Affida max with arginine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AFFFIDA MAX WITH ARGININE (AFFIDA MAX WITH ARGININE)

Composition:

Active substance: ibuprofen;

1 sachet contains 400 mg* of ibuprofen;

Excipients: arginine, aspartame (E 951), sucrose, sodium hydrogencarbonate, sodium saccharin, sodium lauryl sulfate, menthol, peppermint flavor, purified water.

Pharmaceutical form. Granules for oral solution.

Main physicochemical properties: white or almost white granules with a mint flavor.

Pharmacotherapeutic group

Non-steroidal anti-inflammatory and antirheumatic agents.

ATC code M01A E01.

Pharmacological Properties

Pharmacodynamics

Ibuprofen is a non-steroidal compound, a derivative of propionic acid, with pronounced anti-inflammatory, analgesic, and antipyretic properties. Its mechanism of action may be due to inhibition of prostaglandin synthesis. Prostaglandins play an important role in the development of fever, pain, and inflammation. Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when administered concomitantly. Some pharmacodynamic studies have shown that administration of 400 mg of ibuprofen 8 hours before or within 30 minutes after immediate-release acetylsalicylic acid (81 mg) reduced the effect of acetylsalicylic acid on thromboxane or platelet aggregation. However, the limited nature of the experimental data and uncertainty regarding the possibility of extrapolating these findings to clinical situations do not allow definitive conclusions about the regular use of ibuprofen or prediction of clinical effects with intermittent use of ibuprofen.

Pharmacokinetics

Ibuprofen is a medicinal product with linear pharmacokinetic properties.

Absorption

After oral administration, ibuprofen is rapidly absorbed from the gastrointestinal tract (GI tract) by approximately 80%. Ibuprofen with arginine in granules for oral solution demonstrates high and rapid absorption due to the presence of the amino acid L-arginine, which promotes solubilization and enhances its bioavailability. Peak plasma concentrations are achieved as early as 20 minutes after administration. No accumulation of the drug or its metabolites has been observed following administration of ibuprofen with arginine in granules for oral solution.

Distribution

The apparent volume of distribution of ibuprofen after oral administration ranges from 0.1 to 0.2 L/kg. Extensive binding to plasma proteins is approximately 99%.

Metabolism

Ibuprofen is extensively metabolized in the liver via hydroxylation and carboxylation of the isobutyl group. The metabolites of ibuprofen are pharmacologically inactive.

Excretion

Ibuprofen is primarily eliminated from the body via the kidneys within 24 hours. Approximately 10% is excreted unchanged and 90% as inactive metabolites, mainly in the form of glucuronides.

Food intake delays Tmax (from approximately 2 hours on an empty stomach to approximately 3 hours after food intake), although this does not affect the extent of absorption.

Clinical characteristics

Indications

• Symptomatic treatment of fever.
• Treatment of mild to moderate pain, including migraine.
• Symptomatic treatment of arthritides (including juvenile rheumatoid arthritis), osteoarthritis, ankylosing spondylitis, and non-rheumatic inflammation.
• Symptomatic relief in primary dysmenorrhea.

Contraindications

• Hypersensitivity to ibuprofen or to any of the excipients of the medicinal product.
• Hypersensitivity to salicylates or to other NSAIDs (patients with a history of asthma, acute rhinitis, urticaria, angioedema, or other allergic-type reactions after taking substances with similar action).
• Inflammatory bowel diseases.
• Severe hepatic impairment.
• Severe renal impairment.
• Patients with hemorrhagic diathesis or other coagulation disorders.
• History of gastrointestinal bleeding or perforation related to previous NSAID therapy.
• Active peptic ulcer/gastrointestinal bleeding or recurrent history (two or more episodes of confirmed ulcer disease or bleeding).
• Gastric or duodenal ulcer.
• Severe heart failure (NYHA Class IV).
• Third trimester of pregnancy (see section "Special precautions for use").
• Active cerebrovascular or other bleeding.
• Hematopoietic disorders of unknown etiology.
• Severe dehydration (caused by vomiting, diarrhea, or insufficient fluid intake).

Interaction with other medicinal products and other forms of interaction

NSAIDs should be used with caution in combination with other medicinal products that may increase the risk of gastrointestinal ulceration, gastrointestinal bleeding, or renal dysfunction. Experimental data indicate that ibuprofen may inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when used concomitantly. However, due to the limited nature of these data and uncertainty regarding the possibility of extrapolating them to clinical situations, no definitive conclusion can be drawn regarding the regular use of ibuprofen and potential clinical effects with occasional use.

