Farmakopea Subitene 400mg

Ibuprofen

NAME
SUBITENE

ACTIVE PRINCIPLES
Effervescent tablets Each 200 mg tablet contains: Active ingredient: ibuprofen sodium salt dihydrate 256 mg (corresponding to 200 mg of Ibuprofen). Each 400 mg tablet contains: Active ingredient: ibuprofen sodium salt dihydrate 512 mg (corresponding to 400 mg of Ibuprofen). Excipients with known effects: sorbitol. Granules for oral solution Each 200 mg sachet contains: Active ingredient: ibuprofen sodium salt dihydrate 256 mg (corresponding to 200 mg of Ibuprofen). Each 400 mg sachet contains: Active ingredient: ibuprofen sodium salt dihydrate 512 mg (corresponding to 400 mg of Ibuprofen). Excipients with known effects: sucrose, aspartame. Film-coated tablets Each 200 mg tablet contains: Active ingredient: Ibuprofen 200 mg. Excipients with known effects: sucrose. For the full list of excipients, see section 6.1.

EXCIPIENTS
Effervescent tablets Each 200 mg effervescent tablet contains: Potassium carbonate, anhydrous citric acid, sorbitol (E420), mint-licorice flavor, sodium saccharin, potassium acesulfame, monopalmitate sucrose. Each 400 mg effervescent tablet contains: Potassium carbonate, anhydrous citric acid, sorbitol (E420), sodium saccharin, mint-licorice aroma, monopalmitate sucrose. Granules for oral solution Each 200 mg sachet contains: sucrose, potassium bicarbonate, orange flavor, potassium acesulfame, aspartame (E951). Each 400 mg sachet contains: sucrose, potassium bicarbonate, orange flavor, potassium acesulfame, aspartame (E951). Film-coated tablets Each film-coated tablet contains: Tablet core: microcrystalline cellulose, anhydrous colloidal silica, sodium carboxymethyl starch A, magnesium stearate. Film-coating: hypromellose, microcrystalline cellulose, macrogol stearate, sucrose, talc, titanium dioxide (E171).

THERAPEUTIC INDICATIONS
Pain of various origins and nature (headache, toothache, neuralgia, osteo-articular and muscle pain, menstrual pain). Adjuvant in the symptomatic treatment of febrile and flu states.

CONTRAINDICATIONS / EFFECTS YOU DO NOT WANT
Do not administer to children under 12 years of age, Ibuprofen is contraindicated during the third trimester of pregnancy and during breastfeeding (see section 4.6). Hypersensitivity to the active substance, to other antirheumatic products (acetylsalicylic acid, etc.) or to any of the excipients. Active or severe gastroduodenal ulcer or other gastropathies. History of gastrointestinal bleeding or perforation related to previous active treatments or history of recurrent peptic hemorrhage / ulcer (two or more distinct episodes of demonstrated ulceration or bleeding). Severe liver or kidney failure. Severe heart failure (4th class NYHA). The sachets of granules for oral solution contain aspartame; they are therefore contraindicated in people with phenylketonuria (see also section 4.4). Severe dehydration (caused by vomiting, diarrhea or insufficient fluid intake).

DOSAGE
Posology SUBITENE 200 mg effervescent tablets, granules for oral solution and film-coated tablets Adults and children over 12 years: 1–2 tablets or 1–2 sachets, two – three times a day. Do not exceed the dose of 6 tablets or 6 sachets per day. Take the product on a full stomach. SUBITENE 400 mg effervescent tablets and granules for oral solution Adults and children over 12 years: 1 tablet or 1 sachet 2–3 times a day. Do not exceed the dose of 3 tablets or 3 sachets per day. If the use of the medicine is necessary for more than 3 days in adolescents (aged between 12 years and 18 years) or in the case of worsening of the symptoms, the doctor must be consulted. Do not exceed the recommended dose; in particular, elderly patients should comply with the minimum dosages indicated above Elderly: NSAIDs should be used with particular caution in elderly patients who are more prone to adverse events and are at an increased risk of potentially fatal gastrointestinal bleeding, ulceration or perforation (see section 4.4) . If treatment is considered necessary, the lowest dose should be used for the shortest duration necessary for symptom control (see section 4.4). Side effects can be minimized with the use of the lowest effective dose for the shortest possible duration of treatment needed to control symptoms (see section 4.4). Renal insufficiency: in patients with mild or moderate renal impairment, the dosage should be kept as low as possible for the shortest duration necessary to control symptoms and renal function monitored. Hepatic insufficiency: in patients with mild or moderate reduction in liver function, the dosage should be kept as low as possible for the shortest duration necessary to control symptoms and liver function should be monitored. SUBITENE is contraindicated in patients with severe hepatic impairment (see section 4.3). Method of administration Take the product on a full stomach. Effervescent tablets: the dose should be dissolved in a glass of water and taken immediately after the preparation of the solution. Granules for oral solution: the dose must be dissolved in a glass of water mixing with a teaspoon until dissolved and taken immediately after the preparation of the solution.

