INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TEMPOFEN® DUO (TEMPOFEN® DUO)

Composition:

Active substances: ibuprofen, paracetamol;

One film-coated tablet contains: ibuprofen 200 mg, paracetamol 500 mg;

Excipients: sodium croscarmellose, hydroxypropylcellulose;

Extragranular components: sodium croscarmellose, microcrystalline cellulose, colloidal anhydrous silicon dioxide, stearic acid, magnesium stearate;

Film coating: polyvinyl alcohol–polyethylene glycol copolymer, talc, pearl pigment based on mica, glycerol monocaprylocaprate, polyvinyl alcohol, titanium dioxide, iron oxide black (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: grey, film-coated, lustrous, oval tablets with the imprint "200 M 500" on one side.

Pharmacotherapeutic group.

Medicinal products for the treatment of the musculoskeletal system, anti-inflammatory and antirheumatic agents, non-steroidal agents, propionic acid derivatives. Ibuprofen, combinations.

ATC code M01AE51.

Pharmacological Properties

Pharmacodynamics

The pharmacological action of ibuprofen and paracetamol differs in site and mechanism of action, but is synergistic, resulting in enhanced analgesic and antipyretic effects compared to either substance used alone.

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID), a derivative of propionic acid, which has demonstrated efficacy in inhibiting the synthesis of prostaglandins—mediators of pain and inflammation. Ibuprofen exerts analgesic, antipyretic, and anti-inflammatory effects. In addition, ibuprofen reversibly inhibits platelet aggregation.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when both agents are administered concomitantly. Some pharmacodynamic studies have shown that when single doses of 400 mg ibuprofen are administered within 8 hours before or within 30 minutes after immediate-release acetylsalicylic acid (81 mg), a reduced effect of acetylsalicylic acid on thromboxane formation or platelet aggregation is observed. Although uncertainty exists regarding the extrapolation of these data to clinical settings, it cannot be excluded that regular long-term use of ibuprofen may diminish the cardioprotective effect of low-dose acetylsalicylic acid. With occasional, non-systematic use of ibuprofen, such a clinically significant effect is considered unlikely.

The mechanism of action of paracetamol is not fully elucidated; however, convincing evidence supports its central analgesic effect on the central nervous system. Biochemical studies indicate inhibition of cyclooxygenase-2 (COX-2) activity in the central nervous system. Paracetamol may also stimulate descending serotonergic (5-hydroxytryptamine) pathways, thereby suppressing pain signal transmission in the spinal cord.

This medication is particularly suitable for the treatment of pain requiring stronger analgesia than either 400 mg ibuprofen or 1000 mg paracetamol alone.

Studies conducted using this combination in models of acute pain (postoperative dental pain) and chronic knee joint pain have demonstrated high efficacy in reducing the intensity of acute pain (93.2%) and in long-term management of chronic pain (60.2%). This medication has a rapid onset of action, with noticeable pain relief confirmed on average within 18.3 minutes. Significant pain reduction occurs on average within 44.6 minutes. The analgesic effect of this medication is substantially longer (9.1 hours) compared to 500 mg paracetamol (4 hours).

Pharmacokinetics

Ibuprofen is rapidly absorbed from the gastrointestinal tract and is highly bound to plasma proteins. Ibuprofen is detectable in plasma within 5 minutes and reaches peak plasma concentration within 1–2 hours after fasting administration. It is metabolized in the liver and excreted by the kidneys. The elimination half-life is approximately 2 hours.

Paracetamol is rapidly absorbed from the gastrointestinal tract. At therapeutic concentrations, plasma protein binding is low, although it is dose-dependent. Paracetamol is detectable in plasma within 5 minutes and reaches peak plasma concentration within 0.5–0.67 hours after fasting administration.