Ibuprofen, like other NSAIDs, should not be used in combination with the following drugs.

Anticoagulants. NSAIDs may enhance the effects of coumarin-type anticoagulants, such as warfarin (see section "Special precautions for use").

Antiplatelet agents. NSAIDs increase the risk of gastrointestinal bleeding (see section "Special precautions for use").

Acetylsalicylic acid. Concomitant use of ibuprofen with acetylsalicylic acid is generally not recommended due to the potential for increased adverse reactions, except in cases where acetylsalicylic acid (dose not exceeding 75 mg per day) has been prescribed by a physician.

Experimental data indicate that when used concomitantly, ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation. Although there is uncertainty regarding the extrapolation of these data to clinical practice, it cannot be excluded that regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. With occasional use of ibuprofen, such a clinically significant effect is considered unlikely (see section "Pharmacodynamics").

Corticosteroids. Increased risk of gastrointestinal ulcers or bleeding when used with NSAIDs (see section "Special precautions for use").

Selective serotonin reuptake inhibitors (SSRIs). May increase the risk of gastrointestinal bleeding (see section "Special precautions for use").

Other NSAIDs, including selective cyclooxygenase-2 inhibitors. Concomitant administration with other NSAIDs should be avoided, as the use of different NSAIDs may increase the risk of gastrointestinal ulcers or bleeding due to a synergistic effect.

Methotrexate (at doses of 15 mg/week or higher). When NSAIDs and methotrexate are used within a 24-hour interval, an increased plasma methotrexate level is observed (renal clearance of methotrexate may be reduced due to the action of NSAIDs), leading to an increased risk of methotrexate toxicity. Therefore, the use of ibuprofen should be avoided in patients receiving high-dose methotrexate therapy.

Hydantoins and sulfonamides. The toxic effects of these substances may be enhanced when used with NSAIDs. Concomitant use with ibuprofen may increase plasma phenytoin levels.

Ticlopidine. NSAIDs should not be used in combination with ticlopidine due to the risk of additive effects on platelet function inhibition.

Lithium. NSAIDs may increase plasma lithium levels by reducing renal lithium clearance. Concomitant use of lithium with NSAIDs should be avoided except when lithium levels are monitored. A possible reduction in lithium dosage should be considered.

Mifepristone. NSAIDs should not be used within 8–12 days after mifepristone administration, as this may reduce the efficacy of mifepristone.

Caution is advised when using concomitantly with the following medicinal products.

Digoxin. NSAIDs may increase the risk of digoxin toxicity by increasing its plasma levels.

Cardiac glycosides. NSAIDs may exacerbate heart failure by reducing glomerular filtration rate and increasing cardiac glycoside levels.

Methotrexate (at low doses, less than 15 mg/week). Administration of ibuprofen within 24 hours before or after methotrexate may lead to increased methotrexate concentration and increased toxicity. When NSAIDs are used in combination with low-dose methotrexate, blood parameters should be closely monitored, especially during the first weeks of concomitant therapy. In addition, careful monitoring is particularly necessary in cases of renal impairment, regardless of severity, especially in elderly patients, and renal function should be monitored to prevent possible reduction in methotrexate clearance.

Moclobemide. Increases the effect of ibuprofen.

Aminoglycosides. NSAIDs may reduce the elimination of aminoglycosides.

Pentoxifylline. In patients receiving ibuprofen in combination with pentoxifylline, the risk of bleeding may increase; therefore, monitoring of bleeding time is recommended.

Phenytoin. Plasma phenytoin levels may increase when used concomitantly with ibuprofen.

Probenecid and sulfinpyrazone. Concomitant use may lead to increased plasma ibuprofen concentrations. This interaction may be related to inhibition at the site of renal tubular secretion and glucuronidation, and may require adjustment of ibuprofen dosage.

Quinolones. Cases of seizures have been reported, possibly associated with concomitant use of quinolones and certain NSAIDs.

Thiazides, thiazide-like agents, loop diuretics, and potassium-sparing diuretics. NSAIDs may reduce the diuretic effect of these agents. Furthermore, concomitant use of NSAIDs and diuretics may increase the risk of renal impairment due to reduced renal blood flow. As with other NSAIDs, concomitant use with potassium-sparing diuretics may lead to increased potassium levels; therefore, plasma potassium levels should be monitored.

