BRUFEN Pain 40 mg ketoprofen lysine salt orodispersible granules - 20 sachets

Symptomatic treatment of acute pain of mild to moderate severity.

Active Ingredients

One sachet contains: Active ingredient : ketoprofen lysine salt 40 mg (corresponding to 25 mg of ketoprofen) Excipient with known effect : aspartame. For the full list of excipients, see section 6.1.

Excipients

Mannitol, xylitol, LLF flavouring (lime, lemon and frescofort), aspartame, talc, basic butylated methacrylate copolymer, magnesium stearate, colloidal hydrated silica, hypromellose, stearic acid, povidone, sodium lauryl sulphate.

Dosage

Dosage Adults and adolescents over 15 years : 1 sachet, as a single dose, or repeated 2-3 times a day, in the most intense painful forms. The lowest effective dose should be used for the shortest period necessary to relieve the symptoms (see section 4.4). The duration of therapy should be limited to overcoming the painful episode (see section 4.4). Special populations Elderly : elderly patients should adhere to the minimum dosages indicated above. Patients with mild or moderate renal impairment : it is advisable to monitor the volume of diuresis and renal function (see section 4.4). Patients with mild or moderate hepatic insufficiency : they should be carefully monitored and treated with the minimum effective daily dose (see section 4.4). BRUFEN DOLORE should not be used in patients with severe hepatic and renal dysfunction (see section 4.3). Paediatric population BRUFEN DOLORE is contraindicated in children and adolescents under 15 years of age. Method of administration The contents of the sachet can be placed directly on the tongue. It dissolves with saliva: this allows its use without water. It is preferable to take the medicine on a full stomach.

Warnings

Administer with caution in patients with allergic manifestations or a history of allergy. Treatment with ketoprofen lysine salt should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity. Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2 and the sections below on gastrointestinal and cardiovascular risks). The concomitant use of BRUFEN DOLORE with other NSAIDs, including cyclooxygenase-2 selective inhibitors, should be avoided (see section 4.5). Elderly: Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal. Masking of symptoms of underlying infections BRUFEN DOLORE may mask the symptoms of infection, which may delay initiation of adequate treatment and thereby worsen the outcome of the infection. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When BRUFEN DOLORE is administered for the relief of infection-related fever or pain, monitoring for infection is advised. In non-hospital settings, the patient should seek medical attention if symptoms persist or worsen. Cardiovascular and cerebrovascular effects Appropriate monitoring and advice are necessary in patients with a history of hypertension and/or mild to moderate congestive heart failure since fluid retention, hypertension and oedema have been reported in association with NSAID therapy. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude a similar risk for ketoprofen lysine salt when it is administered at a daily dose of one sachet, as a single dose, or repeated 2-3 times a day. Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with ketoprofen lysine salt, as with all NSAIDs, after careful consideration. Similar consideration should be made before initiating long-term treatment in patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking). Gastrointestinal effects Gastrointestinal bleeding, ulceration and perforation, which can be fatal, have been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events. Some epidemiological evidence suggests that ketoprofen lysine salt may be associated with a higher risk of serious GI toxicity compared with other NSAIDs, particularly at high doses. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in the elderly and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3). These patients should start treatment on the lowest dose available. Concomitant use of protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients taking low dose aspirin or other drugs likely to increase gastrointestinal risk (see below and section 4.5). Patients with a history of GI toxicity, particularly when elderly, should report any unusual GI symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5). When GI bleeding or ulceration occurs in patients receiving Ketoprofen lysine salt, the treatment should be withdrawn. NSAIDs should be given with caution to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8). Skin effects Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Ketoprofen lysine salt should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. Renal and hepatic effects As with all NSAIDs, the medicinal product may increase plasma urea nitrogen and creatinine. As with other inhibitors of prostaglandin synthesis, ketoprofen lysine salt may be associated with adverse effects on the renal system which may lead to glomerular nephritis, renal papillary necrosis, nephrotic syndrome and acute renal failure. Renal function should be carefully monitored at the beginning of treatment in patients with heart failure, cirrhosis and nephrosis, in patients on diuretic therapy, with chronic renal insufficiency, especially if elderly. In these patients, the administration of ketoprofen lysine salt may cause a reduction in renal blood flow, caused by prostaglandin inhibition and lead to renal alterations. As with other NSAIDs, the medicinal product may cause small transient increases in some liver parameters and also significant increases in SGOT and SGPT (see section 4.8). In case of significant increases in these parameters, therapy should be discontinued. In patients with impaired liver function or with previous liver diseases, transaminases should be regularly evaluated, especially during long-term therapy. Cases of jaundice and hepatitis have been reported with ketoprofen lysine salt. Caution is required when administering ketoprofen lysine salt to patients with hepatic porphyria, as it may trigger an attack. Ketoprofen lysine salt should be administered with caution to patients with haematopoietic disorders, systemic lupus erythematosus or mixed connective tissue diseases. The use of NSAIDs may impair fertility and is not recommended in women attempting to conceive (see section 4.6). Administration of ketoprofen should be discontinued in women who have difficulties conceiving or who are undergoing investigation of fertility. Treatment should be discontinued in the event of visual disturbances such as blurred vision. Patients with asthma associated with chronic rhinitis and allergy, chronic sinusitis and/or nasal polyposis have a higher risk of allergy to aspirin and/or NSAIDs than the rest of the population. Administration of this medicinal product may cause asthma attacks or bronchospasm, especially in subjects allergic to acetylsalicylic acid (aspirin) or NSAIDs (see sections 4.3 and 4.8). Therefore, in these subjects, as well as in cases of chronic obstructive pulmonary disease or nephropathy, the medicine should only be used under medical supervision. To avoid any phenomena of hypersensitivity or photosensitivity, it is advisable not to expose yourself to the sun during use. Important information about some of the excipients BRUFEN DOLORE contains 10.56 mg of aspartame per dose (1 sachet) equivalent to 31.7 mg per maximum recommended daily dose (3 sachets) equivalent to 0.704 mg/kg Aspartame is a source of phenylalanine. It can be harmful in patients with phenylketonuria, a rare genetic disease that causes the accumulation of phenylalanine because the body cannot eliminate it properly. This medicine contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially 'sodium-free'.