STORAGE
Effervescent tablets Keep the tablet container tightly closed to keep it protected from moisture. Granules for oral solution This medicinal product does not require any special storage precautions. Film-coated tablets. Store in the original package.

WARNINGS
In asthma patients ibuprofen should be used with caution after consulting your doctor. The use of SUBITENE, as of any drug inhibiting the synthesis of prostaglandins and cyclooxygenase is not recommended in women who intend to become pregnant.The administration of SUBITENE should be discontinued in women who have fertility problems or who are undergoing fertility investigations . The use of SUBITENE should be avoided in conjunction with NSAIDs, including selective COX-2 inhibitors. Side effects can be minimized with the use of the lowest effective dose for the shortest possible duration of treatment needed to control symptoms (see the paragraphs below on gastrointestinal and cardiovascular risks) Elderly: elderly patients have an increase in frequency adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which can be fatal (see section 4.2). Gastrointestinal haemorrhage, ulceration and perforation Gastrointestinal haemorrhage, ulceration and perforation, which can be fatal, have been reported during treatment with all NSAIDs, with or without warning symptoms or a previous history of serious gastrointestinal events. In the elderly and in patients with a history of ulcer, especially if complicated by bleeding or perforation (see section 4.3), the risk of gastrointestinal bleeding, ulceration or perforation is higher with increased NSAID doses. These patients should start treatment with the lowest available dose. Concomitant use of protective agents (misoprostol or proton pump inhibitors) should be considered for these patients and also for patients taking low doses of acetylsalicylic acid or other drugs that may increase the risk of gastrointestinal events (see below and section 4.5). . Patients with a history of gastrointestinal toxicity, particularly the elderly, must report any unusual gastrointestinal symptoms (especially gastrointestinal bleeding) especially in the early stages of treatment. Carefully monitor patients taking concomitant medications that could increase the risk of ulceration or hemorrhage, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as acetylsalicylic acid (see section 4.5). When gastrointestinal bleeding or ulceration occurs in patients taking SUBITENE, treatment should be stopped. NSAIDs should be administered with caution in patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions can be exacerbated (see section 4.8). Cardiovascular and cerebrovascular effects Caution is required before starting treatment in patients with a history of hypertension and / or heart failure as fluid retention, hypertension and edema have been reported in association with NSAID treatment (see section 4.5). Clinical studies suggest that the use of ibuprofen, especially at high doses (2400 mg / day), may be associated with a modest increase in the risk of arterial thrombotic events (e.g. myocardial infarction or stroke). In general, epidemiological studies do not suggest that low doses of ibuprofen (≤ 1200 mg / day) are associated with an increased risk of arterial thrombotic events. Patients with uncontrolled hypertension, congestive heart failure (II-III NYHA class), established ischemic heart disease, peripheral arterial disease and / or cerebrovascular disease should only be treated with ibuprofen after careful consideration and high doses (2400 mg / day should be avoided. ). Careful consideration should also be exercised before initiating patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, habit of smoking), especially if high doses are needed (2400 mg / die) of ibuprofen. Dermatological effects Severe 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). In the early stages of therapy, patients appear to be at higher risk: the onset of the reaction occurs in most cases within the first month of treatment. SUBITENE should be discontinued at the first appearance of a skin rash, mucosal lesion or any other sign of hypersensitivity as well as visual disturbances or persistent signs of liver dysfunction. Renal effects Caution should be exercised in patients with considerable dehydration when initiating treatment with ibuprofen. Ibuprofen can cause water and sodium, potassium retention in patients who have never suffered from kidney problems due to its effects on renal perfusion. This can cause edema or heart failure or hypertension in predisposed patients. Long-term use of ibuprofen, as with other NSAIDs, has led to renal papillary necrosis and other renal pathological changes. In general, the usual use of analgesics, especially of the associations of different analgesic active ingredients, can lead to permanent kidney lesions, with the risk of developing kidney failure (analgesic nephropathy). Renal toxicity has been reported in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion. The administration of NSAIDs in these patients may result in a dose-dependent reduction in the formation of prostaglandins and, as a secondary effect, in renal blood flow which can quickly lead to renal failure. The patients most at risk of these reactions are those with reduced kidney function, heart