Sulfonylureas. NSAIDs may enhance the hypoglycemic effect of sulfonylureas by displacing them from plasma protein binding sites. Glucose monitoring is recommended as a precautionary measure during concomitant use.

Cyclosporine, tacrolimus. Concomitant use with NSAIDs may increase the risk of nephrotoxicity due to reduced renal prostaglandin synthesis. Renal function should be closely monitored when these medicinal products are used together.

Antihypertensive agents (including ACE inhibitors or beta-blockers) and diuretics. NSAIDs may reduce the effectiveness of diuretics and antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised renal function), concomitant use of an ACE inhibitor or angiotensin II antagonist with cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, such combinations should be used with caution, especially in elderly patients. If prolonged treatment is necessary, adequate hydration of the patient should be ensured, and monitoring of renal function should be initiated at the start of combination therapy and continued periodically thereafter. Diuretics may increase the risk of nephrotoxic effects of NSAIDs.

Potassium-sparing diuretics. Concomitant use of ibuprofen and potassium-sparing diuretics may lead to hyperkalemia (serum potassium should be checked).

CYP2C9 inhibitor. Concomitant use of ibuprofen with CYP2C9 inhibitors may increase the effect of ibuprofen (a CYP2C9 substrate). In a study with voriconazole and fluconazole (CYP2C9 inhibitors), an 80–100% increase in the effect of S(+)-ibuprofen was observed. Dose reduction of ibuprofen should be considered when co-administered with potent CYP2C9 inhibitors, especially when high doses of ibuprofen are used, both with voriconazole and fluconazole.

Thrombolytics. The risk of bleeding may increase.

Zidovudine. Concomitant use may increase the risk of toxic effects on erythrocytes due to effects on reticulocytes. Severe anemia may occur one week after initiation of NSAID therapy. Blood parameters should be monitored during concomitant therapy with NSAIDs, especially at the beginning of treatment. Evidence suggests an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia receiving concomitant zidovudine and ibuprofen.

Antidiabetic agents. Ibuprofen enhances the glucose-lowering effect of oral antidiabetic agents and insulin. Dose adjustment may be necessary. As a precautionary measure, blood glucose levels should be monitored during concomitant use of these agents.

Herbal extracts. Ginkgo biloba, when used concomitantly with NSAIDs, may increase the risk of bleeding.

Food. Administration of ibuprofen with food delays the rate of ibuprofen absorption (see section "Pharmacokinetics").

Alcohol. Ibuprofen use should be avoided in patients who abuse alcohol (14–20 or more alcoholic drinks per week) due to an increased risk of gastrointestinal adverse effects, including bleeding.

Special precautions for use

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Dosage and administration").

Other NSAIDs. Concomitant use of ibuprofen with other NSAIDs, including selective cyclooxygenase-2 inhibitors, increases the risk of adverse reactions and should be avoided.

Systemic lupus erythematosus and mixed connective tissue diseases. Ibuprofen should be used with caution in patients with systemic lupus erythematosus or mixed connective tissue diseases due to an increased risk of aseptic meningitis.

Porphyria metabolism. Caution should be exercised in patients with inherited disorders of porphyrin metabolism (e.g., acute intermittent porphyria).

Gastrointestinal (GI) risks. Gastrointestinal bleeding, ulceration, or perforation, which may be fatal, have been reported with the use of all NSAIDs at any time during treatment, with or without preceding warning symptoms, regardless of a history of serious GI bleeding.

The risk of GI bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Such patients should start treatment at the lowest possible dose. Consideration should be given to concomitant use of protective agents (e.g., misoprostol or proton pump inhibitors) in patients who are also taking low-dose acetylsalicylic acid or other drugs that may increase GI risk (see section "Interaction with other medicinal products and other forms of interaction").

Patients, particularly elderly patients, with a history of GI disorders should report any unusual abdominal symptoms (including GI bleeding) during treatment, especially in the initial stages of therapy.

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 coumarin anticoagulants or antiplatelet agents like acetylsalicylic acid (see section "Interaction with other medicinal products and other forms of interaction"). Caution is also advised when using ibuprofen concomitantly with oral corticosteroids and SSRIs. In case of GI bleeding or ulceration in patients receiving ibuprofen, treatment should be discontinued immediately (see section "Contraindications").

