Brufen® sache

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BRUFEN® SACHET (BRUFEN® SACHET)

Composition:

Active substance: ibuprofen;

1 sachet contains 600 mg of ibuprofen;

Excipients: microcrystalline cellulose, sodium croscarmellose, malic acid, sodium saccharin, sucrose, povidone, orange flavor, sodium lauryl sulfate, sodium bicarbonate, anhydrous sodium carbonate.

Pharmaceutical form. Effervescent granules.

Main physicochemical properties: fine to coarse granules of white color with an orange odor.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives. Ibuprofen. ATC code M01AE01.

Pharmacological properties.

Pharmacodynamics.

Ibuprofen is a propionic acid derivative and a nonsteroidal anti-inflammatory drug (NSAID) that possesses analgesic, anti-inflammatory, and antipyretic activity. The therapeutic effects of the drug are considered to be due to its inhibitory action on the enzyme cyclooxygenase, resulting in a pronounced reduction in prostaglandin synthesis. These properties provide relief from inflammation, pain, and fever.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid/aspirin on platelet aggregation when both drugs are administered simultaneously. Some pharmacodynamic studies have shown that a single 400 mg dose of ibuprofen taken 8 hours before or 30 minutes after immediate-release acetylsalicylic acid/aspirin (81 mg) reduced the effect of acetylsalicylic acid/aspirin on thromboxane formation or platelet aggregation.

Although there are uncertainties regarding extrapolation of these findings to the clinical setting, the possibility cannot be excluded that regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid/aspirin. Clinically significant interactions are unlikely with occasional use of ibuprofen (see section "Interaction with other medicinal products and other forms of interaction").

Pharmacokinetics.

Ibuprofen is rapidly absorbed from the gastrointestinal tract (GIT), with peak plasma concentrations reached within 1–2 hours after administration. The elimination half-life is approximately 2 hours.

Ibuprofen is metabolized in the liver into two inactive metabolites, which are excreted by the kidneys along with unchanged ibuprofen, either in free form or as conjugates. Renal excretion is rapid and complete. Ibuprofen is highly bound to plasma proteins.

Clinical characteristics.

Indications.

Rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, and other non-rheumatoid (seronegative) arthropathies.

Extra-articular rheumatic and periarticular disorders, such as periarthritis of the shoulder (capsulitis), bursitis, tendinitis, tenosynovitis, and low back pain; soft tissue injuries, such as sprains and ligament strains.

For relief of mild to moderate pain, including dysmenorrhea, dental pain, and postoperative pain, as well as for symptomatic relief of headache, including migraine.

Contraindications.

Known hypersensitivity to the active substance or to any of the excipients.

History of asthma, urticaria, or allergic reactions after taking acetylsalicylic acid/aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs).

Severe heart failure (NYHA functional class IV).

Severe hepatic impairment.

Severe renal impairment (glomerular filtration rate < 30 mL/min).

Conditions associated with an increased risk of bleeding or active bleeding.

Gastrointestinal bleeding or perforation due to previous use of NSAIDs.

Acute or previously experienced ulcerative colitis, Crohn’s disease, recurrent peptic ulcer, or gastrointestinal bleeding (two or more episodes of confirmed ulceration or bleeding).

Third trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

Caution should be exercised when co-administering the following medications due to possible drug interactions observed in some patients.

Antihypertensive agents, β-blockers, and diuretics. NSAIDs may reduce the effectiveness of antihypertensive agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, β-blockers, and diuretics. Diuretics may also increase the risk of NSAID-induced nephrotoxicity.

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

Cholestyramine. Concomitant administration of ibuprofen and cholestyramine may reduce gastrointestinal absorption of ibuprofen. However, the clinical significance of this interaction is unknown.

Lithium. NSAIDs may reduce lithium excretion.

Methotrexate. NSAIDs may inhibit tubular secretion of methotrexate and reduce methotrexate clearance.

Cyclosporine. Increased risk of nephrotoxicity when used concomitantly with NSAIDs.