Paracetamol is metabolized in the liver and excreted in urine primarily as conjugated metabolites. Less than 5% of paracetamol is excreted unchanged. A hydroxylated metabolite, formed in very small amounts in the liver via mixed-function oxidases and normally detoxified by conjugation with hepatic glutathione, may accumulate in cases of paracetamol overdose and cause hepatotoxicity. The elimination half-life is approximately 3 hours. No significant differences in the pharmacokinetic profiles of paracetamol and ibuprofen have been observed in elderly patients. The bioavailability and pharmacokinetic profiles of ibuprofen and paracetamol in this formulation are not altered following single or repeated doses of this combination.

Clinical characteristics.

Indications.

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

Contraindications.

Tempofen® Duo is contraindicated:

in patients with known hypersensitivity to ibuprofen, paracetamol, or any other component of the drug;
when used concomitantly with other paracetamol-containing medications due to increased risk of serious adverse reactions;
in patients with a history of hypersensitivity reactions (e.g., bronchospasm, angioedema, bronchial asthma, rhinitis, or urticaria) after taking ibuprofen, acetylsalicylic acid, or other nonsteroidal anti-inflammatory drugs (NSAIDs);
in patients with a history of gastrointestinal bleeding or perforation related to NSAID use;
in active or recurrent peptic ulcer disease or gastrointestinal bleeding (active or history of two or more distinct episodes of peptic ulcer or bleeding);
in patients with coagulation disorders;
in patients with severe hepatic, renal, or cardiac insufficiency (NYHA Class IV);
when used concomitantly with other NSAID-containing medications, including COX-2 inhibitors and acetylsalicylic acid at daily doses exceeding 75 mg, due to increased risk of adverse reactions;
during the third trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

Tempofen® Duo, like other paracetamol-containing medicinal products, is contraindicated when used concomitantly with other paracetamol-containing medications due to increased risk of serious adverse reactions.

This medication (like other ibuprofen-containing products and NSAIDs) should not be used in combination with the following medications.

Acetylsalicylic acid, as it may increase the risk of adverse reactions, except when acetylsalicylic acid (dose not exceeding 75 mg per day) has been prescribed by a physician.

Experimental data indicate that ibuprofen may inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when used concomitantly. However, the possibility of extrapolating these data to clinical situations is limited; therefore, no definitive conclusions can be drawn regarding whether regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. Clinically significant effects are considered unlikely with occasional, non-regular use of ibuprofen.

Other NSAIDs (including selective COX-2 inhibitors), as this may lead to increased frequency of adverse reactions.

This medication (like other paracetamol-containing products) should be used with caution in combination with the following medicinal products.

Cholestyramine: the absorption rate of paracetamol is reduced by cholestyramine; therefore, paracetamol should be administered at least 1 hour before cholestyramine if maximum analgesia is required.

Metoclopramide and domperidone: absorption of paracetamol is enhanced by metoclopramide and domperidone; however, concomitant administration need not be avoided.

Warfarin: the anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol, increasing the risk of bleeding; occasional use has no significant effect.

Flucloxacillin: paracetamol should be used with caution when administered concomitantly with flucloxacillin, as co-administration has been associated with metabolic acidosis with high anion gap as a result of pyroglutamic acidosis, particularly in patients at risk (see section "Special precautions for use").

This medication (like other ibuprofen-containing products and NSAIDs) should be used with caution in combination with the following medicinal products.

Anticoagulants. NSAIDs may enhance the therapeutic effect of anticoagulants such as warfarin. The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol, increasing the risk of bleeding.

Antihypertensive and diuretic agents. NSAIDs may reduce the therapeutic efficacy of these agents 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 ACE inhibitors or angiotensin II antagonists and COX-inhibiting agents may lead to further deterioration of renal function, possibly resulting in reversible acute renal failure. Therefore, such combinations should be prescribed with caution, especially in elderly patients. Adequate hydration should be ensured if long-term treatment is necessary, 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). The risk of gastrointestinal bleeding may be increased.

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

Cyclosporine. Increased risk of nephrotoxicity is possible.

Glucocorticoids may increase the risk of gastrointestinal adverse reactions (gastrointestinal ulcers or bleeding).

Lithium and methotrexate. Evidence suggests a potential increase in plasma levels of lithium and methotrexate.

