INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Taffa® 6+ (Taffa 6+)

Composition:

Active substance: ibuprofen;

One film-coated tablet contains ibuprofen – 200 mg;

Excipients: microcrystalline cellulose; sodium croscarmellose; lactose monohydrate; colloidal anhydrous silicon dioxide; sodium lauryl sulfate; magnesium stearate;

Film coating: hypromellose; titanium dioxide (E 171); macrogol.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, oval-shaped, biconvex film-coated tablets.

Pharmacotherapeutic group.

Nonsteroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives.

ATC code M01A E01.

Pharmacological Properties

Pharmacodynamics

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) with a short half-life and analgesic, anti-inflammatory, and antipyretic properties necessary for effective treatment of rheumatic diseases.

Various dosage strengths allow individualized therapy.

Experimental evidence has demonstrated that prostaglandins are responsible for the development of pain and inflammation. Ibuprofen strongly inhibits prostaglandin synthesis, which explains its analgesic, anti-inflammatory, and antipyretic effects. These properties provide symptomatic relief of inflammation, pain, and fever.

The same mechanism underlies the inhibition of platelet aggregation and ulcerogenic effects, sodium and water retention, as well as bronchospastic reactions as possible adverse effects.

Although ibuprofen may affect platelet aggregation and bleeding time, clinically significant changes in prothrombin time or blood clotting time do not occur. Ibuprofen reversibly inhibits platelet aggregation.

Experimental data indicate that ibuprofen, when administered concomitantly, may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation. In some pharmacodynamic studies, a reduced effect of acetylsalicylic acid on thromboxane formation or platelet aggregation was observed when a single 400 mg dose of ibuprofen was administered either 8 hours before or 30 minutes after ingestion of immediate-release acetylsalicylic acid (81 mg). Although uncertainty exists regarding the extrapolation of these data to the clinical setting, it cannot be excluded that long-term treatment with ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. A clinically significant effect from occasional use of ibuprofen is unlikely (see section "Interaction with other medicinal products and other forms of interaction").

Pharmacokinetics

Absorption

Ibuprofen is rapidly absorbed, primarily in the small intestine. Following oral administration of 200–600 mg ibuprofen, peak plasma concentrations of 15–55 µg/mL (Cmax) are reached on average within 1–2 hours (tmax). Maximum plasma concentrations are achieved within 45 minutes after oral administration on an empty stomach. This time may vary depending on the pharmaceutical formulation.

When ibuprofen is taken after food intake, absorption is significantly slower, peak plasma concentrations are lower, and peak levels occur within 1–2 hours. After a single oral dose of 400 mg ibuprofen, peak concentration of 8–13 µg/mL in synovial fluid is reached within 6 hours.

Distribution

Ibuprofen is 99% bound to plasma proteins. Binding is a reversible process.

Metabolism

Over 50–60% of an oral dose of ibuprofen is metabolized in the liver into two inactive metabolites. The metabolism of ibuprofen is similar in children and adults.

Elimination

The elimination half-life from plasma is 1.5–2 hours. The short elimination half-life indicates that even with repeated administration, accumulation of ibuprofen does not occur. Ibuprofen and its metabolites are almost completely eliminated from the body within 24 hours after oral administration. It is excreted primarily by the kidneys in the form of inactive metabolites.

Preclinical Data

Mutagenic and carcinogenic potential

Studies on mutagenicity in vitro and in vivo (bacteria, human lymphocytes) provided no evidence of mutagenic effects of ibuprofen. In carcinogenicity studies of ibuprofen in rats and mice, no evidence of carcinogenic effects of ibuprofen was found.

In limited studies, ibuprofen was detected in breast milk at very low concentrations.

Clinical characteristics.

Indications.

Symptomatic treatment of headache, including migraine, toothache, pain associated with dysmenorrhea, neuralgia, back pain, muscle pain, rheumatic pain (except severe cases of arthritis), as well as symptoms of colds and influenza, and fever.

Contraindications.