Mifepristone. A reduction in efficacy is theoretically possible due to the anti-prostaglandin properties of NSAIDs. Limited data suggest that concomitant use of NSAIDs on the day of prostaglandin administration does not alter the effect of mifepristone or prostaglandin on cervical ripening or uterine contractility, nor does it reduce the clinical efficacy of medical termination of pregnancy.

Other NSAIDs, including selective COX-2 inhibitors. Concomitant use with other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, should be avoided due to the risk of additive effects (see section "Special precautions for use").

Acetylsalicylic acid/aspirin. As with other NSAID-containing products, concomitant use of ibuprofen and acetylsalicylic acid/aspirin is generally not recommended due to the increased risk of adverse reactions.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid/aspirin on platelet aggregation when administered concomitantly.

However, despite uncertainties regarding the extrapolation of these findings to clinical practice, it cannot be excluded that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. No clinically significant changes occur with occasional use of ibuprofen (see section "Pharmacodynamics").

Corticosteroids. Increased risk of gastrointestinal ulceration or bleeding when used concomitantly with NSAIDs.

Anticoagulants. NSAIDs may potentiate the effects of anticoagulants such as warfarin.

Quinolone antibiotics. Animal studies indicate that NSAIDs may increase the risk of seizures associated with quinolone antibiotics. Patients receiving NSAIDs and quinolones concomitantly have an increased risk of developing seizures.

Sulfonylureas. NSAIDs may potentiate the effects of sulfonylurea agents. Rare cases of hypoglycemia have been reported in patients taking sulfonylureas during ibuprofen therapy.

Antiplatelet agents and selective serotonin reuptake inhibitors (e.g., clopidogrel and ticlopidine). Increased risk of gastrointestinal bleeding when used concomitantly with NSAIDs.

Tacrolimus. Possible increased risk of nephrotoxicity when NSAIDs are administered to patients receiving tacrolimus.

Zidovudine. NSAIDs increase the risk of hematological toxicity when administered concomitantly with zidovudine. Evidence exists for an increased risk of hemarthrosis and hematoma in HIV-positive patients with hemophilia who are treated with ibuprofen while receiving zidovudine.

Aminoglycosides. NSAIDs may reduce the elimination of aminoglycosides.

Herbal extracts. Ginkgo biloba may potentiate the risk of bleeding associated with NSAIDs.

CYP2C9 inhibitors. Concomitant administration of ibuprofen with CYP2C9 inhibitors may increase ibuprofen exposure (ibuprofen is a CYP2C9 substrate). One study demonstrated that voriconazole and fluconazole (CYP2C9 inhibitors) increased S(+)-ibuprofen exposure by approximately 80–100%. Dose reduction of ibuprofen should be considered when co-administered with CYP2C9 inhibitors, especially when high doses of ibuprofen are prescribed to patients taking voriconazole or fluconazole.

Special precautions for use.

General warnings

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Dosage and administration" and gastrointestinal, cardiovascular risks below).

Prolonged use of any analgesic may lead to medication-overuse headache, which should not be treated by increasing the dose of the medicinal product.

Concomitant use of NSAIDs with alcohol may increase adverse effects related to the active substance, particularly those affecting the gastrointestinal tract or central nervous system.

Each sachet of the medicinal product contains 3.3 g of sucrose per dose. This should be taken into account for patients with diabetes mellitus. Patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not use this medicinal product.

Each sachet of the medicinal product contains 8.6 mmol (or 197 mg)/dose of sodium. This should be considered for patients who need to restrict sodium intake.

Elderly patients

In elderly patients, the frequency of adverse reactions during NSAID use is higher, especially gastrointestinal bleeding and perforation, which can be fatal.

Gastrointestinal bleeding, ulceration, and perforation

NSAIDs should be used with caution in patients with a history of peptic ulcer or other gastrointestinal disorders, as their condition may worsen (see section "Contraindications").

