Taffa® intensive

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

Composition:

Active substances: ibuprofen, paracetamol;

One film-coated tablet contains 200 mg of ibuprofen and 500 mg of paracetamol;

Excipients: maize starch, povidone (E 1201), sodium croscarmellose, microcrystalline cellulose (E 460), colloidal anhydrous silicon dioxide, glycerol dibehenate (E 471); coating: Opadry white AMB II (partially hydrolyzed polyvinyl alcohol, talc, titanium dioxide, glycerol monocaprylocaprate (GMCC type 1/ mono- and diglycerides), sodium lauryl sulfate).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, elongated, biconvex film-coated tablets with a double marking in the form of a circle on one side.

Pharmacotherapeutic group. Musculoskeletal system agents, anti-inflammatory and antirheumatic agents, nonsteroidal, propionic acid derivatives. Combinations of ibuprofen.

ATC code M01AE51.

Pharmacological Properties.

Pharmacodynamics.

The pharmacological actions of ibuprofen and paracetamol differ in their site and mechanism of action. These complementary mechanisms are also synergistic, meaning that the medicinal product has stronger antinociceptive and antipyretic properties than its active ingredients administered separately. Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) whose action inhibits the synthesis of prostaglandins, as confirmed in standard animal models of inflammation. Prostaglandins sensitize nociceptive afferent nerve endings to mediators such as bradykinin. The analgesic effect of ibuprofen is due to peripheral inhibition of the cyclooxygenase-2 (COX-2) isoenzyme and subsequent reduction in sensitivity of nociceptive nerve endings. Ibuprofen also inhibits leukocyte migration induced by inflammation. Ibuprofen exerts a significant effect on the spinal cord, partly due to its ability to inhibit COX activity. The antipyretic effect of ibuprofen is mediated by central inhibition of prostaglandin synthesis in the hypothalamus. Ibuprofen reversibly inhibits platelet aggregation. In humans, ibuprofen reduces pain caused by inflammation, swelling, and fever.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when both are administered concomitantly. Some pharmacodynamic studies have shown that administration of a single dose of ibuprofen (400 mg) within 8 hours before or within 30 minutes after immediate-release acetylsalicylic acid (81 mg) reduced the effect of acetylsalicylic acid on thromboxane production or platelet aggregation. Despite uncertainty regarding the extrapolation of these data to clinical situations, it cannot be excluded that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. This effect is not considered clinically significant with occasional use of ibuprofen (see section "Interaction with other medicinal products and other forms of interaction").

The exact mechanism of action of paracetamol has not yet been fully elucidated, but there is substantial evidence supporting the hypothesis of its central antinociceptive effect. Results from various biochemical assays suggest inhibition of central COX-2 enzyme activity. Paracetamol may also stimulate the activity of descending 5-hydroxytryptamine (serotonin) pathways that inhibit nociceptive signal transmission in the spinal cord. Studies have shown that paracetamol is a very weak inhibitor of peripheral COX-1 and COX-2 isoenzymes.

The clinical efficacy of ibuprofen and paracetamol has been demonstrated in pain associated with headache, dental pain, dysmenorrhea, and fever. Additionally, efficacy has been demonstrated in patients with pain and fever associated with cold and influenza, as well as in such pain models as sore throat, muscular pain or soft tissue injury, and back pain.

This medicinal product is particularly effective for treating pain requiring stronger analgesia than 400 mg ibuprofen or 1000 mg paracetamol administered separately, or as an analgesic for faster pain relief than ibuprofen alone.

Studies using this combination in models of acute pain (postoperative dental pain) and chronic knee joint pain have shown high efficacy in reducing the intensity of acute pain (93.2%) and in long-term treatment of chronic pain (60.2%). This medicinal product has a rapid onset of action, with a confirmed perceptible pain reduction observed on average within 18.3 minutes. Significant pain reduction is observed on average within 44.6 minutes. The analgesic effect of this medicinal product is significantly longer (9.1 hours) than that of 500 mg paracetamol (4 hours).

Pharmacokinetics.

Ibuprofen

Absorption

Ibuprofen is well absorbed from the gastrointestinal tract. Plasma levels of ibuprofen are detectable within 5 minutes, and maximum plasma concentration (C_max) is reached within 1–2 hours after administration on an empty stomach. When the medicinal product is taken with food, the peak plasma level of ibuprofen is lower and delayed by a median of 25 minutes, but the overall extent of absorption is equivalent.