NSAIDs should be used with caution in patients with a history of ulcerative colitis or Crohn’s disease, as these conditions may be exacerbated (see section "Adverse reactions").

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

Clinical trial data and epidemiological evidence suggest that the use of ibuprofen, particularly at high doses (2400 mg daily), may be associated with a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low-dose ibuprofen (e.g., ≤1200 mg daily) leads to an increased risk of arterial thrombotic complications.

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

Careful clinical evaluation should also be performed before initiating long-term treatment in patients with cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes, smoking), especially if high-dose ibuprofen (2400 mg daily) is required.

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

Serious skin reactions (SSRs). Serious skin adverse reactions (SSRs), including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal, have been reported with ibuprofen (see section "Adverse reactions"). Most such reactions occur within the first month of treatment.

If signs or symptoms suggestive of these reactions occur, ibuprofen should be discontinued immediately and alternative therapy considered (if necessary).

In rare cases, varicella may lead to severe skin and soft tissue infections. A negative influence of NSAIDs on the worsening of such infections cannot currently be excluded; therefore, the use of ibuprofen in cases of varicella is not recommended.

Allergy. Caution should be exercised in patients with allergic reactions to other substances, as such patients may have an increased risk of hypersensitivity reactions when using ibuprofen.

Patients with hay fever, nasal polyps, chronic obstructive respiratory diseases, or a history of allergic conditions have an increased risk of allergic reactions, which may manifest as asthma attacks (so-called analgesic-induced asthma), Quincke’s edema, or urticaria.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, may occur, even without prior exposure to the drug.

Surgery. Caution should be exercised immediately after major surgical procedures.

Effects on kidneys/liver. Ibuprofen should be used with caution in patients with kidney or liver disease, particularly when concomitantly treated with diuretics, as prostaglandin inhibition may lead to fluid retention and further deterioration of renal function. These patients should receive the lowest possible dose of ibuprofen, and renal function should be monitored regularly. During prolonged ibuprofen use, liver function, renal function, and hematological parameters/blood counts should be monitored regularly.

Effects on the respiratory system. Ibuprofen should be prescribed with caution to patients with bronchial asthma or a history of asthma, as NSAIDs may induce bronchospasm in such patients (see section "Adverse reactions").

Effects on female fertility. Limited data suggest that drugs inhibiting cyclooxygenase/prostaglandin synthesis, when used long-term (doses of 2400 mg daily and treatment duration exceeding 10 days), may impair female fertility by affecting ovulation. This effect is reversible upon discontinuation of treatment.

Other. Like other NSAIDs, ibuprofen may cause a slight, temporary increase in certain liver function parameters, as well as significant elevations in AST and ALT levels. If marked increases in these parameters occur, treatment should be discontinued (see sections "Dosage and administration" and "Contraindications").

Ibuprofen, like other NSAIDs, may reversibly inhibit platelet aggregation and prolong bleeding time. Caution is recommended when ibuprofen is used concomitantly with oral anticoagulants.

Adverse reactions 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).

The incidence of adverse reactions with NSAIDs is higher in elderly patients, particularly gastrointestinal bleeding and perforation, which may be fatal (see section "Dosage and administration").

As with other NSAIDs, ibuprofen may mask symptoms of underlying infections.

Masking symptoms of underlying infections. Ibuprofen may mask symptoms of infectious disease, potentially delaying the initiation of appropriate treatment and thereby complicating the course of illness. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. If the medicinal product is used for fever or pain relief during infection, monitoring of the infectious disease is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Warnings regarding excipients. This medicinal product contains aspartame, a phenylalanine derivative, which may be harmful to patients with phenylketonuria.

The medicinal product contains sucrose. Patients with hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not use this medicinal product.

Patients with known sugar intolerances should consult a physician before taking this medicinal product.

Use during pregnancy or breastfeeding

First and second trimesters of pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and congenital malformations (particularly cardiac defects and gastroschisis) following the use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%. This risk is considered to increase with dose and duration of treatment. From the 20th week of gestation, ibuprofen use may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there have been reports of arterial duct constriction following second-trimester treatment, most of which resolved after stopping treatment. Therefore, ibuprofen should not be prescribed during the first and second trimesters unless clearly necessary. If ibuprofen is used by women attempting to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and treatment duration as short as possible. Prenatal monitoring for oligohydramnios and arterial duct constriction should be considered after several days of ibuprofen exposure starting from the 20th gestational week. Treatment with Affida Max with arginine should be discontinued if oligohydramnios or arterial duct constriction is detected.