Gastrointestinal bleeding, ulceration, or perforation have been reported during treatment with all NSAIDs at any time. These adverse reactions may be fatal and may occur with or without warning symptoms or serious gastrointestinal disorders in history.

The risk of gastrointestinal bleeding, ulceration, or perforation is higher with increasing doses of ibuprofen, in patients with a history of ulcers (especially if complicated by bleeding or perforation), and in elderly patients. Such patients should initiate treatment with the lowest effective dose.

Concomitant use of protective agents (e.g., misoprostol or proton pump inhibitors) should be considered for these patients, as well as for patients who are concurrently taking low-dose acetylsalicylic acid/aspirin or other drugs that increase the risk of gastrointestinal injury (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ibuprofen with other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, should be avoided due to an increased risk of ulceration or bleeding (see section "Interaction with other medicinal products and other forms of interaction").

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

Ibuprofen should be prescribed with caution to patients receiving concomitant therapy with drugs that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid/aspirin (see section "Interaction with other medicinal products and other forms of interaction").

If gastrointestinal bleeding or ulceration occurs in a patient receiving ibuprofen, the drug should be discontinued.

Respiratory disorders

Ibuprofen should be prescribed with caution to patients suffering from bronchial asthma, chronic rhinitis, allergic diseases, or with a history of such conditions, as ibuprofen has been reported to induce bronchospasm, urticaria, or angioedema in such patients.

Impairment of cardiac, renal, and hepatic function

NSAIDs should be used with caution in patients with impaired renal, hepatic, or cardiac function, as this may lead to worsening of renal function.

Regular concomitant use of such analgesics further increases this risk.

Patients with impaired renal, hepatic, or cardiac function should use the lowest effective dose for the shortest possible duration, and renal function should be monitored, especially during long-term treatment (see section "Contraindications").

Cardiovascular and cerebrovascular effects

Ibuprofen should be prescribed with caution to patients with a history of heart failure or hypertension, as edema has been reported with ibuprofen use. Clinical studies indicate that ibuprofen use, especially at high doses (2400 mg daily), may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Overall, epidemiological studies do not suggest a clear association between low-dose ibuprofen use (i.e., ≤1200 mg daily) and an increased risk of arterial thrombotic events.

Ibuprofen should be prescribed to patients with uncontrolled hypertension, congestive heart failure (NYHA functional class II–III), diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease only after careful consideration, and high doses of ibuprofen (2400 mg daily) should be avoided.

Careful consideration is also required before initiating long-term ibuprofen therapy in patients with risk factors for cardiovascular disease (such as hypertension, hyperlipidemia, diabetes mellitus, smoking), especially if high doses of ibuprofen (2400 mg daily) are required.

Cases of Kounis syndrome have been reported in patients receiving ibuprofen treatment. Kounis syndrome is defined as cardiovascular symptoms caused by an allergic or hypersensitivity reaction associated with coronary artery spasm, which may potentially lead to myocardial infarction.

Cutaneous effects

Serious skin adverse reactions (SSARs)

Serious skin adverse reactions (SSARs), including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal, have been reported during ibuprofen use (see section "Adverse reactions"). Most such reactions occurred within the first month of therapy. If signs or symptoms suggesting these reactions occur, ibuprofen should be discontinued immediately and alternative therapy considered (if necessary).

In rare cases, serious skin and soft tissue infections may occur during varicella. The role of NSAIDs in worsening these infections has not been established. Therefore, it is recommended to avoid ibuprofen use in cases of varicella.

Renal effects

Treatment with ibuprofen should be initiated with caution in patients with significant dehydration. There is a risk of impaired renal function, especially in children, adolescents, and elderly patients with dehydration. As with other NSAIDs, prolonged use of ibuprofen may lead to renal papillary necrosis and other renal pathological changes. Renal toxicity has also been observed in patients in whom renal prostaglandins play a compensatory role in maintaining renal perfusion. Administration of NSAIDs to such patients may cause dose-dependent reduction in prostaglandin synthesis and, secondarily, decreased renal blood flow, potentially leading to renal failure.