Distribution

Ibuprofen is highly bound to plasma proteins. Ibuprofen diffuses into synovial fluid.

Biotransformation

Ibuprofen is metabolized in the liver into two major metabolites, with primary excretion via the kidneys, either unchanged or as major conjugates, along with a small amount of unchanged ibuprofen.

Elimination

Renal elimination is rapid and complete. The elimination half-life is approximately 2 hours. Limited studies have shown that ibuprofen appears in breast milk at very low concentrations. No significant differences in the pharmacokinetic profile of ibuprofen have been observed in elderly individuals.

Paracetamol

Absorption

Paracetamol is readily absorbed from the gastrointestinal tract (GI tract).

Distribution

At usual therapeutic concentrations, plasma protein binding is minimal and dose-dependent. Plasma levels of paracetamol are detectable within 5 minutes, and C_max is observed within 0.5–0.67 hours after administration on an empty stomach. When the medicinal product is taken with food, the peak plasma level of paracetamol is lower and delayed on average by 55 minutes, but the overall extent of absorption is equivalent.

Biotransformation

Paracetamol is metabolized in the liver.

A minor hydroxylated metabolite, normally produced in very small amounts through mixed oxidase activity in the liver and detoxified via conjugation with hepatic glutathione, may accumulate after paracetamol overdose and cause liver damage.

No significant differences in the pharmacokinetic profile of paracetamol have been observed in elderly individuals.

Elimination

Paracetamol is excreted in urine, primarily as glucuronide and sulfate conjugates, with approximately 10% as glutathione conjugates. Less than 5% is excreted as unchanged paracetamol. The elimination half-life is approximately 3 hours.

The bioavailability and pharmacokinetic profiles of ibuprofen and paracetamol when administered as part of this medicinal product are not altered by concomitant or repeated administration.

Clinical characteristics.

Indications.

Symptomatic treatment of mild to moderate pain associated with migraine, headache, back pain, menstrual pain, dental pain, rheumatic and muscular pain, pain in mild forms of arthritis, cold and flu symptoms, sore throat, and fever. This medication is particularly suitable for the treatment of pain requiring stronger analgesic effect than that provided by ibuprofen or paracetamol used separately.

Contraindications.

• Hypersensitivity to ibuprofen, paracetamol, or to any of the excipients of the medicinal product.
• History of hypersensitivity reactions (e.g., bronchospasm, angioedema, asthma, rhinitis, or urticaria) associated with acetylsalicylic acid or other NSAIDs.
• History of gastrointestinal bleeding or perforation related to previous NSAID therapy.
• Active or recurrent peptic ulcer/hemorrhage (two or more distinct episodes of confirmed ulcer or bleeding).
• In patients with coagulation disorders.
• In patients with severe hepatic insufficiency, severe renal insufficiency, or severe heart failure (NYHA class IV) (see section "Special precautions for use").
• Concomitant use with other medicinal products containing NSAIDs, including selective COX-2 inhibitors and acetylsalicylic acid doses exceeding 75 mg per day – increased risk of adverse reactions (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with other medicinal products containing paracetamol – increased risk of serious adverse reactions (see section "Interaction with other medicinal products and other forms of interaction").
• During the third trimester of pregnancy due to the risk of premature closure of the fetal ductus arteriosus and potential development of pulmonary hypertension (see section "Use in pregnancy or lactation").

Interaction with other medicinal products and other forms of interaction.

This medicinal product (like other medicinal products containing paracetamol) is contraindicated in combination with other medicinal products containing paracetamol due to increased risk of serious adverse reactions (see section "Contraindications").

This medicinal product (like any other product containing ibuprofen and NSAIDs) is contraindicated in combination with the following medicinal products:

• Acetylsalicylic acid

Concomitant use of ibuprofen and acetylsalicylic acid is generally not recommended due to the potential for increased adverse reactions.

• Other NSAIDs, including selective COX-2 inhibitors, as they may increase the risk of adverse reactions (see section "Contraindications").