Conservation

This medicinal product does not require any special storage conditions.

Contraindications

BRUFEN DOLORE must not be administered in the following cases: • hypersensitivity to the active substance, to other non-steroidal anti-inflammatory drugs (NSAIDs) or to any of the excipients listed in section 6.1. • patients with a history of hypersensitivity reactions, such as bronchospasm, asthma attacks, acute rhinitis, nasal polyps, urticaria, angioneurotic oedema or other allergic-type reactions to ketoprofen or substances with a similar mechanism of action [for example acetylsalicylic acid (ASA) or other non-steroidal anti-inflammatory drugs (NSAIDs)]. Serious, rarely fatal, anaphylactic reactions have been reported in these patients (see section 4.8). • active peptic ulcer/haemorrhage, or previous history of gastrointestinal bleeding, ulceration or perforation (two or more distinct, proven episodes of bleeding or ulceration) or chronic dyspepsia; • gastrointestinal bleeding or gastrointestinal perforation resulting from previous NSAID therapy or other active bleeding or haemorrhagic disorders; • severe cardiac insufficiency; • severe hepatic insufficiency; • severe renal insufficiency; • haemorrhagic diathesis and other coagulation disorders, or patients undergoing anticoagulant therapy; • patients undergoing major surgery; • third trimester of pregnancy and breastfeeding (see section 4.6); • children and adolescents under 15 years of age.