Mifepristone. NSAIDs should not be used earlier than 8–12 days after administration of mifepristone, as they may reduce its efficacy.

Quinolone antibiotics. Animal studies suggest that NSAIDs may increase the risk of seizures associated with quinolone antibiotics. The risk of seizures increases when NSAIDs are used concomitantly with quinolones.

Tacrolimus. Increased risk of nephrotoxicity may occur when NSAIDs are used concomitantly with tacrolimus.

Zidovudine. Increased risk of hematological toxicity with concomitant use of zidovudine and NSAIDs. Evidence suggests an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia receiving concomitant treatment with zidovudine and ibuprofen.

Antiemetics. The absorption rate of paracetamol may be increased by metoclopramide or domperidone.

Special precautions for use.

Do not exceed the recommended doses.

If symptoms worsen, consult a physician.

Paracetamol

Paracetamol should be administered with caution in patients with severe renal or hepatic impairment. The risk of paracetamol overdose is higher in patients with non-cirrhotic alcoholic liver disease. In case of overdose, immediate medical attention is required, even if the patient feels well, due to the risk of delayed, severe liver damage.

Do not use other medications containing paracetamol. If this occurs, seek immediate medical advice, even if the patient feels well, as it may lead to overdose.

Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoproline (pyroglutamic acid) acidosis have been reported in patients with severe conditions such as severe renal impairment and sepsis, or in patients with malnutrition and 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 and close monitoring are recommended. 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.

Ibuprofen

Adverse reactions can be minimized by using the lowest effective dose required to relieve symptoms, for the shortest duration necessary to control symptoms, and taken with food.

Elderly patients

In elderly patients, the frequency of adverse reactions associated with NSAIDs, particularly gastrointestinal bleeding or perforation, increases and may be fatal. If NSAID use is necessary, the lowest effective dose should be used for the shortest possible duration.

Patients should be regularly monitored for possible gastrointestinal bleeding during NSAID therapy.

Respiratory effects

Bronchospasm may occur in patients with asthma or allergic conditions after NSAID use, or with a history of such conditions.

Systemic lupus erythematosus and mixed connective tissue disease

In patients with systemic lupus erythematosus and mixed connective tissue disease, the risk of aseptic meningitis may be increased.

Cardiovascular and cerebrovascular effects

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

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, which may potentially lead to myocardial infarction.

Clinical trial data indicate that the use of ibuprofen, particularly at high doses (2400 mg per day), may be associated with an increased risk of arterial thrombotic complications (e.g., myocardial infarction or stroke). Overall, epidemiological data do not suggest that low-dose ibuprofen (e.g., ≤ 1200 mg per day) is associated with an increased risk of arterial thrombotic complications.

Patients with uncontrolled hypertension, congestive heart failure (NYHA class II-III), diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with ibuprofen only after careful clinical assessment. High doses (2400 mg per day) should be avoided. Careful clinical evaluation is also required before initiating long-term treatment in patients with risk factors for cardiovascular complications (hypertension, hyperlipidemia, diabetes, smoking), especially if high doses of ibuprofen (2400 mg per day) are needed.

Cardiovascular, hepatic, and renal impairment

NSAID use may cause dose-dependent reduction in prostaglandin synthesis and development of renal impairment. Patients at increased risk include those with impaired renal, cardiac, or hepatic function, those taking diuretics, and elderly patients. Renal function should be monitored in such patients.

Gastrointestinal effects

NSAIDs should be prescribed with caution in patients with a history of gastrointestinal disorders (ulcerative colitis and Crohn’s disease), as these conditions may be exacerbated.

Cases of gastrointestinal bleeding, perforation, and ulcers, which may be fatal, have been reported during NSAID therapy at any stage of treatment, regardless of the presence of warning symptoms or a history of severe gastrointestinal disorders.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, a history of peptic ulcer (especially with complications such as bleeding or perforation), and in elderly patients. For these patients, treatment should be initiated at the lowest effective dose. Concomitant protective therapy (e.g., misoprostol or proton pump inhibitors) should be considered, especially in patients requiring concomitant low-dose aspirin or other agents that may increase gastrointestinal risk.

