the development of gastrointestinal ulcers or bleeding.

Lithium and methotrexate. Possible increase in plasma levels of lithium and methotrexate.

Mifepristone. NSAIDs should not be used earlier than 8–12 days after administration of mifepristone, as they may reduce its efficacy.

Quinolone antibiotics. Concomitant use of NSAIDs and quinolone antibiotics increases the risk of seizures.

Tacrolimus. Increased risk of nephrotoxicity with concomitant use of NSAIDs and tacrolimus.

Zidovudine. Increased risk of hematological toxicity when zidovudine is used concomitantly with NSAIDs. Evidence exists for increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia receiving concomitant treatment with zidovudine and ibuprofen.

This medicinal product, like other paracetamol-containing medicinal products, should be used with caution in combination with the following medicinal products:

Cholestyramine. Absorption of paracetamol may be reduced by cholestyramine. Therefore, cholestyramine should not be administered within one hour after taking paracetamol to achieve maximum analgesic effect.

Antiemetics. The rate of paracetamol absorption may be increased by metoclopramide or domperidone.

Warfarin. Regular prolonged use of paracetamol may potentiate the anticoagulant effect of warfarin and other coumarins, increasing the risk of bleeding; occasional use does not show significant effect.

Special precautions for use.

Paracetamol should be administered with caution to patients with severe renal or hepatic impairment. The risk of paracetamol overdose is higher in patients with non-cirrhotic alcoholic liver disease. In case of overdose, immediate medical attention should be sought, even if the patient feels well, due to the risk of delayed, serious liver damage.

Do not use with other medicinal products containing paracetamol. In such cases, immediate medical attention should be sought, even if the patient feels well, as this may lead to overdose.

Adverse effects can be minimized by taking the lowest effective dose necessary to relieve symptoms for the shortest duration required to control symptoms, taken with food.

Respiratory effects. Bronchospasm may occur in patients with bronchial asthma or allergic disorders following the use of nonsteroidal anti-inflammatory drugs (NSAIDs), or in patients with such conditions in their medical history.

Renal effects. Risk of renal impairment due to worsening kidney function. Patients at high risk of this reaction include those with impaired renal function, cardiac disorders, hepatic dysfunction, patients taking diuretics, and elderly patients. Renal function should be monitored in these patients.

Hepatic effects. The medicinal product may impair liver function.

Cardiovascular and cerebrovascular effects. Patients with a history of arterial hypertension and/or heart failure should begin treatment with caution (medical consultation is required), as fluid retention, hypertension, and edema have been reported during therapy with ibuprofen and other NSAIDs.

Clinical trial data indicate that the use of ibuprofen, particularly at high doses (2400 mg per day), increases the risk of arterial thrombotic complications (e.g., myocardial infarction or stroke). Overall, epidemiological studies have not shown an association between low-dose ibuprofen (e.g., ≤1200 mg per day) and an increased risk of arterial thrombotic complications.

Ibuprofen should be prescribed to patients with uncontrolled arterial hypertension, congestive heart failure (NYHA class II–III), ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease only after careful assessment of the clinical picture. High doses (2400 mg per day) should be avoided.

Careful evaluation of the clinical picture is also required before initiating long-term treatment in patients with risk factors for cardiovascular complications (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking), especially if high doses of ibuprofen (2400 mg per day) are required.

Gastrointestinal effects. Cases of gastrointestinal bleeding, perforation, and ulcers, which may be fatal, have been reported during NSAID therapy at any stage of treatment, regardless of the presence of warning symptoms or a history of severe gastrointestinal disorders.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, a history of peptic ulcer (especially with complications such as bleeding or perforation), and in elderly patients. These patients should start treatment with the lowest effective dose. For these patients, as well as those requiring concomitant use of low-dose acetylsalicylic acid or other drugs that increase gastrointestinal risk, the physician should consider prescribing combination therapy with gastroprotective agents (e.g., misoprostol or proton pump inhibitors).

Patients with a history of gastrointestinal disorders, particularly elderly patients, should be advised to report any adverse gastrointestinal symptoms (especially bleeding), particularly at the beginning of treatment.

The medicinal product should be used with caution in patients receiving concomitant medications that increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as aspirin.

The occurrence of gastrointestinal bleeding or ulcers in patients receiving medications containing ibuprofen requires immediate discontinuation of treatment with this product.

NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis and Crohn’s disease), as these conditions may worsen.

Systemic lupus erythematosus and mixed connective tissue disease. The use of the medicinal product in patients with systemic lupus erythematosus or mixed connective tissue disease increases the risk of aseptic meningitis.

Skin reactions. Very rarely, severe and sometimes fatal skin reactions, including exfoliative dermatitis, Stevens–Johnson syndrome, and toxic epidermal necrolysis, may occur during long-term use of NSAIDs. The risk of such reactions is highest at the beginning of treatment: most cases occur within the first month of taking the drug. The use of this medicinal product should be discontinued at the first signs of skin rash, mucosal lesions, or other signs of hypersensitivity.

