INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT THERMIDOL (TERMIDOL)

Composition:

Active substance: ibuprofen;

1 capsule contains ibuprofen 200 mg or 400 mg;

Excipients: polyethylene glycol (macrogol), potassium hydroxide, purified water;

Capsule shell: gelatin; sorbitol liquid, partially dehydrated (E 420).

Dosage form. Soft capsules.

Main physicochemical properties: soft gelatin capsules, oval-shaped with a seam, transparent, light yellow-brown in color. The capsule contents is a transparent, colorless or slightly yellowish, viscous liquid.

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

Pharmacological properties.

Pharmacodynamics. Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID), a propionic acid derivative, which has demonstrated efficacy in inhibiting the synthesis of prostaglandins—mediators of pain, inflammation, and fever. 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 these drugs are used concomitantly. Some pharmacodynamic studies have shown that administration of single 400 mg doses of ibuprofen within 8 hours before or within 30 minutes after immediate-release acetylsalicylic acid (81 mg) resulted in reduced effects of acetylsalicylic acid (aspirin) on thromboxane formation or platelet aggregation. Although uncertainty remains regarding the extrapolation of these data to clinical settings, the possibility 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.

Pharmacokinetics. After oral administration, ibuprofen is rapidly absorbed, partially already in the stomach and completely in the small intestine.

Following metabolism in the liver (hydroxylation, carboxylation, conjugation), pharmacologically inactive metabolites are excreted predominantly in the urine (90%) and also in bile. The elimination half-life in healthy volunteers as well as in patients with hepatic or renal disease ranges from 1.8 to 3.5 hours. Plasma protein binding is approximately 99%. After oral administration of the conventional release dosage form, maximum plasma concentration is reached within 1–2 hours.

According to available data from two pharmacokinetic studies, the time to reach maximum plasma concentration (Tmax) for ibuprofen in solid dosage forms was 60 and 90 minutes, compared to 35 and 40 minutes, respectively, for ibuprofen in soft capsule dosage form. The mean Cmax is achieved twice as fast with ibuprofen in the soft capsule dosage form. Ibuprofen remains detectable in plasma for more than 8 hours after drug intake.

Clinical characteristics.

Indications.

Symptomatic treatment of mild to moderate pain of various origin (headache, toothache, dysmenorrhea), including pain associated with colds 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 taking ibuprofen, acetylsalicylic acid (aspirin), or other NSAIDs.
Active peptic ulcer/hemorrhage or history of recurrent episodes (two or more distinct episodes of peptic ulcer or bleeding).
History of gastrointestinal bleeding or perforation associated with previous use of NSAIDs.
Severe hepatic impairment, severe renal impairment, severe heart failure (NYHA Class IV).
Third trimester of pregnancy.
Active cerebrovascular or other bleeding.
Hemorrhagic diathesis or coagulation disorders.
Unexplained disturbances of blood formation.
Severe dehydration (caused by vomiting, diarrhea, or insufficient fluid intake).
Patient weight less than 40 kg or patient age under 12 years.
Children with body weight less than 20 kg (for 200 mg dose).
Concomitant use of this medicinal product with other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, should be avoided.

Interaction with other medicinal products and other forms of interaction.

Ibuprofen, like other NSAIDs, should not be used in combination with:

Acetylsalicylic acid (aspirin), as this increases the risk of adverse reactions, except when aspirin (at a 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 (aspirin) on platelet aggregation when administered concomitantly. However, limitations in extrapolating these data to clinical settings prevent definitive conclusions regarding whether regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose aspirin. Clinically significant interactions are considered unlikely with occasional, short-term use of ibuprofen.

Other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors:

Concomitant use of multiple NSAIDs may increase the risk of gastrointestinal ulcers and bleeding due to synergistic effects. Therefore, combination therapy with ibuprofen and other NSAIDs should be avoided.

Ibuprofen should be used with caution in combination with the following medicinal products:

Anticoagulants: NSAIDs may enhance the effects of anticoagulants such as warfarin.

Antihypertensive agents (ACE inhibitors, angiotensin II antagonists) and diuretics: NSAIDs may attenuate the effects of diuretics and other antihypertensive drugs. 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 with cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including potentially reversible acute renal failure. Therefore, such combinations should be prescribed with caution, particularly in elderly patients. Adequate hydration should be ensured, and monitoring of renal function should be considered at the initiation of combination therapy and periodically thereafter, especially during prolonged treatment. Diuretics may increase the risk of nephrotoxic effects of NSAIDs.