failure, liver dysfunction, the elderly and all those patients who take diuretics and ACE inhibitors. Discontinuation of NSAID therapy is usually followed by recovery of the pretreatment state. There is a risk of impaired renal function in dehydrated adolescents. In case of prolonged use, monitor renal function particularly in case of diffuse lupus erythematosus. Respiratory disorders SUBITENE should be prescribed with caution in patients with bronchial asthma, chronic rhinitis, or current or past allergic disease because bronchospasm may occur. The same applies to those subjects who experienced bronchospasm after the use of acetylsalicylic acid or other NSAIDs. Hypersensitivity reactions Analgesics, antipyretics, NSAIDs, can cause potentially serious hypersensitivity reactions (anaphylactoid reactions), even in subjects not previously exposed to this type of drugs. The risk of hypersensitivity reactions after taking ibuprofen is greater in subjects who have presented such reactions after the use of other analgesics, antipyretics, NSAIDs and in subjects with bronchial hyperreactivity (asthma), hay fever, nasal polyposis or chronic respiratory diseases obstructive or previous episodes of angioedema (see sections 4.3 and 4.8). Hypersensitivity reactions can occur in the form of asthma attacks (so-called analgesic asthma), Quincke's edema or urticaria. Serious hypersensitivity reactions (e.g. anaphylactic shock) have been observed rarely. At the first signs of a hypersensitivity reaction after ibuprofen administration, treatment should be stopped. Medically assisted measures must be initiated by specialized medical personnel, in line with the symptomatology. Reduced cardiac, renal and hepatic function Special care should be taken in the treatment of patients with reduced cardiac, hepatic or renal function. Periodic monitoring of clinical and laboratory parameters should be used in such patients, especially in the case of prolonged treatment. Haematological effects Ibuprofen, like other NSAIDs, can inhibit platelet aggregation and has shown evidence of prolonged bleeding time in healthy subjects. Therefore, patients with coagulation defects or on anticoagulant therapy should be carefully observed. Aseptic meningitis Symptoms of aseptic meningitis have been observed on rare occasions in patients receiving ibuprofen. Although this is more likely to occur in patients with systemic lupus erythematosus and related connective tissue disorders, it has also been observed in patients who did not experience concomitant chronic conditions (see section 4.8). Since ocular changes have been detected during animal studies with NSAIDs, it is recommended, in case of prolonged treatments, to carry out periodic ophthalmological checks. Alcohol consumption should be avoided as it can intensify the side effects of NSAIDs, especially those affecting the gastrointestinal tract or central nervous system. Ibuprofen can mask the signs or symptoms of infection (fever, pain and swelling). Important information about some of the ingredients SUBITENE 200 mg and 400 mg effervescent tablets contain sorbitol: patients with rare hereditary fructose disease problems should not take this medicine. SUBITENE 200 mg and 400 mg granules for oral solution contain: - sucrose: patients with rare hereditary fructose disease, glucose and galactose malabsorption and sucrase-isomaltase insufficiency must not take this medicine. - aspartame, a source of phenylalanine. Therefore it is contraindicated in subjects with phenylketonuria. SUBITENE 200 mg film-coated tablets contain sucrose: patients with rare hereditary fructose disease, glucose and galactose malabsorption and sucrase-isomaltase insufficiency should not take this medicine. SUBITENE 200 mg effervescent tablets contains: - 27 mg of sodium (1.2 mmol) per tablet. This must be taken into account by patients on a controlled sodium diet. - 866 mg of potassium (22 mmol) per tablet. This should be taken into account by patients with reduced renal function or on a hypopotassic diet. Sucrose: patients with rare hereditary fructose disease, glucose and galactose malabsorption and sucrase-isomaltase insufficiency should not take this medicine. SUBITENE 400 mg effervescent tablets contains: - 50 mg of sodium (2.2 mmol) per tablet. This should be taken into account by patients with reduced kidney function or on a low sodium diet. - 866 mg of potassium (22 mmol) per tablet. This should be taken into account by patients with reduced renal function or on a hypopotassic diet. - sucrose: patients with rare hereditary fructose disease, glucose and galactose malabsorption and sucrase-isomaltase insufficiency must not take this medicine. SUBITENE 200 mg granules for oral solution contains: - 23 mg sodium (1 mmol) per sachet. This must be taken into account by patients on a controlled sodium diet. - 90 mg of potassium (2.3 mmol) per sachet. This should be taken into account by patients with reduced renal function or on a hypopotassic diet. SUBITENE 400 mg granules for oral solution contains: - 45 mg of sodium (1.9 mmol) per sachet. This should be taken into account by patients with reduced kidney function or on a low sodium diet. - 90 mg of potassium (2.3 mmol) per sachet. To be taken into consideration in people with reduced kidney function or on a hypopotassic diet.