This medicinal product (like any other medicinal products containing paracetamol) should be used with caution in combination with:

• Chloramphenicol (chloramphenicol): increased plasma concentration of chloramphenicol.
• Cholestyramine: absorption rate of paracetamol is reduced due to cholestyramine; therefore, cholestyramine should not be taken within one hour if maximum analgesia is required.
• Metoclopramide and domperidone: absorption of paracetamol is increased by metoclopramide and domperidone; however, simultaneous use should not be avoided.
• Warfarin: anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol, increasing the risk of bleeding; occasional doses do not show significant effect.
• Flucloxacillin: paracetamol should be used with caution when administered concomitantly with flucloxacillin, as co-administration has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions for use").

This medicinal product (like any other medicinal products containing ibuprofen and NSAIDs) should be used with caution in combination with the following medicinal products:

• Anticoagulants: NSAIDs may enhance the effect of anticoagulants such as warfarin (see section "Special precautions for use").

Antihypertensive and diuretic agents: NSAIDs may reduce the therapeutic effect of these drugs and increase the risk of nephrotoxic effects. 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 and cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, possibly resulting in acute renal failure, which is usually reversible. Therefore, such combinations should be prescribed 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 considered at the start of combination therapy and periodically thereafter. Diuretics may increase the risk of NSAID-induced nephrotoxicity.

• Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section "Special precautions for use").
• Acetylsalicylic acid: experimental data suggest that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when administered simultaneously; although uncertainties exist regarding extrapolation of these data to clinical situations, it cannot be excluded that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid; no clinically significant effect is considered likely with occasional use of ibuprofen.
• Cardiac glycosides: NSAIDs may exacerbate heart failure, reduce glomerular filtration rate (GFR), and increase plasma levels of glycosides.
• Cyclosporine: increased risk of nephrotoxicity.
• Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section "Special precautions for use").
• Lithium: reduced elimination of lithium.
• Methotrexate: reduced elimination of methotrexate.
• Mifepristone: NSAIDs should not be used within 8–12 days after administration of mifepristone, as NSAIDs may reduce the effect of mifepristone.
• Quinolone antibiotics: animal studies indicate that NSAIDs may increase the risk of seizures associated with quinolone antibiotics; patients receiving NSAIDs and quinolones may have an increased risk of developing seizures.
• Tacrolimus: possible increased risk of nephrotoxicity when NSAIDs are administered concomitantly with tacrolimus.
• Zidovudine: increased risk of hematological toxicity with NSAIDs when used concomitantly with zidovudine; data indicate an increased risk of hemarthrosis and hematoma in HIV (+) hemophiliacs receiving zidovudine and ibuprofen simultaneously.

Special precautions for use.

The risk of paracetamol overdose is higher in patients with alcoholic liver disease without symptoms of cirrhosis. In cases of overdose, immediate medical attention is required even if the patient feels well, as there is a risk of delayed, severe liver damage. To reduce the risk of adverse reactions, the lowest effective dose should be used for the shortest duration necessary to relieve symptoms (see section "Dosage and administration", as well as gastrointestinal and cardiovascular disorders below), and the medication should be taken with food (see section "Dosage and administration").

Masking of symptoms of concomitant infections

The medicinal product Tauffa® Intensive may mask symptoms of infection, potentially leading to delayed initiation of appropriate treatment and thus worsening the outcome of the infection. This has been observed in bacterial community-acquired pneumonia and bacterial complications of varicella. During treatment with this medicinal product for fever and pain relief associated with infection, monitoring for infection is recommended. If the patient is not hospitalized but symptoms persist or worsen, medical consultation is required.

Elderly patients

Adverse reactions to NSAIDs occur more frequently in elderly patients, particularly gastrointestinal bleeding and perforation, which may be fatal (see section "Dosage and administration").

Caution is required in patients with certain conditions:

• Respiratory disorders

Cases of sudden bronchoconstriction after NSAID treatment have been reported in patients with bronchial asthma or a history of asthma.

• Cardiovascular, renal and hepatic disorders

Administration of NSAIDs may cause dose-dependent inhibition of prostaglandin synthesis and accelerate the onset of renal failure. Patients at greatest risk of this reaction include those with impaired renal function, heart failure, hepatic dysfunction, those taking diuretics, and elderly patients. Renal function should be monitored in these patients (see section "Contraindications").

• Cardiovascular and cerebrovascular effects

Appropriate monitoring and medical consultation are required for patients with mild to moderate arterial hypertension or congestive heart failure, as fluid retention and edema have been reported during NSAID therapy.