Hypersensitivity to ibuprofen or to any component of the medicinal product.
Hypersensitivity reactions (e.g. bronchial asthma, rhinitis, angioedema, or urticaria) previously observed after administration of ibuprofen, acetylsalicylic acid/aspirin, or other NSAIDs in the patient's history.
Third trimester of pregnancy (see section "Use in pregnancy or lactation").
Active peptic ulcer or duodenal ulcer and/or gastrointestinal bleeding, or history of recurrent episodes (two or more episodes of confirmed peptic ulcer or gastrointestinal bleeding in the past).
Active or previous inflammatory bowel diseases (such as Crohn’s disease, ulcerative colitis).
History of gastrointestinal bleeding or perforation associated with NSAID use.
Increased tendency to bleeding.
Severe hepatic insufficiency (liver cirrhosis, ascites).
Severe renal insufficiency (creatinine clearance <30 mL/min).
Severe heart failure (NYHA class III–IV).
Postoperative pain management following coronary artery bypass graft (CABG) surgery (or use of cardiopulmonary bypass).

Interaction with other medicinal products and other forms of interaction.

Other NSAIDs, including salicylates. Concomitant use of multiple NSAIDs, including selective cyclooxygenase-2 inhibitors, may increase the risk of gastrointestinal ulcers and bleeding due to synergistic effects. Therefore, concomitant use of ibuprofen with other NSAIDs should be avoided (see section "Special precautions for use"). Salicylic acid displaces ibuprofen during protein binding in the blood.

Glucocorticoids. Enhanced adverse effects on the gastrointestinal tract, increased risk of gastrointestinal bleeding and ulcers (see section "Special precautions for use").

Alcohol. Enhanced adverse effects on the gastrointestinal tract, increased risk of gastrointestinal bleeding.

Diuretics, antihypertensives, ß-blockers. NSAIDs may reduce the effectiveness of diuretics, antihypertensive agents such as ACE inhibitors and ß-blockers. Diuretics may also increase the risk of NSAID-induced nephrotoxicity.

Probenecid, sulfinpyrazone. Slowed elimination of ibuprofen; the uricosuric effect of probenecid and sulfinpyrazone is diminished.

Oral anticoagulants. NSAIDs may enhance the effects of anticoagulants such as warfarin (see section "Special precautions for use").

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs). Increased risk of gastrointestinal bleeding when NSAIDs are used (see section "Special precautions for use").

Aminoglycosides. NSAIDs may reduce the excretion of aminoglycosides.

Acetylsalicylic acid. Experimental data indicate that ibuprofen, when used concomitantly, may competitively inhibit the antiplatelet effect of low-dose acetylsalicylic acid. Although uncertainty exists regarding the extrapolation of these data to clinical settings, it cannot be excluded that long-term ibuprofen therapy may reduce the cardioprotective effect of low-dose acetylsalicylic acid. A clinically significant effect from occasional use of ibuprofen is unlikely.

Oral antidiabetic agents. The effect of oral antidiabetic agents (sulfonylurea derivatives) may be enhanced by ibuprofen, as with other NSAIDs. Rare cases of hypoglycemia have been reported in patients receiving ibuprofen during sulfonylurea therapy. Blood glucose levels should be monitored regularly, and the dose of antidiabetic agent adjusted as necessary.

H2-histamine receptor antagonists. Clinically significant interaction between ibuprofen and cimetidine or ranitidine has not been established.

Digoxin. Plasma digoxin concentration may be increased.

Phenytoin. Plasma phenytoin concentration may be increased.

Lithium. NSAIDs may reduce lithium excretion, leading to increased plasma lithium concentration. Monitoring of plasma lithium levels is recommended.

Metotrexate. Use of NSAIDs may lead to increased plasma methotrexate concentrations. NSAIDs may inhibit methotrexate secretion in the proximal tubules and reduce its clearance.

Baclofen. Use of NSAIDs increases baclofen toxicity.

Quinolones. Central nervous system effects are enhanced.

Cholestyramine. Concomitant use of ibuprofen with cholestyramine may reduce ibuprofen absorption in the gastrointestinal tract. However, clinical significance is unknown.