Patients with a history of gastrointestinal disorders, particularly elderly patients, should be informed about any adverse gastrointestinal symptoms (especially bleeding), particularly at the beginning of treatment.

The drug should be prescribed with caution in patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as aspirin.

The occurrence of gastrointestinal bleeding or ulcers in patients receiving ibuprofen-containing medications requires immediate discontinuation of the drug.

Serious skin adverse reactions (SSARs)

Serious skin adverse reactions (SSARs), including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), 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 of treatment.

Ibuprofen should be discontinued immediately at the first signs or symptoms of skin involvement, and alternative treatment should be considered (if necessary).

Masking symptoms of underlying infections

The medicinal product Temofen® Duo may mask symptoms of infectious disease, potentially delaying the initiation of appropriate treatment and thereby complicating the disease course. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When Temofen® Duo is used for fever or to relieve pain associated with infection, monitoring for infectious disease is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Effect on female fertility

Limited data suggest that medicinal products that inhibit COX/prostaglandin synthesis may affect ovulation. This effect is reversible upon discontinuation of treatment. Women experiencing fertility problems or undergoing infertility evaluation should avoid using the drug.

This medicinal product contains sodium; therefore, caution is advised in patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy

There is no experience with the use of the drug in pregnant women.

Extensive data in pregnant women do not indicate either malformative 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, but it should be administered at the lowest effective dose, for the shortest possible duration, and with the lowest possible frequency.

Congenital anomalies have been reported after NSAID use in humans, but they are infrequent and usually lack a clear pattern. Due to the known effects of NSAIDs on the fetal cardiovascular system (risk of premature closure of the ductus arteriosus), use during the third trimester is contraindicated. Prolonged labor or increased duration of labor, along with increased tendency to bleeding in both mother and child, may occur.

During the first and second trimesters of pregnancy, as well as during labor, use of the drug should be avoided.

Starting from the 20th week of pregnancy, use of Temofen® Duo may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there are reports of ductus arteriosus constriction after treatment during the second trimester, most of which resolved after stopping treatment. Therefore, Temofen® Duo should not be prescribed during the first and second trimesters unless clinically necessary.

If Temofen® Duo is used by a woman trying 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 Temofen® Duo exposure for several days starting from the 20th gestational week. Temofen® Duo 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, Temofen® Duo 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 concentrations (0.0008% of the maternal dose). Harmful effects on infants are unknown.

Paracetamol is excreted in breast milk but in clinically insignificant amounts. Available published data do not preclude the use of the drug during breastfeeding.

Therefore, there is no need to discontinue breastfeeding during short-term therapy with this drug at recommended doses.

Ability to affect reaction speed when driving or operating machinery.

Possible adverse reactions such as dizziness, drowsiness, fatigue, and visual disturbances may occur after NSAID use. Patients experiencing such adverse reactions should not drive or operate machinery.

Dosage and Administration

For oral short-term use only.

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

If symptoms persist for more than 3 days, a physician should be consulted for reassessment of diagnosis and adjustment of treatment. The duration of treatment is determined individually by the physician, depending on the course of the disease and the patient's condition.

Adults: Take 1 tablet up to 3 times daily, with intervals between doses of at least 6 hours. Tablets should be taken with water.

If 1 tablet does not relieve symptoms, 2 tablets per dose may be taken, but not more than 3 times daily. The interval between doses must be at least 6 hours. Do not take more than 6 tablets (3000 mg paracetamol, 1200 mg ibuprofen) within 24 hours.

To minimize the risk of adverse reactions, the drug should be taken during meals.

Elderly patients

Dosage adjustment is not required.

Due to the increased risk of adverse reactions, elderly patients should be monitored particularly closely. If NSAID therapy is necessary, the lowest effective dose should be used for the shortest possible duration. Patients should be regularly monitored for gastrointestinal bleeding throughout NSAID therapy.