INTERACTIONS
It is advisable to seek medical advice in the event of any concomitant therapy before administration of the product. Ibuprofen (like other NSAIDs) should be taken with caution in combination with the substances listed below. Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section 4.4). Anticoagulants: NSAIDs can increase the effects of anticoagulants, such as warfarin or heparin (see section 4.4). In case of concomitant treatment, monitoring of the coagulation status is recommended. Acetylsalicylic acid, cyclooxygenase-2 inhibitors (COX-2) and other NSAIDs: these substances can increase the risk of adverse reactions in the gastrointestinal tract (see section 4.4). However, ibuprofen should not be combined with acetylsalicylic acid or other NSAIDs, including selective COX-2 inhibitors, for potential additive effect (see section 4.4). Acetylsalicylic acid: concomitant administration of ibuprofen and acetylsalicylic acid is generally not recommended due to the potential increase in side effects. Experimental data suggest that ibuprofen can competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when the two drugs are administered simultaneously. Although there are uncertainties regarding the extrapolation of these data to the clinical situation, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded. No relevant clinical effects were considered likely following occasional ibuprofen use (see section 5.1). Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4). Diuretics, ACE inhibitors and angiotensin II antagonists: NSAIDs can reduce the effect of diuretics and other antihypertensive drugs. Diuretics can also increase the risk of nephrotoxicity associated with NSAIDs. In some patients with impaired renal function (e.g. dehydrated patients or elderly patients with impaired renal function) the co-administration of an ACE inhibitor or an angiotensin II antagonist and agents that inhibit the cyclooxygenase system may lead to further deterioration of renal function, which includes possible acute renal failure, generally reversible. These interactions should be considered in patients taking SUBITENE concomitantly with ACE inhibitors or angiotensin II antagonists. Hence, the combination should be administered with caution, especially in elderly patients. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy. Phenytoin and lithium: the concomitant administration of ibuprofen and phenytoin or lithium preparations can lead to a reduced elimination of these medicines with consequent increase in their plasma levels with the possibility of reaching the toxic threshold. If this association is deemed necessary, monitoring of the plasma levels of phenytoin and lithium is recommended in order to adapt the appropriate dosage during simultaneous treatment with ibuprofen. Methotrexate: NSAIDs can inhibit the tubular secretion of methotrexate and reduce its clearance with consequent increased risk of toxicity. Moclobemide: increases the effect of ibuprofen. Aminoglycosides: NSAIDs can decrease the excretion of aminoglycosides by increasing their toxicity. Cardiac glycosides: NSAIDs can exacerbate heart failure, reduce the rate of glomerular filtration and increase the plasma levels of cardiac glycosides. Monitoring of serum glycoside levels is recommended. Cholestyramine: concomitant administration of ibuprofen and cholestyramine may prolong and reduce the absorption of ibuprofen in the gastrointestinal tract. However, the clinical relevance of this interaction is unknown. Cyclosporins: concomitant administration of ciclosporin and some NSAIDs causes an increased risk of kidney damage. This effect cannot be excluded for the combination of cyclosporine and ibuprofen. Plant extracts: Ginkgo Biloba can increase the risk of bleeding in association with NSAIDs. Mifepristone: due to the anti-prostaglandin properties of NSAIDs, their use after administration of mifepristone may result in a reduction of the effect of mifepristone. Limited evidence suggests that co-administration of NSAIDs and prostaglandins on the same day does not adversely affect the effects of mifepristone or prostaglandin on cervical maturation or uterine contractility and does not reduce the clinical efficacy of the medicine on termination of pregnancy. Quinolone antibiotics: animal data indicate that NSAIDs may increase the risk of seizures associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing seizures. Sulphonylureas: NSAIDs can increase the hypoglycaemic effect of sulphonylureas. In the case of simultaneous treatment, monitoring of blood glucose levels is recommended. Tacrolimus: co-administration of NSAIDs and tacrolimus may lead to an increased risk of nephrotoxicity. Zidovudine: there is evidence of an increased risk of hemarthrosis and hematoma in HIV positive haemophiliac patients concomitantly with Zidovudine and other NSAIDs. A haematological examination is recommended 1–2 weeks after starting treatment. Ritonavir: may cause an increase in the plasma concentrations of NSAIDs. Probenecid: slows the excretion of ibuprofen, with possible increase in their plasma concentrations. CYP2C9 inhibitors: concomitant administration of ibuprofen and CYP2C9 inhibitors may slow the elimination of ibuprofen (CYP2C9 substrate) resulting in increased exposure to ibuprofen. In a study with voriconazole and fluconazole (CYP2C9 inhibitors), an increased exposure to S (+) - ibuprofen was observed from approximately 80% to 100%. Dose reduction of ibuprofen should be considered in cases of co-administration with strong CYP2C9 inhibitors. Alcohol, bisphosphonates and oxpentifylline (pentoxyflline): they can enhance gastrointestinal side effects and the risk of bleeding and ulcers. Baclofen: high toxicity of baclofen.