Cyclosporine. Increased risk of nephrotoxicity when used with NSAIDs.

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

Mifepristone. Theoretically, reduced efficacy of mifepristone may occur due to the anti-prostaglandin properties of NSAIDs. Limited evidence suggests that combined administration of NSAIDs on the day of prostaglandin administration does not negatively affect the cervical ripening or uterine contractility effects of mifepristone or prostaglandins, and does not reduce the clinical efficacy of pregnancy termination.

Quinolone antibiotics. Experimental animal studies have shown that seizures associated with quinolones may be potentiated by NSAIDs. Patients concurrently taking quinolones and NSAIDs have an increased risk of seizures.

Tacrolimus. Risk of nephrotoxicity may increase with concomitant use of tacrolimus and NSAIDs.

Zidovudine. Concomitant use of zidovudine and NSAIDs increases the risk of hematological toxicity. In HIV-positive individuals with poor blood clotting, data indicate that concomitant use of zidovudine and NSAIDs increases the risk of hemarthrosis and hematoma formation.

CYP2C9 inhibitors. Concomitant administration of ibuprofen and CYP2C9 inhibitors may prolong the effect (exposure) of ibuprofen (a CYP2C9 substrate). Studies with voriconazole and fluconazole (CYP2C9 inhibitors) have shown an approximately 80–100% increase in S(+)-ibuprofen exposure. Consideration should be given to reducing the dose of ibuprofen when strong CYP2C9 inhibitors are used concomitantly, especially when high doses of ibuprofen are administered or when used with voriconazole or fluconazole.

Special precautions for use.

Gastrointestinal ulcers, bleeding, or perforation may occur during treatment with NSAIDs, whether selective or non-selective COX-2 inhibitors, at any time, even without prior warning symptoms or history. To reduce this risk, the lowest effective dose should be used for the shortest duration possible.

In placebo-controlled studies, certain selective COX-2 inhibitors have been shown to increase the risk of thrombotic cardiovascular and cerebrovascular complications. It is not yet known whether this risk directly correlates with the COX-1/COX-2 selectivity of individual NSAIDs. Since comparable clinical trial data for ibuprofen at maximum doses and long-term therapy are currently lacking, such an increased risk cannot be excluded. Until appropriate information becomes available, ibuprofen should be used in patients with clinically confirmed ischemic heart disease, cerebrovascular disorders, peripheral arterial occlusion, or significant risk factors (e.g., high blood pressure, hyperlipidemia, diabetes, smoking) only after careful assessment of benefit-risk balance. Due to this risk, the lowest effective dose should be used for the shortest possible treatment duration.

NSAID effects on the kidneys include fluid retention with edema and/or arterial hypertension. Therefore, ibuprofen should be used with caution in patients with cardiac impairment and other conditions associated with fluid retention. Caution is also advised in patients concurrently receiving diuretics or angiotensin-converting enzyme (ACE) inhibitors, as well as in individuals at increased risk of hypovolemia.

Concomitant alcohol consumption may enhance adverse effects of NSAIDs, particularly those affecting the gastrointestinal tract or central nervous system.

With prolonged use of analgesics, headache may develop, which should not be treated with increased doses of the medication.

Respiratory disorders. Ibuprofen may cause bronchospasm, urticaria, or angioedema in patients with a history of or current bronchial asthma, chronic rhinitis, or allergic disease.

Impairment of heart, kidney, or liver function. Caution is required in patients with impaired liver, kidney, or heart function, as NSAID use may worsen renal function. Concomitant use of other analgesics further increases this risk. For such high-risk patients, the dose should be kept as low as possible, and renal function should be monitored regularly, especially during long-term therapy.

NSAIDs may worsen heart failure, reduce glomerular filtration rate, and increase plasma concentrations of cardiac glycosides.

Concomitant use of the medicinal product Tauffa® 6+ with NSAIDs, including selective cyclooxygenase-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").