Effects on female fertility. According to some data, medicinal products that inhibit cyclooxygenase/prostaglandin synthesis may affect the process of ovulation and are therefore not recommended for women attempting to conceive. This effect is reversible upon discontinuation of treatment. This medication should be discontinued in women experiencing difficulties in becoming pregnant or undergoing infertility evaluation.

Elderly patients. The frequency of adverse reactions associated with NSAID use is increased in elderly patients, particularly gastrointestinal bleeding or perforation, which may be fatal. If NSAIDs are necessary, the lowest effective dose should be used for the shortest possible duration.

Patients should be regularly monitored for gastrointestinal bleeding during NSAID therapy.

Use during pregnancy or breastfeeding.

Use of ibuprofen from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation of the drug. Additionally, cases of ductus arteriosus constriction have been reported after treatment in the second trimester of pregnancy, most of which resolved after stopping treatment. Therefore, ibuprofen should not be prescribed during the first and second trimesters of pregnancy unless clearly necessary. If ibuprofen is used by a woman attempting to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Prenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered if ibuprofen is used for several days starting from the 20th gestational week. Ibuprofen use should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

When used during the third trimester of pregnancy, all prostaglandin synthesis inhibitors may cause the following risks.

Risks to the fetus:

• cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction.

Risks to the mother at the end of pregnancy and to the newborn:

• possible prolongation of bleeding time, anti-aggregatory effect, which may occur even with very low doses;
• inhibition of uterine contractions, leading to delayed or prolonged labor.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product has a negligible influence on the ability to drive vehicles or operate machinery. After taking NSAIDs, adverse reactions such as dizziness, drowsiness, fatigue, and visual disturbances may occur. Patients experiencing such reactions should refrain from driving or operating machinery.

Method of Administration and Dosage.

For short-term oral use only.

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms.

Adults should take 1 tablet up to 3 times daily, with intervals between doses of at least 6 hours. Tablets should be taken with water.

If 1 tablet does not relieve symptoms, 2 tablets per dose may be taken, but not more than 3 times daily. The interval between doses should be at least 6 hours. Do not exceed 6 tablets (3000 mg paracetamol, 1200 mg ibuprofen) per day. To minimize adverse effects, patients are advised to take this medicinal product with food.

If symptoms persist for more than 3 days, a physician should be consulted for diagnosis clarification and treatment adjustment. The duration of treatment is determined individually by a physician, depending on the course of the disease and the patient's condition.

There is no need to adjust the dose for elderly patients.

Elderly patients are at increased risk of serious adverse reactions. If NSAID use is considered necessary, the lowest effective dose should be used for the shortest possible duration. Patients require regular monitoring for gastrointestinal bleeding risk during NSAID therapy.

Children.

Do not use in children under 18 years of age.

Overdose.

Paracetamol. Liver damage is possible in adults who have taken 10 g (equivalent to 20 tablets) or more of paracetamol. Liver damage may occur after ingestion of 5 g (equivalent to 10 tablets) or more of paracetamol if:

• the patient has been receiving long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs that induce liver enzymes;
• the patient regularly consumes alcohol in amounts exceeding recommended limits;
• the patient may have glutathione deficiency, for example in fibrocystic degeneration, cystic fibrosis, HIV infection, cachexia, or fasting.

Symptoms. Symptoms of paracetamol overdose within the first 24 hours include pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage may manifest 12–48 hours after overdose, indicated by abnormal liver function tests. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, liver failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and may be fatal. Acute renal failure with acute tubular necrosis may present with severe flank pain, hematuria, proteinuria, and may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have also been reported.

Treatment. Prompt medical attention is required in case of paracetamol overdose. The patient should be immediately taken to hospital for medical evaluation, even if early symptoms are absent. Symptoms may be limited to nausea and vomiting and may not reflect the severity of overdose or risk of organ damage. Treatment should be carried out according to established guidelines.

Consider treatment with activated charcoal within 1 hour of ingestion of an excessive paracetamol dose. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier concentrations are unreliable).

Treatment with N-acetylcysteine can be administered within 24 hours after paracetamol ingestion, but maximum protective effect is achieved when administered within 8 hours after overdose. The efficacy of the antidote decreases sharply after this time.

If necessary, intravenous N-acetylcysteine should be administered according to current guidelines. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside hospital settings.

Treatment of patients with severe liver function impairment within 24 hours after paracetamol ingestion should be conducted according to current guidelines.

Ibuprofen. Ibuprofen overdose symptoms may occur in children after ingestion of doses exceeding 400 mg/kg. In adults, dose-dependent effects are less pronounced. The elimination half-life in overdose is 1.5–5 hours.

Symptoms. In most patients who have ingested a clinically significant amount of nonsteroidal anti-inflammatory drugs, only nausea, vomiting, epigastric pain, or very rarely diarrhea may occur. Tinnitus, headache, and gastrointestinal bleeding may also occur. In more severe poisoning, toxic effects on the central nervous system may develop, such as drowsiness, occasionally nervous excitation, disorientation, or coma. Seizures may be observed in some patients. Severe poisoning may lead to metabolic acidosis; prothrombin index/international normalized ratio (INR) may be elevated, possibly due to effects on blood coagulation factors. Acute renal failure and liver damage may occur, particularly in the presence of dehydration. In patients with bronchial asthma, disease exacerbation may occur.