Children

Not recommended for use in children (under 18 years of age).

Overdose

Paracetamol

Hepatotoxicity may occur in adults who have ingested 10 g (equivalent to 20 tablets) or more of paracetamol. Liver damage may occur with ingestion of 5 g (equivalent to 10 tablets) or more of paracetamol if:

the patient is chronically taking carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs that induce hepatic enzymes;
the patient regularly consumes alcohol;
the patient is likely to have glutathione deficiency, e.g., cystic fibrosis, HIV infection, cachexia, or fasting.

Symptoms: Within the first 24 hours, symptoms of paracetamol overdose may include pallor, nausea, vomiting, anorexia, and abdominal pain. Hepatic damage may become evident 12–48 hours after overdose, manifested by abnormal liver function tests. Glucose metabolism disturbances and metabolic acidosis may also occur. In severe poisoning, hepatic failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and may be fatal. Acute renal failure with acute tubular necrosis may present as severe flank pain, hematuria, proteinuria, and may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have also been reported.

Treatment: Immediate medical attention is required in case of paracetamol overdose. The patient should be taken to hospital immediately for medical evaluation, even if early symptoms are absent. Symptoms may be limited to nausea and vomiting and may not reflect the severity of overdose or risk of organ damage. Treatment should be carried out according to established treatment guidelines.

Activated charcoal should be considered within 1 hour of ingestion of a potentially toxic dose. Plasma paracetamol concentration should be measured at least 4 hours after ingestion (earlier concentrations are unreliable).

Antidotal treatment with N-acetylcysteine may be administered within 24 hours of paracetamol ingestion, but maximum protective effect is achieved when administered within 8 hours of overdose. The efficacy of the antidote decreases sharply after this time.

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

Patients who develop severe hepatic dysfunction within 24 hours of paracetamol ingestion should be treated according to established guidelines.

Ibuprofen

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

Symptoms: In most patients who have ingested a clinically significant amount of NSAIDs, only nausea, vomiting, epigastric pain, and very rarely diarrhea may occur. Tinnitus, headache, and gastrointestinal bleeding may also develop. In more severe poisoning, toxic effects on the central nervous system may occur, manifesting as drowsiness, occasionally nervous excitation, disorientation, or coma. Seizures may occasionally be observed. Severe poisoning may lead to metabolic acidosis; prothrombin time/international normalized ratio (INR) may be prolonged, possibly due to effects on blood coagulation factors. Acute renal failure and liver damage may occur, particularly in the presence of dehydration. In patients with bronchial asthma, exacerbation of the disease may occur.

Treatment: Treatment should be symptomatic and supportive, including maintenance of airway patency and monitoring of cardiac function and vital signs until stabilization. Oral activated charcoal is recommended within 1 hour of ingestion of a potentially toxic dose. For frequent or prolonged seizures, intravenous diazepam or lorazepam should be administered. Bronchodilators should be used for the treatment of bronchial asthma.

Adverse Reactions

Clinical studies conducted with this medicinal product do not indicate the presence of any additional adverse reactions beyond those observed with ibuprofen or paracetamol when used separately.

The adverse reactions listed below were observed in patients treated with ibuprofen or paracetamol alone, during both short-term and long-term use.

Frequency is defined 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), frequency not known (cannot be estimated from the available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Blood and lymphatic system disorders: very rare: disorders of the hematopoietic system¹.

Immune system disorders: uncommon: hypersensitivity reactions including urticaria and pruritus²; very rare: severe hypersensitivity reactions. Symptoms may include facial, tongue, and laryngeal edema, dyspnea, tachycardia, and hypotension (anaphylaxis, angioedema, or severe shock)².

Psychiatric disorders: very rare: confusion, depression, and hallucinations.

Nervous system disorders: uncommon: headache and dizziness; rare: paresthesia; very rare: aseptic meningitis³, optic neuritis, and somnolence.

Eye disorders: very rare: visual disturbances.

Ear and labyrinth disorders: very rare: tinnitus and vertigo.