Elderly patients. Elderly patients are more likely to experience adverse effects during NSAID therapy, particularly gastrointestinal bleeding and perforation, which may be fatal.

Gastrointestinal bleeding, ulcers, and perforation. Gastrointestinal bleeding, ulcers, and perforation have been reported with all NSAIDs, even with fatal outcomes. These may occur with or without warning symptoms or history of serious gastrointestinal complications at any time during therapy.

The risk of gastrointestinal 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. These patients should start treatment with the lowest possible dose. For these patients, as well as for those requiring concomitant therapy with low-dose acetylsalicylic acid or other drugs that may increase gastrointestinal tract injury risk, consideration should be given to concomitant protective therapy (e.g., misoprostol or proton pump inhibitors) (see section "Interaction with other medicinal products and other forms of interaction").

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

Caution is advised when patients are concurrently receiving medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors (SSRIs), or antiplatelet agents such as acetylsalicylic acid (see section "Interaction with other medicinal products and other forms of interaction").

In case of gastrointestinal bleeding or ulceration in patients receiving ibuprofen, treatment should be discontinued immediately.

Ibuprofen should be prescribed only under strict indications and under medical supervision in patients with gastrointestinal complications or impaired liver function, as the condition of internal organs may worsen (see "Adverse reactions").

Cardiovascular and cerebrovascular effects. Patients with a history of hypertension and/or decompensated heart failure should be appropriately monitored and advised, as fluid retention and edema have been reported with NSAID therapy.

Clinical studies indicate that ibuprofen use, particularly at high doses (2400 mg daily), may be associated with a small increased risk of arterial thrombotic complications (e.g., myocardial infarction, stroke). Overall, epidemiological studies do not suggest that low-dose ibuprofen (e.g., <1200 mg daily) is associated with an increased risk of arterial thrombotic complications.

Patients with uncontrolled arterial hypertension, heart failure (NYHA II), established ischemic heart disease, peripheral arterial occlusion, and/or cerebrovascular disease should be treated with ibuprofen only after careful consideration and should avoid high doses (2400 mg daily). The clinical picture should also be carefully evaluated before initiating long-term treatment in patients with risk factors for cardiovascular complications (e.g., high blood pressure, 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 caused by an allergic or hypersensitivity reaction associated with coronary artery spasm, potentially leading to myocardial infarction.

Severe cutaneous adverse reactions (SCARs), 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 with ibuprofen use (see section "Adverse reactions"). Most such reactions occurred within the first month.

If signs or symptoms suggesting these reactions appear, ibuprofen should be discontinued immediately, and alternative treatment considered (if necessary).

In rare cases, varicella may lead to serious skin infections and soft tissue complications. The potential involvement of NSAIDs in exacerbating such infections has not been ruled out. Therefore, it is recommended to avoid prescribing ibuprofen in cases of varicella.

Renal effects. Patients with severe dehydration or postoperative fluid volume changes should be rehydrated before starting ibuprofen therapy and then closely monitored. There is a risk of renal impairment, particularly in children, adolescents, and elderly patients with dehydration.

During long-term therapy, as with other NSAIDs, renal papillary necrosis and other kidney tissue damage may occur. Toxic kidney injury may also occur in patients in whom renal prostaglandins play a supportive role in renal perfusion. In these patients, NSAID administration may cause dose-dependent reduction in renal prostaglandin production, decreased renal blood flow, and overt renal decompensation. These reactions occur primarily in patients with renal, cardiac, or hepatic insufficiency, those concurrently taking diuretics or ACE inhibitors, and in elderly patients.

Hematological effects. Like other NSAIDs, ibuprofen reduces platelet aggregation and prolongs bleeding time.

Masking symptoms of underlying infection. Ibuprofen may mask symptoms of infection, potentially leading to delayed appropriate treatment and worsening of infection. This has been observed in cases of bacterial community-acquired pneumonia and bacterial complications associated with varicella. If ibuprofen is prescribed for fever or pain related to infection, monitoring of the infectious disease course is recommended. Outpatients should consult a physician if symptoms persist or worsen.