Patients at high risk of such reactions include those with impaired renal function, heart failure, hepatic dysfunction, those taking diuretics and angiotensin-converting enzyme (ACE) inhibitors, and elderly patients. Discontinuation of NSAIDs is usually followed by recovery to the pre-treatment state.

Renal tubular acidosis and hypokalemia may develop after acute overdose and in patients taking high doses of ibuprofen for prolonged periods (usually longer than 4 weeks), including doses exceeding the recommended daily dose.

Hematological effects

Ibuprofen, like other NSAIDs, may inhibit platelet aggregation and prolong bleeding time in healthy volunteers.

Aseptic meningitis

Rarely, aseptic meningitis has been observed in patients treated with ibuprofen. Although aseptic meningitis is more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, cases have been reported in patients without these chronic conditions.

Masking symptoms of underlying infections

Like other NSAIDs, ibuprofen may mask symptoms of infectious diseases, potentially delaying the initiation of appropriate treatment and thereby complicating the course of the infection. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When ibuprofen is used for fever or pain relief in infectious diseases, monitoring of the condition is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Use during pregnancy or breastfeeding

Fertility

Ibuprofen use may impair female fertility and is not recommended for women attempting to conceive. Women who have fertility problems or are undergoing infertility investigations should consider discontinuing ibuprofen use.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and congenital heart defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. This risk is considered to increase with dose and duration of treatment. Animal studies have shown that prostaglandin synthesis inhibitors increase pre- and post-implantation losses and embryo/fetal mortality. Furthermore, an increased incidence of various malformations, including cardiovascular, has been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.

From the 20th week of pregnancy, ibuprofen use may cause oligohydramnios due to fetal renal dysfunction. This condition may occur soon after initiation of treatment and is usually reversible upon discontinuation. Additionally, there are reports of ductus arteriosus constriction after second-trimester treatment, which in most cases resolved after treatment cessation. Therefore, during the first and second trimesters of pregnancy, ibuprofen should be used only if clearly necessary. When ibuprofen is used by women planning pregnancy or during the first or second trimester, 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 may be appropriate after ibuprofen exposure for several days starting from the 20th gestational week. The use of ibuprofen-containing medicinal products should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may affect the fetus by causing:

• cardio-pulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction (see above).

At the end of pregnancy, prostaglandin synthesis inhibitors in the mother and newborn may cause:

• possible prolongation of bleeding time, antiplatelet effect, which may occur even at very low doses;
• inhibition of uterine contractions, potentially leading to delayed or prolonged labor.

Therefore, ibuprofen is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Labour and delivery

Ibuprofen is not recommended during labour and delivery.

Onset of labour may be delayed, and its duration prolonged, along with increased risk of bleeding in both mother and child.

Breastfeeding

Limited available data indicate that ibuprofen is excreted in breast milk in very low concentrations. Ibuprofen is not recommended for use in women during breastfeeding.

Ability to influence reaction speed when driving vehicles or operating machinery

Ibuprofen may affect patients' reaction speed, which should be considered when engaging in activities requiring high concentration, such as driving vehicles or operating machinery. The effect on reaction speed is significantly enhanced when combined with alcohol.

After taking NSAIDs, adverse events such as dizziness, somnolence, fatigue, and visual disturbances may occur. If such events occur during NSAID use, patients should not drive vehicles or operate machinery.

Method of Administration and Dosage.

Doses

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Special Warnings and Precautions for Use").

Adults

The recommended dose of Brufen® Sache is 1200–1800 mg daily, administered in 2–3 divided doses. Some patients may be adequately managed with 600–1200 mg daily. In general, the maximum daily dose should not exceed 2400 mg, given in several divided doses.

Elderly Patients

There is an increased risk of serious adverse reactions when administering the drug to elderly patients. If nonsteroidal anti-inflammatory drugs (NSAIDs) are required, the lowest effective dose should be used for the shortest possible duration. Regular monitoring for gastrointestinal bleeding during NSAID therapy is necessary. Dose adjustment is required individually in case of hepatic or renal impairment.