Third trimester of pregnancy

During the third trimester, all prostaglandin synthesis inhibitors may pose the following risks.

Risks to the fetus:

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

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 at very low doses;
• Inhibition of uterine contractions, leading to delayed or prolonged labor.

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

Fertility

The use of ibuprofen may impair female fertility and is not recommended for women attempting to conceive. For women experiencing infertility or undergoing fertility investigations, discontinuation of ibuprofen should be considered.

Breastfeeding period

In limited studies, ibuprofen has been detected in breast milk at very low concentrations, making it unlikely to adversely affect the breastfed infant. However, ibuprofen is not recommended for use in breastfeeding women due to the potential risk of prostaglandin synthesis inhibition in newborns.

Ability to influence reaction speed when driving or operating machinery

Patients who experience dizziness, vertigo, somnolence, visual disturbances, or other central nervous system disorders while taking ibuprofen should refrain from driving or operating machinery. No special precautions are required when using a single dose or short-term treatment.

Dosage and Administration

The risk of adverse reactions 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

Dosage should be individually adjusted depending on the severity of the condition and the patient's response.

The recommended daily dose is 1200 mg of ibuprofen, divided into several doses.

If long-term treatment is required, the lowest effective dose providing adequate symptom control should be prescribed.

For rheumatoid arthritis, higher doses may be necessary; however, the maximum daily dose must not exceed 2400 mg.

For primary dysmenorrhea, the recommended dose is 400 mg of ibuprofen for pain relief. The maximum single dose is 400 mg, and the maximum daily dose is 1200 mg.

For inflammatory conditions, the recommended daily dose is 1200–1800 mg of ibuprofen, divided into several doses. The maintenance dose is usually 800–1200 mg. The maximum daily dose must not exceed 2400 mg.

For mild to moderate pain and fever symptoms, the recommended daily dose is 800–1600 mg, divided into several doses, depending on symptom severity and response to treatment.

Children

In juvenile rheumatoid arthritis, ibuprofen may be used at a dose of up to 40 mg/kg body weight per day, divided into several doses.

Elderly patients

No significant differences in pharmacokinetic profile have been observed in elderly patients; therefore, dosage adjustment or frequency of administration is generally not required. However, if NSAID therapy is necessary, the lowest effective dose should be prescribed due to the increased risk of adverse reactions in elderly patients, who are more likely to have reduced renal, hepatic, and cardiovascular function, as well as potential drug interactions. The smallest effective dose is recommended. Only after established tolerance may the dose be increased to the standard adult dose.

Renal impairment

NSAIDs should be used with caution in patients with renal impairment. Treatment should be initiated at the lowest possible dose in patients with mild to moderate renal dysfunction. Contraindicated in patients with severe renal impairment (see section "Contraindications").

Hepatic impairment

Although the pharmacokinetics of ibuprofen are not altered in patients with hepatic impairment, NSAIDs should be used with particular caution in these patients.

Treatment should be initiated at the lowest possible dose under close monitoring in patients with mild to moderate hepatic impairment. Contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Administration method

For oral use.

Before administration, the contents of one sachet should be poured into half a glass of water and stirred for 2 minutes.

Patients with gastrointestinal disorders should take the medication with milk and/or food.

Children

The product is not recommended for children under 12 years of age, as the ibuprofen dose contained in the medication does not correspond to the recommended dose for this age group.

Overdose

Most reported cases of overdose were asymptomatic. The risk of symptoms increases with ibuprofen doses exceeding 80–100 mg/kg.

Symptoms of overdose typically occur within 4 hours after ingestion and may include abdominal pain, nausea, vomiting (with blood), diarrhea (with blood), and central nervous system disturbances such as headache, spasms, diplopia, tinnitus, dizziness, and mild vertigo. In addition to decreased blood pressure, renal dysfunction and loss of consciousness may occur. Rarely, nystagmus, hypothermia, renal dysfunction, gastrointestinal bleeding, coma, apnea, and CNS and respiratory depression have been reported. Cardiovascular toxicity, including hypotension, bradycardia, and tachycardia, has also been reported.

In cases of significant overdose, renal failure and liver damage may occur. Severe poisoning may lead to metabolic acidosis. Prolonged use of doses exceeding the recommended levels or excessive use may cause renal tubular acidosis and hypokalemia.