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

Corticosteroids: Increased risk of gastrointestinal ulcers and bleeding.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding.

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

Digoxin: Plasma levels of both drugs may be increased.

Lithium: Evidence suggests a potential increase in plasma lithium levels.

Phenytoin: Concomitant use with phenytoin may increase its serum concentration.

Metotrexate: Administration of ibuprofen within 24 hours before or after methotrexate may increase methotrexate concentrations and enhance its toxicity.

Cyclosporine: Increased risk of nephrotoxicity.

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

Tacrolimus: Possible increased risk of nephrotoxicity when used concomitantly with NSAIDs.

Zidovudine: Increased risk of hematological toxicity is known when zidovudine is used concomitantly with NSAIDs. Evidence suggests an increased risk of hemarthrosis and hematomas in HIV-infected patients with hemophilia receiving concomitant treatment with zidovudine and ibuprofen.

Quinolone antibiotics: Concurrent use with ibuprofen may increase the risk of seizures.

Sulfonylureas: Blood glucose levels should be monitored as a precautionary measure during concomitant use.

Probenecid and sulfinpyrazone: May delay the elimination of ibuprofen.

Inhibitors of CYP2C9: Concomitant use of ibuprofen with CYP2C9 inhibitors may enhance the effect of ibuprofen (a CYP2C9 substrate). In studies with voriconazole and fluconazole (CYP2C9 inhibitors), the exposure to S(+)-ibuprofen increased by approximately 80–100%. Dose reduction of ibuprofen should be considered when used concomitantly with potent CYP2C9 inhibitors, especially when high doses of ibuprofen are used with voriconazole or fluconazole.

Special precautions for use.

The adverse effects of ibuprofen and NSAIDs in general can be minimized by using the lowest effective dose required to treat symptoms, for the shortest possible duration.

Caution is necessary when treating patients:

with systemic lupus erythematosus or mixed connective tissue disease – increased risk of aseptic meningitis (see section "Adverse reactions");
with congenital porphyrin metabolism disorders (e.g., acute intermittent porphyria) (see section "Adverse reactions");
with gastrointestinal disorders and chronic inflammatory bowel diseases (ulcerative colitis, Crohn’s disease) (see section "Adverse reactions");
with arterial hypertension and/or heart failure (see sections "Contraindications" and "Adverse reactions");
with impaired renal function, as kidney function may worsen (see sections "Contraindications" and "Adverse reactions");
with impaired liver function (see sections "Contraindications" and "Adverse reactions");
following major surgical procedures;
with allergic reactions to other substances, as they also have an increased risk of hypersensitivity reactions when using the drug;
who suffer from hay fever, nasal polyps, chronic obstructive respiratory diseases, or have a history of allergic diseases, as they are at increased risk of allergic reactions. In such patients, asthma attacks (so-called analgesic-induced asthma), Quincke's edema, or urticaria may occur.

Elderly patients have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforations, which may be fatal.

Respiratory effects

Bronchospasm may occur in patients suffering from bronchial asthma or allergic diseases, or with a history of such conditions.

Other NSAIDs

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

Systemic lupus erythematosus and mixed connective tissue diseases

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

Porphyrin metabolism

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

Effects on the cardiovascular and cerebrovascular systems

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

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

Patients with uncontrolled arterial hypertension, congestive heart failure (NYHA class II–III), diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful clinical assessment. High doses (2400 mg per day) should be avoided.

The clinical picture should also be carefully evaluated before initiating long-term treatment in patients with cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking), especially if high ibuprofen doses (2400 mg per day) are required.

Cases of Kounis syndrome have been reported in patients receiving ibuprofen. Kounis syndrome manifests as cardiovascular symptoms related to coronary artery spasm due to an allergic or hypersensitivity reaction, which may lead to myocardial infarction.

Effects on the kidneys

Ibuprofen should be used with caution in patients with impaired renal function, as kidney function may deteriorate.

Effects on the liver

Liver function impairment is possible.

Surgical procedures

Caution is required immediately after major surgical interventions.

Effects on female fertility

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

Effects on the gastrointestinal system

NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn’s disease), as these conditions may worsen. Cases of gastrointestinal bleeding, perforation, and ulcers, possibly fatal, have been reported at any stage of NSAID treatment, regardless of prior warning symptoms or history of severe gastrointestinal disorders.