Method of Administration

For oral use.

To achieve faster onset of action, the medication may be taken on an empty stomach. However, patients with gastrointestinal disorders should take the medication with food.

Before administration, the contents of one sachet should be dissolved in a glass of water. It is advisable to take it during or after a meal.

A transient burning sensation in the mouth or throat may occur when taking Brufen® Sache; ensure that the medication is dissolved in an adequate amount of water.

Children

Brufen® Sache in this pharmaceutical form is contraindicated for use in children.

Overdose.

Toxicity

Toxic symptoms are generally not observed with doses below 100 mg/kg in adults and children. However, supportive measures may be required in some cases. In children, toxic symptoms have been reported after ingestion of 400 mg/kg or more.

Symptoms

In most patients, symptoms of overdose develop within 4–6 hours after ingestion of a large amount of ibuprofen.

The most common symptoms of overdose include nausea, vomiting, abdominal pain, lethargy, and drowsiness. Central nervous system (CNS) manifestations: headache, tinnitus, dizziness, seizures, and loss of consciousness. Rarely reported: nystagmus, metabolic acidosis, hypothermia, renal symptoms, gastrointestinal bleeding, coma, apnea, and CNS and respiratory depression. Cardiovascular toxicity has been reported, including arterial hypotension, bradycardia, and tachycardia.

In cases of significant overdose, renal failure and hepatic injury may develop. Significant overdose is generally well tolerated if no other drugs have been co-ingested. In severe poisoning, metabolic acidosis and prolonged prothrombin time/international normalized ratio (INR) may occur, likely due to interaction with circulating coagulation factors. Prolonged use at doses exceeding recommended levels may lead to severe hypokalemia and renal tubular acidosis. Symptoms may include decreased level of consciousness and generalized weakness (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions").

Treatment

There is no specific antidote for ibuprofen overdose. If the ingested amount exceeds 400 mg/kg, gastric lavage/emptying is recommended within one hour of ingestion, followed by symptomatic treatment. Activated charcoal should be administered within one hour after ingestion of a potentially toxic amount. Treatment should include maintaining airway patency and monitoring cardiac function and vital signs until the patient's condition stabilizes.

Ensure adequate diuresis.

Renal and hepatic function should be closely monitored. If necessary, correct serum electrolyte imbalances.

Patients who have ingested a potentially toxic amount should be observed for at least four hours.

Frequent or prolonged seizures should be treated with intravenous diazepam. Other interventions may be indicated based on the patient's clinical condition.

For the most up-to-date information, contact the local toxicology center.

Side effects

Adverse reactions to ibuprofen are similar to those observed with other NSAIDs.

Gastrointestinal tract: Adverse reactions of the gastrointestinal tract (GIT) are the most commonly observed. Peptic ulcers, perforation, or gastrointestinal hemorrhage, sometimes fatal, particularly in elderly patients, may occur (see section "Special precautions").

Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, gastrointestinal bleeding, and exacerbation of colitis and Crohn’s disease have been reported during ibuprofen use (see section "Contraindications"). Gastritis, duodenal ulcer, gastric ulcer, and gastrointestinal perforation have been observed less frequently.

During intake of ibuprofen granules, transient burning sensation in the mouth or throat may occur.

Immune system disorders: Hypersensitivity reactions have been reported with ibuprofen use. These include non-specific allergic reactions and anaphylaxis; respiratory tract reactivity, including asthma, worsening of asthma, bronchospasm, or dyspnea; and various skin manifestations, including rashes of different types, pruritus, urticaria, purpura, angioedema, and very rarely – erythema multiforme, bullous dermatoses (including Stevens-Johnson syndrome, toxic epidermal necrolysis).

Infections and infestations

Rhinitis and aseptic meningitis (particularly in patients with pre-existing autoimmune disorders such as systemic lupus erythematosus and mixed connective tissue diseases) with symptoms such as neck rigidity, headache, nausea, vomiting, fever, or disorientation (see section "Special precautions").