SIDE EFFECTS
The side effects observed with ibuprofen are generally common to other analgesics, antipyretics, non-steroidal anti-inflammatories and are reported below using the following convention: Very common (≥ 1/10) Common (≥ 1/100 to <1/10) Not common (≥ 1 / 1,000, <1/100) rare (≥1 / 10,000, <1 / 1,000) very rare (<1 / 10,000). Gastrointestinal disorders 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). Gastrointestinal perforation with the use of ibuprofen has been rarely observed. Following administration of SUBITENE, sense of weight in the stomach, nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, epigastric pain, gastric heartburn, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease ( see section 4.4). Uncommon: gastritis. Very rare: pancreatitis Immune system disorders The following side effects have been reported following treatment with NSAIDs: - non-specific allergic reaction and anaphylaxis - uncommon: hypersensitivity reactions such as rash of various types, urticaria, pruritus, purpura, angioedema, exanthema, reactions respiratory tract including asthma, even severe, bronchospasm or dyspnea asthma attacks (sometimes with hypotension). - rare: lupus erythematosus syndrome - very rare: severe hypersensitivity reactions. Symptoms may include: facial edema, swelling of the tongue, internal larynx swelling with constriction of the airways, dyspnoea, tachycardia, anaphylaxis, exfoliative and bullous dermatitis (including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme). Cardiac and vascular disorders Edema, fatigue, hypertension and heart failure have been reported in association with NSAID treatment. Clinical studies suggest that the use of ibuprofen, especially at high doses (2400 mg / day), may be associated with a modest increase in the risk of arterial thrombotic events (e.g. myocardial infarction or stroke) (see section 4.4). Very rare: palpitations, heart failure, myocardial infarction, acute pulmonary edema, edema, hypertension. These phenomena generally tend to regress with the suspension of treatment. Other adverse events reported less frequently and for which causality has not necessarily been established include: Blood and lymphatic system disorders Rare: leukopenia, thrombocytopenia, neutropenia, agranulocytosis, aplastic anemia and hemolytic anemia. Psychiatric disorders Uncommon: insomnia, anxiety Rare: depression, confusional state, hallucinations. Nervous system disorders Common: dizziness. Uncommon: paraesthesia, somnolence. Rare: optic neuritis, aseptic meningitis Infections and infestations Rhinitis and aseptic meningitis (especially in patients with pre-existing autoimmune disorders, such as systemic lupus erythematosus and mixed connective tissue) with symptoms of neck stiffness, headache, nausea, vomiting, fever or disorientation (see section 4.4). The exacerbation of infection-related inflammations (e.g. development of necrotizing fasciitis) has been described. Uncommon: rhinitis. Rare: aseptic meningitis Respiratory system disorders Uncommon: bronchospasm, dyspnoea, apnea. Eye disorders Uncommon: visual disturbances. Rare: ocular alteration with consequent visual disturbances, toxic optic neuropathy. Ear and labyrinth disorders Uncommon: impaired hearing, tinnitus, vertigo. Hepatobiliary disorders Uncommon: impaired liver function, hepatitis and jaundice. Very rare: hepatic insufficiency Skin and subcutaneous tissue disorders Uncommon: photosensitivity reactions Very rare: bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Renal and urinary disorders Uncommon: renal function damage and toxic nephropathy in various forms, including interstitial nephritis, nephrotic syndrome and renal failure. General disorders and administration site conditions Common: malaise, fatigue. Rare: edema. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili.