The risk of gastrointestinal bleeding, perforation, and ulcers increases with higher NSAID doses, in patients with a history of peptic ulcer (especially complicated by bleeding or perforation), and in elderly patients. Such patients should start treatment with the lowest doses. For these patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid or other drugs that may increase gastrointestinal risk, consideration should be given to combining therapy with protective agents (e.g., misoprostol or proton pump inhibitors).

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

Caution is required when treating 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 (e.g., aspirin).

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

Severe skin adverse reactions

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

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

In rare cases, varicella (chickenpox) may lead to severe skin and soft tissue infections. At present, a negative influence of NSAIDs on the course of these infections cannot be ruled out; therefore, it is recommended to avoid ibuprofen use in cases of varicella.

Masking symptoms of underlying infections

Ibuprofen may mask symptoms of infectious diseases, potentially delaying appropriate treatment and worsening disease progression. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When the drug is used for fever or pain relief during infection, monitoring for infection is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Allergy

Caution is required in patients with allergic reactions to other substances, as they have an increased risk of hypersensitivity reactions when using ibuprofen.

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

This medicinal product contains sorbitol. If you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medicinal product.

NSAIDs may mask symptoms of infection and fever.

Other

Severe acute hypersensitivity reactions (e.g., anaphylactic shock) are very rare. At the first signs of hypersensitivity after drug administration, treatment must be discontinued. Symptomatic and specialized therapy is required in such cases.

Ibuprofen may temporarily inhibit platelet function (affect platelet aggregation). Therefore, careful monitoring is recommended in patients with coagulation disorders.

During prolonged use of the drug Termadol, liver and kidney function tests, as well as blood counts, should be monitored regularly.

Prolonged use of any analgesics for headache treatment may worsen this condition. If suspected or confirmed, medical advice should be sought and treatment discontinued. Medication-overuse headache should be considered in patients with frequent or daily headaches, despite (or because of) regular use of headache medications.

Chronic use of analgesics, especially combinations of multiple analgesics, may lead to persistent kidney dysfunction with a risk of renal failure (analgesic nephropathy). This risk may be increased by electrolyte loss and dehydration.

Concomitant use of NSAIDs with alcohol may increase the risk of adverse effects related to the active substance, particularly gastrointestinal or central nervous system (CNS) effects.

There is a risk of impaired kidney function in dehydrated children and adolescents.

Use during pregnancy or breastfeeding

Pregnancy. Inhibition of prostaglandin synthesis may negatively affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage, congenital heart defects, and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of therapy.

From the 20th week of pregnancy, ibuprofen use may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, cases of arterial duct constriction have been reported after second-trimester treatment, most of which resolved after stopping the drug. Therefore, ibuprofen should not be prescribed during the first and second trimesters unless necessary. If ibuprofen is used by women 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 arterial duct constriction should be considered after several days of ibuprofen exposure starting from the 20th gestational week. Ibuprofen use should be discontinued if oligohydramnios or arterial duct 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 arterial duct and pulmonary hypertension);
renal dysfunction (see above);

Risks to the mother at the end of pregnancy and to the newborn:

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

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

Breastfeeding period. In limited studies, ibuprofen has been detected in breast milk at very low concentrations, making it unlikely to adversely affect the breastfed infant. However, NSAIDs are not recommended during breastfeeding.

Fertility

Ibuprofen use may affect female fertility. This effect is reversible upon discontinuation of treatment. Therefore, ibuprofen use is not recommended for women with fertility problems.

Ability to affect reaction speed when driving or operating machinery

Patients who experience dizziness, drowsiness, or visual disturbances while taking ibuprofen should avoid driving or operating machinery. Single-dose administration or short-term use of ibuprofen generally does not require special precautions. This mainly applies when the drug is used concomitantly with alcohol.

When used according to recommended doses and treatment duration, the drug does not affect reaction speed during driving or operating machinery.

Dosage and Administration

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

The drug is taken orally by adults and children aged 12 years and older with body weight > 40 kg. Use only for short-term treatment. Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

Children with body weight 20–29 kg: recommended initial dose – 1 capsule (equivalent to 200 mg of ibuprofen). Maximum daily dose is 3 capsules (equivalent to 600 mg of ibuprofen).

Children with body weight 30–39 kg: recommended initial dose – 1 capsule (equivalent to 200 mg of ibuprofen). Maximum daily dose is 4 capsules (equivalent to 800 mg of ibuprofen).