Clinical studies indicate that the use of ibuprofen, particularly at high doses (2400 mg per day), may be associated with a small increased risk of arterial thromboembolic events (e.g., myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low doses of ibuprofen (e.g., ≤1200 mg per day) are associated with an increased risk of arterial thromboembolic events.

Patients with uncontrolled hypertension, congestive heart failure (NYHA II-III), established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only take ibuprofen after careful consideration and should avoid high doses (2400 mg per day).

Factors increasing the risk of cardiovascular disorders should also be carefully evaluated before initiating long-term treatment (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking), especially when high doses of ibuprofen (2400 mg per day) are required.

• Gastrointestinal bleeding, ulcers, and perforation

Gastrointestinal bleeding, ulcers, and perforation, which may be fatal, have been reported during treatment with all NSAIDs at any time, with or without warning symptoms or history of serious gastrointestinal adverse reactions.

The risk of gastrointestinal bleeding, ulcers, or perforation increases with higher NSAID doses in patients with a history of peptic ulcer, especially if complicated by hemorrhage or perforation (see section "Contraindications"), and in elderly patients. These patients should start treatment with the lowest available dose. Consideration should be given to combining therapy with protective agents (e.g., misoprostol or proton pump inhibitors) for these patients, as well as for patients requiring concomitant low-dose acetylsalicylic acid or other medications that may increase gastrointestinal risk (see below and 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 gastrointestinal symptoms (especially gastrointestinal bleeding), particularly during the initial stages of treatment.

The medicinal product should be used with caution in patients concurrently taking 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").

If gastrointestinal bleeding or ulcers occur during ibuprofen treatment, therapy should be discontinued. NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn's disease), as these conditions may be exacerbated (see section "Adverse reactions").

• Systemic lupus erythematosus (SLE) and mixed connective tissue disorders

Patients with SLE and mixed connective tissue disorders may have an increased risk of developing aseptic meningitis (see section "Adverse reactions").

• Serious skin reactions

Serious skin reactions, including fatal cases such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been rarely reported with NSAID use (see section "Adverse reactions"). Patients appear to be at highest risk for these reactions early in therapy, with most cases occurring within the first month of treatment. Acute generalized exanthematous pustulosis (AGEP) associated with ibuprofen and other paracetamol-containing medications has been documented. Use of this medicinal product should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

• Metabolic acidosis

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe underlying conditions such as severe renal failure and sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g., chronic alcoholism), who were treated with paracetamol at therapeutic doses for prolonged periods or in combination with flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with close patient monitoring. Measurement of urinary 5-oxoproline levels may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

• Impairment of fertility in women

Use of this medicinal product may impair fertility in women; therefore, it is not recommended for women planning pregnancy. Women experiencing difficulties with conception or undergoing infertility investigations should consider discontinuing the medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

There is no experience with the use of this medicinal product in pregnant women.

Extensive data in pregnant women do not indicate teratogenic or fetotoxic/neonatal toxic effects. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero have yielded inconclusive results. If clinically necessary, paracetamol may be used during pregnancy at the lowest effective dose, for the shortest duration, and with the lowest possible frequency.

From the 20th week of gestation, the use of ibuprofen may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation. Additionally, there have been reports of ductus arteriosus constriction after second-trimester treatment, 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 attempting to conceive or during the first and second trimesters of pregnancy, 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 should be considered after several days of ibuprofen exposure starting from the 20th gestational week. Ibuprofen use 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:

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

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

Breastfeeding period

Ibuprofen and its metabolites may pass into breast milk in very low amounts (0.0008% of the dose given to the mother). No harmful effects on infants have been observed.

Paracetamol is excreted in breast milk, but not in clinically significant amounts. Available published data do not justify discontinuation of breastfeeding.

Therefore, breastfeeding need not be interrupted for short-term treatment with the recommended dose of this medicinal product.

Fertility

Information regarding fertility in women is provided in the section "Special precautions for use".

Ability to influence reaction rate when driving or operating machinery.

After taking this medicinal product, as with other NSAIDs, adverse reactions such as dizziness, drowsiness, fatigue, and visual disturbances may occur. If these symptoms occur, patients should not drive or operate machinery.

Method of Administration and Dosage

Dosage

For short-term use only.