Aseptic meningitis, systemic lupus erythematosus, and mixed connective tissue disorders. In isolated cases, symptoms of aseptic meningitis have been observed during ibuprofen use. Patients with systemic lupus erythematosus and collagen vascular diseases appear to be predisposed. However, cases have also been observed in patients without such chronic conditions.

This medicinal product contains lactose monohydrate. If a patient has known intolerance to certain sugars, consultation with a physician is required before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. Epidemiological data suggest an increased risk of miscarriage and congenital heart defects and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The risk is believed to increase with higher doses and longer duration of treatment.

In animal studies, prostaglandin synthesis inhibitors have led to increased pre- and post-implantation embryo loss and embryofetal mortality. Additionally, increased incidence of various developmental abnormalities, including cardiac defects, 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 may occur shortly after starting treatment and is usually reversible upon discontinuation. Additionally, there are reports of ductus arteriosus constriction after treatment in the second trimester, most of which resolved after treatment cessation. Therefore, ibuprofen should not be prescribed during the first and second trimesters unless clearly necessary. If ibuprofen is used by a woman trying to conceive or during the first and second trimesters, the dose should be as low as possible and treatment duration as short as possible. Fetal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after several days of ibuprofen exposure starting from the 20th gestational week. Treatment with Tauffa® 6+ should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may pose 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 prolonged bleeding time, anti-aggregatory effect, which may occur even at very low doses;
Inhibition of uterine contractions, leading to delayed or prolonged labor.

Therefore, Tauffa® 6+ is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Breastfeeding

NSAIDs pass into breast milk. For safety reasons, ibuprofen is not recommended for breastfeeding women. If treatment is necessary, the infant should be switched to artificial feeding.

Fertility

Ibuprofen use may negatively affect female fertility and is therefore not recommended for women attempting to conceive. Consideration should be given to discontinuing ibuprofen in women experiencing difficulties with conception or undergoing infertility evaluation.

Ability to affect reaction speed when driving or operating machinery.

Appropriate studies have not been conducted. However, it is known that ibuprofen may sometimes have adverse effects on the central nervous system, such as reduced reaction speed. This should be considered when high alertness is required, particularly when driving vehicles or operating machinery. This effect may be especially pronounced when taken with alcohol.

Dosage and Administration

For short-term use only. Use the lowest effective dose required to relieve symptoms for the shortest duration necessary.

Most patients can take the medicinal product Tauffa® 6+ on an empty stomach without gastrointestinal discomfort.

The single dose for children aged 12 years and older and adults is 1–2 tablets (200–400 mg of ibuprofen) up to 3 times daily, every 4–6 hours as needed. The maximum daily dose is 1200 mg (6 tablets per day).

Children aged 6 to 12 years

The daily dose is 20 mg per kg of body weight, divided into several doses. For children with body weight below 30 kg, the maximum daily dose of ibuprofen should not exceed 600 mg.

Tablets should be taken with sufficient amount of water. Tablets should be swallowed whole and not chewed, broken, crushed, or sucked to avoid oral cavity discomfort and throat irritation.

Children

The medicinal product Tauffa® 6+ must not be used in children under 6 years of age.

Overdose

Symptoms of toxicity are generally not observed in children or adults at doses below 100 mg/kg body weight. However, supportive measures may be required in some cases. Symptoms of toxicity in children have been reported after ingestion of doses starting from 400 mg/kg.

Symptoms
In most patients who have ingested a significant amount of ibuprofen, symptoms develop within 4–6 hours. The most commonly reported symptoms of overdose include nausea, vomiting, abdominal pain, drowsiness, and lethargy. Central nervous system (CNS) effects include headache, tinnitus, dizziness, seizures, and loss of consciousness. Rarely reported effects include nystagmus, metabolic acidosis, hypothermia, renal impairment, gastrointestinal bleeding, coma, apnea, and CNS and respiratory depression. Cardiovascular toxicity has also been reported, including hypotension, bradycardia, and tachycardia. Significant overdose may lead to renal failure and hepatic injury. Significant overdose is generally well tolerated if no other drugs are co-ingested.