OVERDOSE
Toxicity The signs and symptoms of toxicity have generally not been observed at doses below 100 mg / kg in children or adults. However, in some cases, supportive treatment may be needed. Children have been shown to exhibit signs and symptoms of toxicity after ingestion of ibuprofen at doses of 400 mg / kg or greater. Symptoms Most patients who have ingested significant amounts of ibuprofen will experience symptoms within 4–6 hours. The most commonly reported symptoms of overdose include: nausea, vomiting, abdominal pain, lethargy and somnolence. Central nervous system (CNS) effects include headache, tinnitus, dizziness, seizures and loss of consciousness. Nystagmus, metabolic acidosis, hypothermia, kidney effects, gastrointestinal bleeding, coma, apnea, diarrhea and depression of the CNS and respiratory system have also been reported rarely. Disorientation, excitement, fainting and cardiovascular toxicity including hypotension, bradycardia and tachycardia have been reported. In cases of significant overdose, renal failure and liver damage are possible. Treatment There is no specific antidote for ibuprofen overdose. In the event of an overdose, symptomatic and supportive treatment is therefore indicated. Particular attention is due to the control of blood pressure, acid-base balance and any gastrointestinal bleeding. Activated charcoal administration should be considered within one hour of ingesting a potentially toxic quantity. Alternatively, in adults, gastric lavage should be considered within one hour of ingesting a potentially life-threatening overdose. Adequate diuresis must be ensured and renal and hepatic functions must be closely monitored. The patient must remain under observation for at least four hours after ingesting a potentially toxic amount of the drug. Any appearance of frequent or prolonged seizures should be treated with intravenous diazepam. Other supportive measures may be required depending on the patient's clinical condition. For more information, contact your local poison control center. In case of overdose, gastric lavage is indicated, correction of blood electrolytes. There is no specific antidote for ibuprofen.

PREGNANCY AND BREAST-FEEDING
Pregnancy Inhibition of prostaglandin synthesis can adversely affect pregnancy and / or embryo / fetal development. Results of epidemiological studies suggest an increased risk of abortion and cardiac malformation and gastroschisis after the use of a prostaglandin synthesis inhibitor in the early stages of pregnancy. The absolute risk of cardiac malformations increased from less than 1% to around 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 and embryo-fetal mortality. In addition, an increase in the incidence of various malformations, including cardiovascular malformations, has been reported in animals that have received synthetic prostaglandin synthesis inhibitors during the organogenetic period. During the first and second trimester of pregnancy, SUBITENE should not be administered except in strictly necessary cases. If SUBITENE is used by a woman awaiting conception or during the first and second trimester of pregnancy, the dose and duration of treatment should be kept as low as possible. During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the fetus to: - cardiopulmonary toxicity (with premature closure of the arterial duct and pulmonary hypertension); - renal dysfunction, which can progress to renal failure with oligo-idroamnios; the mother and the newborn, at the end of pregnancy, to: - possible prolongation of the bleeding time, and antiplatelet effect which may occur even at very low doses; - inhibition of uterine contractions resulting in delayed or prolonged labor. Consequently SUBITENE is contraindicated during the third trimester of pregnancy. Breastfeeding Ibuprofen is excreted in breast milk, but at therapeutic doses during short-term treatment, the risk of influence on the newborn seems unlikely. If, on the other hand, treatment is longer term, early weaning should be considered. NSAIDs should be avoided during breastfeeding. Fertility The use of Ibuprofen can impair female fertility and is not recommended in women awaiting conception. This effect is reversible upon discontinuation of treatment.