Treatment is symptomatic; there is no specific antidote for ibuprofen overdose.

After ingestion of small amounts of the drug (less than 50 mg/kg of ibuprofen), drinking water is recommended to minimize gastrointestinal disturbances. After ingestion of significant amounts, oral administration of activated charcoal is recommended. Gastric emptying by emesis may be beneficial only within 60 minutes of drug intake. Gastric lavage is recommended if less than 1 hour has passed since ingestion of a potentially toxic or life-threatening dose. The benefit of forced diuresis, hemodialysis, and hemoperfusion is questionable due to ibuprofen's high plasma protein binding.

Adverse Reactions

Adverse reactions are mainly related to the pharmacological action of ibuprofen on prostaglandin synthesis.

Gastrointestinal (GI) adverse reactions occur most frequently. Peptic ulcers, gastrointestinal perforations, or hemorrhages, sometimes fatal, may occur, particularly in elderly patients (see section "Special Warnings and Precautions for Use").

Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbations of colitis and Crohn's disease may occur during ibuprofen use (see section "Special Warnings and Precautions for Use"). Gastritis has been reported less frequently. Cases of edema, hypertension, and heart failure associated with NSAID use have been reported.

Adverse reactions possibly related to ibuprofen are listed below by system organ class and 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 not known (cannot be estimated from the available data).

System Organ Class according to MedDRA	Frequency
	Common	Uncommon	Rare	Very rare	Frequency not known
Infections and infestations				Exacerbation of inflammatory infectious diseases (necrotizing fasciitis)
Blood and lymphatic system disorders			Aplastic anemia	Anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis, prolonged bleeding time
Immune system disorders		Allergic reactions, hypersensitivity reactions with skin rash, pruritus, and asthma attacks	Anaphylaxis	Severe hypersensitivity reactions with bronchospasm, dyspnea, tachycardia, hypotension, and shock	Anaphylactic shock
Psychiatric disorders		Insomnia, anxiety, restlessness	Psychotic reactions, nervousness, irritability, depression, confusion, disorientation
Nervous system disorders	Fatigue, somnolence, headache, dizziness	Insomnia, excitement, irritability	Paraesthesia	Aseptic meningitis
Eye disorders		Visual disturbances	Reversible toxic amblyopia		Optic nerve disc swelling
Ear and labyrinth disorders	Dizziness	Tinnitus	Hearing impairment
Cardiac disorders				Tachycardia, heart failure	Acute cardiovascular failure, Kounis syndrome
Vascular disorders				Arterial hypertension	Arterial thrombosis
Respiratory, thoracic and mediastinal disorders		Asthma, asthma exacerbation, bronchospasm, dyspnea			Throat irritation
Gastrointestinal disorders	Heartburn, abdominal pain, nausea, vomiting, flatulence, diarrhea, constipation, minor bleeding	Gastrointestinal ulcers with possible hemorrhage and perforation, ulcerative stomatitis, colitis exacerbation, Crohn's disease exacerbation, melena, gastritis	Hematemesis	Esophagitis, pancreatitis, intestinal stricture	Anorexia
Hepatobiliary disorders			Liver injury, hepatic function abnormalities, hepatitis, jaundice
Skin and subcutaneous tissue disorders	Skin rash	Angioneurotic edema, urticaria, pruritus, purpura	Anaphylactic reactions	Severe cutaneous adverse reactions (SCARs) (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis)	Photosensitivity reactions, enhanced skin reactions, drug-induced eosinophilia with systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP)
Renal and urinary disorders			Hematuria	Edema, papillary necrosis, increased serum uric acid levels, interstitial nephritis, nephrotic syndrome, and renal failure
General disorders and administration site conditions				Exacerbation of infection-related inflammation	Edema
Investigations			Liver function test abnormalities		Renal function test abnormalities

Reporting of adverse reactions after registration of the medicinal product is important. This allows monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

Store at a temperature not exceeding 30 °C. Keep out of reach and sight of children.

Packaging

10, 20, 30, or 40 sachets in a cardboard box.

Supply category

Over-the-counter (without prescription).

Manufacturer

TOLL MANUFACTURING SERVICES, S.L.

LAMB S.P.A.

Manufacturer's address and place of business

C/ Aragoneses, 2, Madrid, 28108 Madrid, Spain.

Via della Pace, 25/A – 41030 San Prospero (MO), Italy.

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∗ 400 mg ibuprofen = 740 mg ibuprofen arginate