Side effects

The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). The frequency and severity of these effects are reduced when the medicinal product is taken with food. Manifestations of hypersensitivity may take the form of severe systemic reactions (laryngeal oedema, glottis oedema, dyspnoea, palpitation) up to anaphylactic shock. In these cases, immediate medical assistance is required. The following adverse reactions have been observed following administration of ketoprofen lysine salt in adults. The frequency of adverse events is classified as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), not known (frequency cannot be estimated from the available data). Infections and infestations . Not known: aseptic meningitis, lymphangitis Blood and lymphatic system disorders. Rare: haemorrhagic anaemia; Not known: agranulocytosis, thrombocytopenia, bone marrow aplasia, haemolytic anaemia, leukopenia, neutropenia, aplastic anaemia, leukocytosis, thrombocytopenic purpura. Immune system disorders . Not known: anaphylactic reactions (including shock), hypersensitivity. Psychiatric disorders . Not known: depression, hallucinations, mood alterations, excitability, insomnia. Nervous system disorders . Uncommon: headache, dizziness, somnolence; Rare: paraesthesia; Not known: syncope, convulsions, dysgeusia, tremor, hyperkinesia, dyskinesia, vertigo. Eye disorders . Rare: blurred vision (see section 4.4); Not known: periorbital oedema. Ear and labyrinth disorders . Rare: tinnitus. Cardiac disorders . Not known: cardiac failure, palpitations, tachycardia. Vascular disorders . Not known: hypotension, hypertension, vasodilation, vasculitis. Respiratory, thoracic and mediastinal disorders . Rare: asthma; Not known: laryngeal oedema, bronchospasm (especially in patients with known hypersensitivity to acetylsalicylic acid and other NSAIDs), rhinitis, dyspnoea, laryngospasm, acute respiratory failure. Gastrointestinal disorders . Common: nausea, vomiting, dyspepsia, abdominal pain; Uncommon: constipation, diarrhoea, flatulence, gastritis; Rare: ulcerative stomatitis, peptic ulcer; Not known: exacerbation of colitis and Crohn's disease, gastrointestinal haemorrhage and perforation (see section 4.4), gastric ulcer, duodenal ulcer, pancreatitis, melaena, haematemesis, gastric pain, erosive gastritis, tongue oedema. Hepatobiliary disorders . Rare: hepatitis, increased serum transaminases, elevated serum bilirubin levels due to liver disorders, jaundice. Skin and subcutaneous tissue disorders . Uncommon: rash, pruritus; Not known: photosensitivity, alopecia, urticaria, angioedema, bullous eruptions, including Stevens-Johnson syndrome, Lyell's syndrome and toxic epidermal necrolysis, erythema, exanthema, maculo-papular rash, purpura, dermatitis. Renal and urinary disorders . Not known: fluid retention, haematuria, acute renal failure, tubulointerstitial nephritis, nephritic syndrome, glomerular nephritis, acute tubular necrosis, renal papillary necrosis, nephrotic syndrome, oliguria, renal function test abnormalities, dysuria. General disorders and administration site conditions . Uncommon: oedema, fatigue; Not known: chills, asthenia, facial oedema, peripheral oedema. Investigations . Rare: weight gain. Reporting of suspected adverse reactions Reporting of suspected adverse reactions that occur after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.

Overdose

Cases of overdose with doses greater than 2.5 g of ketoprofen lysine salt have been reported. In most cases, symptoms observed include: lethargy, drowsiness, nausea, vomiting and epigastric pain. Symptoms of overdose may also include: central nervous system disorders, such as headache, dizziness, confusion and loss of consciousness. Hypotension, respiratory depression and cyanosis may occur. Renal failure, convulsions and coma have also been described. A single case of anxiety, visual hallucinations, hyperexcitability and altered behaviour has been reported in a paediatric patient who had taken twice the recommended dose. The symptoms disappeared spontaneously within 1-2 days. There are no specific antidotes for an overdose of ketoprofen lysine salt. If a serious overdose is suspected, gastric lavage and supportive and symptomatic therapy are recommended to compensate for dehydration, monitor renal function, and correct acidosis if present. Hemodialysis may be useful in removing the drug from the circulation in renal failure.

Pregnancy

Pregnancy Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Results of epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiac malformations increased from less than 1%, up to approximately 1.5%. The risk was believed to increase with dose and duration of therapy. In animals, administration of prostaglandin synthesis inhibitors has been shown to result in increased pre- and post-implantation loss, embryo-foetal mortality and an increased incidence of various malformations, including cardiovascular (see section 5.3). From the 20th week of pregnancy onwards, the use of ketoprofen may cause oligohydramnios resulting from fetal renal dysfunction. This condition may occur soon after initiation of treatment and is usually reversible upon discontinuation of treatment. In addition, cases of constriction of the ductus arteriosus have been reported following treatment in the second trimester, most of which resolved after discontinuation of treatment. Therefore, during the first and second trimester of pregnancy, ketoprofen should not be administered unless clearly necessary. If ketoprofen is used by a woman planning a pregnancy, or during the first and second trimester of pregnancy, the lowest possible dose should be used for the shortest possible duration. Following exposure to ketoprofen for several days from the 20th week of gestation onwards, antenatal monitoring for oligohydramnios and constriction of the ductus arteriosus should be considered. In case of oligohydramnios or constriction of the ductus arteriosus, treatment with ketoprofen should be discontinued. During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the fetus to: • cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension); • renal dysfunction (see above); the mother and the neonate, at the end of pregnancy, to: • possible prolongation of bleeding time, an antiaggregant effect which may occur even at very low doses; • inhibition of uterine contractions resulting in delayed or prolonged labor. Consequently, BRUFEN DOLORE is contraindicated during the third trimester of pregnancy (see sections 4.3 and 5.3). Breastfeeding Since no data are available on the secretion of ketoprofen lysine salt in breast milk, ketoprofen should not be administered during breastfeeding. Fertility The use of ketoprofen lysine salt, as with any drug that inhibits the synthesis of prostaglandins and cyclooxygenase, is not recommended in women who intend to become pregnant. The administration of ketoprofen lysine salt must be suspended in women who have fertility problems or who are undergoing investigation of fertility.