Treatment. Treatment should be symptomatic and supportive, including ensuring airway patency and monitoring cardiac symptoms and vital signs until stabilization. Oral administration of activated charcoal is recommended within 1 hour after ingestion of a potentially toxic dose. In cases of frequent or prolonged seizures, intravenous diazepam or lorazepam should be administered. Bronchodilators should be used for bronchial asthma treatment.

Adverse Reactions

During clinical studies of the medicinal product, no additional adverse reactions were identified other than those observed with ibuprofen or paracetamol used separately.

The adverse reactions listed below have been observed in patients treated with ibuprofen or paracetamol alone, during both short-term and long-term use.

The following frequency classification is used to describe the incidence of adverse reactions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders. Rare: blood disorders (agranulocytosis, anaemia, aplastic anaemia, haemolytic anaemia, leucopenia, neutropenia, pancytopenia, and thrombocytopenia). Initial symptoms may include fever, sore throat, oral ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding, bruising, and nosebleeds.

Immune system disorders. Uncommon: hypersensitivity reactions including urticaria and pruritus; rare: severe hypersensitivity reactions. Symptoms may include facial, tongue, or laryngeal swelling, dyspnoea, tachycardia, and hypotension (anaphylaxis, angioneurotic oedema, or severe shock). Hypersensitivity reactions may include non-specific allergic reactions and anaphylaxis, respiratory tract reactivity including asthma, exacerbation of asthma, bronchospasm, and dyspnoea, various skin reactions including pruritus, urticaria, purpura, angioedema, and less frequently exfoliative and bullous dermatoses, including toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme.

Psychiatric disorders. Rare: confusion, depression, and hallucinations.

Nervous system disorders. Uncommon: headache, dizziness; rare: paraesthesia, optic neuritis, somnolence, aseptic meningitis, individual symptoms of which (nuchal rigidity, headache, nausea, vomiting, fever, or confusion) may occur in patients with autoimmune disorders such as systemic lupus erythematosus or mixed connective tissue disease.

Eye disorders. Rare: visual disturbances.

Ear and labyrinth disorders. Rare: tinnitus and vertigo.

Cardiac disorders. Rare: heart failure, oedema.

Clinical trial data and epidemiological evidence suggest that the use of ibuprofen, particularly at high doses (2400 mg daily) and over prolonged periods, may be associated with an increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Vascular disorders. Rare: arterial hypertension.

Respiratory, thoracic and mediastinal disorders. Rare: respiratory tract reactivity including bronchial asthma, exacerbation of asthma, bronchospasm, and dyspnoea. See also immune system-related adverse reactions above.

Gastrointestinal disorders. Adverse reactions affecting the gastrointestinal tract are the most frequently reported. Common: abdominal pain, vomiting, diarrhoea, nausea, dyspepsia, gastric discomfort; uncommon: peptic ulcer, gastrointestinal perforation or gastrointestinal haemorrhage, melaena, haematemesis (sometimes fatal, especially in elderly patients), ulcerative stomatitis, exacerbation of colitis and Crohn’s disease, gastritis, pancreatitis, flatulence, constipation.

Hepatobiliary disorders. Rare: liver function abnormalities, hepatitis, jaundice. In cases of paracetamol overdose, acute liver failure, liver failure, liver necrosis, and liver damage may occur.

Skin and subcutaneous tissue disorders. Common: hyperhidrosis; uncommon: skin rash (see also immune system-related adverse reactions above); rare: bullous reactions including Stevens-Johnson syndrome, erythema multiforme, and toxic epidermal necrolysis (see also immune system-related adverse reactions above), exfoliative dermatitis, purpura, photosensitivity; frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS), phototoxic reactions.

Renal and urinary disorders. Rare: nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome, and acute or chronic renal failure, acute impairment of kidney function, particularly with prolonged use of NSAIDs, associated with increased serum urea levels and oedema. Papillary necrosis.

General disorders and administration site conditions. Rare: fatigue and malaise.

Investigations. Common: increased alanine aminotransferase levels, increased gamma-glutamyl transferase levels, impaired liver function tests, increased blood creatinine levels, increased blood urea levels; uncommon: increased aspartate aminotransferase levels, increased alkaline phosphatase levels in blood, increased blood creatine phosphokinase levels, decreased haemoglobin levels, increased platelet count.

Shelf life. 3 years.

Storage conditions. No special storage temperature requirements. Store in the original packaging to protect from light. Keep out of reach of children.

Packaging. 6, 8, or 10 tablets in a blister; 1 blister with 6 tablets, or 2 blisters with 8 tablets, or 1 or 2 blisters with 10 tablets per cardboard box.

Pharmaceutical category. Over-the-counter (without prescription).

Manufacturer.

Lek Pharmaceuticals d.d.

Rontis Hellas Medical and Pharmaceutical Products S.A.

Manufacturer's address and place of business.

Verovškova 57, Ljubljana 1526, Slovenia.

P.O. Box 3012 Larissa Industrial Area, Larissa, 41004, Greece.