Cases of worsening skin inflammation due to infection (e.g., development of necrotizing fasciitis) have been described during NSAID use. If signs of infection develop or worsen during ibuprofen treatment, patients should seek immediate medical attention.

Skin and subcutaneous tissue disorders

In rare cases, severe skin infections and soft tissue complications may occur during varicella (chickenpox) (see also "Infections and infestations").

Cardiovascular system

Edema, hypertension, and heart failure have been reported in association with NSAID therapy.

Clinical trial data indicate that the use of ibuprofen, especially at high doses (2400 mg per day), may slightly increase the risk of arterial thrombotic events (e.g., myocardial infarction or stroke) (see section "Special precautions").

The adverse reactions listed below may be associated with ibuprofen and are classified by frequency and organ systems according to MedDRA.

Adverse reactions are categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders: Rare – leukopenia, thrombocytopenia, aplastic anemia, neutropenia, agranulocytosis, hemolytic anemia.

Psychiatric disorders: Uncommon – insomnia, anxiety disorders; rare – depression, confusion.

Nervous system disorders: Common – headache, dizziness; uncommon – paresthesia, somnolence; rare – optic neuritis.

Infections and infestations: Uncommon – rhinitis; rare – aseptic meningitis (see section "Special precautions").

Eye disorders: Uncommon – visual disturbances; rare – toxic optic neuropathy.

Ear and labyrinth disorders: Uncommon – hearing impairment, vertigo, tinnitus.

Hepatobiliary disorders: Uncommon – hepatitis, jaundice, liver function abnormalities; very rare – liver failure.

Skin and subcutaneous tissue disorders: Common – rash; uncommon – urticaria, pruritus, purpura, angioedema; very rare – severe cutaneous adverse reactions (SCARs) (including erythema multiforme, exfoliative dermatitis, bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis). Frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP), photosensitivity reactions.

Metabolism and nutrition disorders: Frequency not known – decreased appetite, hypokalemia*.

Renal and urinary disorders: Uncommon – toxic nephropathy in various forms, including tubulointerstitial nephritis, nephrotic syndrome, and renal failure; very rare – acute renal failure; frequency not known – ureteric colic, dysuria, renal tubular acidosis*.

General disorders and administration site conditions: Common – malaise/fatigue; rare – edema.

Immune system disorders: Uncommon – hypersensitivity; rare – anaphylactic reaction.

Cardiac disorders: Very rare – heart failure, myocardial infarction (see section "Special precautions"); frequency not known – Kounis syndrome.

Vascular disorders: Very rare – arterial hypertension.

Respiratory system disorders: Uncommon – bronchial asthma, bronchospasm, dyspnea.

Gastrointestinal disorders: Common – dyspepsia, diarrhea, nausea, vomiting, abdominal pain, flatulence, constipation, melena, hematemesis, gastrointestinal bleeding; uncommon – gastritis, duodenal ulcer, gastric ulcer, ulcerative stomatitis, gastrointestinal perforation; very rare – pancreatitis; frequency not known – colitis and Crohn’s disease.

* Renal tubular acidosis and hypokalemia have been reported during the post-marketing period, usually after prolonged use of ibuprofen at doses exceeding the recommended levels.

Shelf life.

3 years.

Storage conditions.

Keep out of reach and sight of children. Store at a temperature not exceeding 25 °C.

Packaging.

30 sachets per cardboard box.

Prescription status.

Prescription only.

Manufacturer. AbbVie S.r.l., Italy / AbbVie S.r.l., Italy.

Manufacturer's address and place of business. C.R. 148 Pontina KM 52, SNC - Campoverde di Aprilia (loc. Aprilia) - 04011 Aprilia (LT), Italy / S.R. 148 Pontina KM 52, SNC - Campoverde di Aprilia (loc. Aprilia) - 04011 Aprilia (LT), Italy.