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms (see section "Special Instructions for Use").

The patient should consult a physician if symptoms persist or worsen, or if it becomes necessary to use this medication for more than 3 days.

Adults

Take one tablet up to three times daily with water. At least 6 hours should elapse between doses.

If one dose does not relieve symptoms, a maximum of two tablets may be taken up to three times daily. At least 6 hours should elapse between doses.

Do not exceed 6 tablets (3000 mg paracetamol, 1200 mg ibuprofen) within 24 hours.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to relieve symptoms (see section "Special Instructions for Use").

To minimize adverse effects, patients are advised to take Tauffa® Intensiv with food.

Elderly Patients

No specific dosage adjustments are required (see section "Special Instructions for Use").

Elderly patients are at increased risk of serious adverse reactions. If use of this medication is considered necessary, the lowest effective dose should be used for the shortest possible duration. During NSAID therapy, patients should be monitored regularly for gastrointestinal bleeding.

Pediatric Population

Not recommended for children under 18 years of age.

Route of Administration

For oral use.

Overdose

Paracetamol

In adults, ingestion of 10 g (equivalent to 20 tablets) or more of paracetamol may result in liver damage. Oral intake of 5 g (equivalent to 10 tablets) or more of paracetamol may lead to hepatotoxicity if the patient has one or more of the following risk factors:

a) Receiving long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs that induce hepatic enzymes.

b) Regularly consuming alcohol in excess of recommended amounts.

c) Conditions likely to deplete glutathione, such as malnutrition, cystic fibrosis, HIV infection, fasting, or cachexia.

Symptoms of Overdose

Symptoms of paracetamol overdose within the first 24 hours include pallor, nausea, vomiting, anorexia, and abdominal pain. Hepatic injury may become apparent 12–48 hours after ingestion, with abnormal liver function tests. Hypoglycemia and metabolic acidosis may also occur. In severe poisoning, hepatic failure may progress to encephalopathy, hemorrhage, hypoglycemia, cerebral edema, and even death. Acute renal failure with acute tubular necrosis, characterized by severe flank pain, hematuria, and proteinuria, may develop even in the absence of direct kidney injury. Cardiac arrhythmias and pancreatitis have also been reported.

Treatment of Overdose

Prompt treatment is essential in managing paracetamol overdose. Despite the absence of prominent early symptoms, patients should be urgently referred to a hospital for immediate medical care. Symptoms such as nausea or vomiting may be the only early signs and do not necessarily reflect the severity of overdose or risk of organ damage. Management should follow established treatment guidelines.

Activated charcoal should be considered if overdose occurred within 1 hour. Plasma paracetamol concentration should be measured at least 4 hours or later after ingestion (earlier measurements are unreliable).

N-acetylcysteine treatment may be administered up to 24 hours after paracetamol ingestion; maximum protective effect is achieved within 8 hours after ingestion. Beyond this time, the efficacy of the antidote declines sharply.

If required, intravenous N-acetylcysteine should be administered according to established dosing protocols. In the absence of vomiting, oral methionine may be used as an alternative, particularly in remote areas outside hospital settings.

Patients with severe renal dysfunction lasting more than 24 hours after drug ingestion should receive treatment according to established guidelines.

Ibuprofen

Ibuprofen overdose in children at doses exceeding 400 mg/kg may cause overdose symptoms. In adults, dose-dependent effects are less pronounced. The elimination half-life in overdose is 1.5–3 hours.

Symptoms of Overdose

In most patients who have ingested clinically significant amounts of NSAIDs, adverse reactions include nausea, vomiting, epigastric pain, and less frequently, diarrhea. Tinnitus, headache, and gastrointestinal bleeding may also occur. In more severe cases, central nervous system toxicity may manifest as drowsiness, sometimes with agitation, disorientation, or coma. Seizures may occasionally occur. Metabolic acidosis may develop, and prothrombin time/INR may be prolonged, likely due to effects on clotting factor activity. Acute renal failure and hepatic injury may occur in the presence of concomitant dehydration. In asthmatic patients, asthma exacerbation may occur.

Treatment of Overdose

Treatment should be symptomatic and supportive, including maintenance of airway patency and monitoring of cardiac and vital signs until stabilization. Consider oral administration of activated charcoal if overdose is detected within 1 hour of ingestion of a potentially toxic dose. In cases of frequent or prolonged seizures, intravenous diazepam or lorazepam should be administered. Bronchodilators should be used in asthmatic patients.