Cardiac disorders: common: edema; very rare: heart failure⁴; frequency not known: Kounis syndrome.

Vascular disorders: very rare: arterial hypertension⁴.

Respiratory, thoracic and mediastinal disorders: very rare: respiratory hypersensitivity, including asthma, asthma exacerbation, bronchospasm, and dyspnea².

Gastrointestinal disorders: common: abdominal pain, vomiting, diarrhea, nausea, dyspepsia, and gastrointestinal discomfort⁵; uncommon: peptic ulcer, gastrointestinal perforation or gastrointestinal hemorrhage, melena, hematemesis⁶, oral ulcers, exacerbation of colitis and Crohn’s disease⁷, gastritis, pancreatitis, flatulence, and constipation.

Metabolism and nutrition disorders: frequency not known: high anion gap metabolic acidosis¹⁰.

Hepatobiliary disorders: very rare: hepatic function abnormalities, hepatitis, and jaundice⁸.

Skin and subcutaneous tissue disorders: common: increased sweating; uncommon: various skin rashes²; very rare: bullous reactions, severe skin adverse reactions (SSARs) (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis²), purpura; frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome); acute generalized exanthematous pustulosis, photosensitivity reactions.

Renal and urinary disorders: very rare: nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome, acute and chronic renal failure⁹.

General disorders: very rare: fatigue and malaise.

Investigations: common: increased alanine aminotransferase, increased gamma-glutamyl transferase, and impaired liver function tests due to paracetamol; increased blood creatinine, increased blood urea. Uncommon: increased aspartate aminotransferase, increased alkaline phosphatase in blood, increased creatine phosphokinase in blood, decreased hemoglobin, and increased platelet count.

Description of selected adverse reactions

¹ Examples include agranulocytosis, anemia, aplastic anemia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, and thrombocytopenia. Initial signs include fever, sore throat, oral ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding, bruising, and epistaxis.

² Reports exist of hypersensitivity reactions. These include (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract reactions such as bronchial asthma, asthma exacerbation, bronchospasm, or dyspnea, or (c) various skin reactions such as rashes of different types, pruritus, urticaria, purpura, angioedema, and less frequently, exfoliative and bullous dermatoses (including epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme).

³ The pathogenic mechanism of drug-induced aseptic meningitis is not fully understood. However, available data on aseptic meningitis associated with NSAIDs suggest a hypersensitivity reaction (due to symptom onset during drug use and symptom resolution after discontinuation). Specifically, cases of aseptic meningitis symptoms such as nuchal rigidity, headache, nausea, vomiting, fever, or disorientation have been observed in patients with pre-existing autoimmune disorders (systemic lupus erythematosus, mixed connective tissue disease) during ibuprofen treatment (see section "Special precautions").

⁴ Clinical data suggest that ibuprofen use, particularly at high doses (2400 mg/day), may be associated with a small increased risk of arterial thrombotic events such as myocardial infarction or stroke (see section "Special precautions").

⁵ The most frequently observed adverse reactions are gastrointestinal in nature.

⁶ Sometimes fatal, especially in elderly patients.

⁷ See section "Special precautions".

⁸ Paracetamol overdose may cause acute liver failure, liver failure, hepatic necrosis, and liver damage (see section "Overdose").

⁹ Particularly with long-term use, associated with elevated serum urea levels and edema. Also includes papillary necrosis.

¹⁰ High anion gap metabolic acidosis. Cases of high anion gap metabolic acidosis resulting from pyroglutamic acidosis have been reported in patients with risk factors using paracetamol (see section "Special precautions"). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.

Reporting of suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions.

Keep out of reach and sight of children.

No special storage conditions are required for this medicinal product.

Packaging.

10 film-coated tablets in a blister pack made of PVC/PVDC film and aluminum foil. One blister pack in a cardboard box.

Prescription status. Over-the-counter (without prescription).

Manufacturer.

JSC "Sofarma".

Manufacturer's address and location of operations.

16 Iliensko Shose Str., Sofia, 1220, Bulgaria.

Tempofen® duo