Treatment
There is no specific antidote for ibuprofen overdose. Patients should be treated symptomatically as necessary. Activated charcoal should be administered within one hour after ingestion of a potentially toxic amount. If needed, serum electrolyte imbalances should be corrected.

If the drug has already been absorbed, alkalinizing agents should be given to promote urinary excretion of ibuprofen.

Adverse reactions

The most commonly observed adverse reactions associated with the use of NSAIDs affect the gastrointestinal tract. Peptic ulcers, perforations, or gastrointestinal bleeding, sometimes fatal, particularly in elderly patients (see section "Special precautions"), may occur. Other gastrointestinal reactions include nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, and hematemesis.

Ulcerative stomatitis, exacerbations of colitis, and Crohn’s disease have been reported following administration. Gastritis occurs less frequently. Rare cases of gastrointestinal perforation have been reported with ibuprofen use.

Exacerbation of skin infections, including development of necrotizing fasciitis, has been described during concomitant use of NSAIDs. If any signs of infection appear or worsen during treatment with ibuprofen, the patient should seek immediate medical attention.

Clinical studies indicate that the use of ibuprofen, particularly at high doses (2400 mg per day), may be associated with a slightly increased risk of arterial thrombotic events (such as myocardial infarction or stroke) (see section "Special precautions***").

The frequency of adverse reactions is defined as follows: "very common" (>1/10), "common" (>1/100, <1/10), "uncommon" (>1/1000, <1/100), "rare" (>1/10000, <1/1000), "very rare" (<1/10000), "frequency not known" (cannot be estimated from available data). The following adverse reactions have been observed with ibuprofen:

Infections and parasitic diseases: uncommon – rhinitis; rare – aseptic meningitis.

Blood and lymphatic system disorders: rare – hematological manifestations such as leukopenia, agranulocytosis, thrombocytopenia, neutropenia, aplastic anemia, hemolytic anemia.

Immune system disorders: uncommon – hypersensitivity; rare – anaphylactic reaction, lupus-like syndrome, autoimmune hemolytic anemia.

Psychiatric disorders: uncommon – insomnia, anxiety; rare – depression, confusion; very rare – psychiatric disorders.

Nervous system disorders: common – central nervous system effects such as reduced reaction time (especially when combined with alcohol), headache, dizziness; uncommon – paresthesia, somnolence.

Eye disorders: uncommon – visual disturbances (usually reversible upon discontinuation of treatment); rare – toxic amblyopia, toxic optic neuropathy, optic neuritis.

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

Cardiac disorders: very rare – heart failure, edema, infarction; frequency not known – Kounis syndrome.

Vascular disorders: very rare – arterial hypertension.

Respiratory, thoracic and mediastinal disorders: uncommon – bronchial asthma, bronchospasm, dyspnea, risk of acute pulmonary edema in patients with heart failure.

Gastrointestinal disorders: common – dyspepsia, diarrhea, nausea, vomiting, constipation, abdominal pain, flatulence, melena, hematemesis, gastrointestinal bleeding; rare – gastritis, gastrointestinal ulcers, ulcerative stomatitis, gastrointestinal perforation; very rare – pancreatitis; frequency not known – exacerbation of colitis or Crohn’s disease. A transient burning sensation in the mouth or throat may occur during administration.

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

Skin and subcutaneous tissue disorders: common – exanthema; rare – urticaria, pruritus, purpura, angioneurotic edema; very rare – severe skin adverse reactions (SSARs) (including erythema multiforme, exfoliative dermatitis, 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.

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

Renal and urinary disorders: rare – toxic nephropathy in various forms, including renal papillary necrosis, interstitial nephritis, impaired renal function with edema up to renal failure.

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

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients are encouraged to report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

No special storage conditions required.

Keep out of reach and sight of children.

Packaging. 10 tablets per blister. 1 or 5 blisters per carton.

Availability. Over-the-counter (without prescription).

Manufacturer.

JSC "Farmak".

Manufacturer's address and place of business.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.