Adverse reactions.

During clinical trials, no additional adverse reactions were recorded other than those observed with ibuprofen or paracetamol used separately.

The adverse reactions listed below are those reported in patients treated with ibuprofen alone or paracetamol alone during short-term and long-term use.

Frequency is defined as: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

From the blood and lymphatic system	very rare	Blood disorders (agranulocytosis, anemia, aplastic anemia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, and thrombocytopenia). Initial symptoms: Fever, sore throat, mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising, nosebleeds.
From the immune system	very rare	hypersensitivity reactions, such as non-specific hypersensitivity reactions and anaphylactic reactions. Severe hypersensitivity reactions. Symptoms: Swelling of the face, tongue, and larynx; shortness of breath; tachycardia; hypotension (anaphylactic reaction, Quincke's edema, vascular or life-threatening shock).
Psychiatric disorders	very rare	Confusion, depression, and hallucinations
From the nervous system	uncommon	Headache and dizziness
	very rare	Paresthesia, optic neuritis, and somnolence. Isolated cases of aseptic meningitis have been observed in patients with pre-existing autoimmune disorders (SLE and mixed connective tissue diseases) during ibuprofen treatment with symptoms such as neck stiffness, headache, nausea, vomiting, fever, or disorientation (see section "Special precautions for use").
From the eye	very rare	Visual disturbances
	frequency not known	Photosensitivity reactions
From the ear and labyrinth	very rare	Tinnitus and vertigo
From the heart	very rare	Heart failure and edema.1
From the vascular system	very rare	Hypertension1
From the respiratory system, thoracic organs and mediastinum	very rare	Respiratory disorders, including asthma (including exacerbated asthma), bronchospasm, and dyspnea
From the gastrointestinal system	common	Abdominal pain, diarrhea, dyspepsia, nausea, abdominal discomfort, vomiting.
	uncommon	Flatulence and constipation. Gastrointestinal ulcers, gastrointestinal perforation, or gastrointestinal bleeding, manifested as melena or hematemesis, sometimes fatal, particularly in elderly patients (see section "Special precautions for use"). Ulcerative stomatitis, exacerbation of colitis and Crohn's disease after drug administration (see section "Special precautions for use"). Gastritis and pancreatitis have been reported less frequently.
From the hepatobiliary system	very rare	Liver function abnormalities, hepatitis, or jaundice. In case of paracetamol overdose, acute liver failure, liver failure, liver necrosis, and liver damage may occur (see section "Overdose").
From the skin and subcutaneous tissue	common	Increased sweating
	uncommon	Various skin rashes, including pruritus and urticaria. Quincke's edema and facial swelling.
	very rare	Exfoliative dermatosis and purpura. Bullous reactions, including erythema multiforme, 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.
From the kidneys and urinary system	very rare	Various forms of nephrotoxicity, including interstitial nephritis, nephrotic syndrome, and acute or chronic renal failure.
Metabolism and nutrition disorders	not known	Metabolic acidosis with high anion gap
General disorders and administration site conditions	very rare	Fatigue and malaise
Investigations	common	Elevated alanine aminotransferase levels, elevated gamma-glutamyl transferase activity, and changes in liver function tests after paracetamol intake. Elevated blood creatinine, elevated blood urea.
	uncommon	Elevated aspartate aminotransferase levels, elevated alkaline phosphatase in blood, elevated creatine phosphokinase in blood, decreased hemoglobin, and increased platelet count.

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

Description of selected adverse reactions

Metabolic acidosis with high anion gap

Cases of metabolic acidosis with high anion gap as a result of pyroglutamic acidosis have been observed in patients with risk factors who used paracetamol (see section "Special precautions for use"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Reporting of adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: http://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

This medicinal product does not require special storage conditions.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 1 or 2 blisters in a cardboard box.

Prescription status.

Over-the-counter (without prescription).

Manufacturer.

ALKALOID AD Skopje.

ALKALOID AD Skopje.

Manufacturer's address and location of operations.

Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.

Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.

Marketing Authorization Holder.

JSC "Farmak".

Address of the Marketing Authorization Holder.

63, Kyrylivska Street, Kyiv, 04080, Ukraine.