Children with body weight ≤ 39 kg: the drug may be administered to children with body weight of at least 20 kg. The maximum daily dose of ibuprofen is 20–30 mg per kg of body weight, divided into 3–4 doses, with dosing intervals of 6–8 hours. Do not exceed the maximum recommended daily dose.

Capsules should be taken preferably during or after meals, without chewing, and swallowed with water.

Single dose for children aged 12 years and older with body weight > 40 kg and adults: 1 capsule (400 mg of ibuprofen). If necessary, 1 capsule may be taken every 6 hours. Maximum daily dose is 1200 mg (3 capsules per day). Use the lowest effective dose required to treat symptoms for the shortest possible duration.

If symptoms worsen or persist for more than 3 days in adolescents, consult a physician for diagnosis clarification and treatment adjustment.

If fever persists for more than 3 days or pain continues for more than 4 days in adults, or if symptoms worsen, consult a physician for diagnosis clarification and treatment adjustment.

Treatment duration should be determined individually by a physician, depending on the course of the disease and the patient's condition.

Elderly patients do not require special dose adjustment, except in cases of severe renal or hepatic impairment. Due to the risk of adverse effects, elderly patients require careful monitoring.

Patients with mild to moderate renal impairment do not require dose reduction; for patients with severe renal impairment, see section "Special Warnings and Precautions for Use".

Dose reduction is not required for patients with mild or moderate hepatic impairment; for patients with severe hepatic impairment, see section "Special Warnings and Precautions for Use".

Children.

200 mg capsules – not to be used in children with body weight less than 20 kg.

400 mg capsules – not to be used in children under 12 years of age or in children with body weight < 40 kg.

Overdose.

Administration of the drug to children in doses exceeding 400 mg/kg may cause symptoms of intoxication. In adults, the dose effect is less pronounced. The elimination half-life in overdose is 1.5–3 hours.

In acute overdose, symptoms depend on the amount ingested and the time elapsed since ingestion.

Symptoms. In most patients who have taken clinically significant amounts of NSAIDs, only nausea, vomiting, epigastric pain, or very rarely diarrhea occur. Tinnitus, headache, and gastrointestinal bleeding may also occur. In more severe poisoning, toxic effects on the central nervous system may develop, manifesting as vertigo, drowsiness, occasionally agitation and disorientation, or coma. Seizures may occasionally occur in patients. Severe poisoning may lead to hyperkalemia and metabolic acidosis. Prolongation of prothrombin time/increased prothrombin index may be observed, possibly due to effects on circulating coagulation factors. Acute renal failure, liver damage, arterial hypotension, respiratory failure, and cyanosis may develop. In patients with bronchial asthma, exacerbation of the disease is possible.

Treatment. Treatment should be symptomatic and supportive, including ensuring airway patency and monitoring of cardiac function and vital signs until condition stabilizes. Oral administration of activated charcoal or gastric lavage is recommended within 1 hour after ingestion of a potentially toxic dose. If ibuprofen has already been absorbed, alkalizing agents may be administered to enhance renal excretion of acidic ibuprofen. In cases of frequent or prolonged seizures, intravenous diazepam or lorazepam should be administered. For treatment of bronchial asthma exacerbation, bronchodilators should be used.

There is no specific antidote. Symptomatic treatment is based on monitoring vital functions, measuring arterial blood pressure, performing ECG, and interpreting symptoms indicating possible gastrointestinal bleeding, metabolic acidosis, and central nervous system disturbances.

Side effects.

The list of adverse reactions observed after treatment with ibuprofen includes all side effects reported during short-term use as well as those observed during long-term high-dose therapy in patients with rheumatism. The frequency stated beyond very rare reports refers to short-term use of doses (maximum 1200 mg ibuprofen per day) for oral dosage forms and maximum 1800 mg per day for suppositories.

The development of adverse reactions to the medicinal product primarily depends on the dose and individual characteristics of the organism.

The most commonly observed adverse reactions are related to the gastrointestinal tract. Peptic ulcers, perforation, or gastrointestinal bleeding, sometimes with fatal outcomes, may occur, particularly in elderly patients. During treatment, nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis, and Crohn's disease have been reported. Gastritis occurs less frequently. The risk of gastrointestinal bleeding mainly depends on the dose and duration of treatment. Cases of edema, arterial hypertension, and heart failure associated with NSAID therapy have been reported.

Clinical studies indicate that the use of ibuprofen, especially at high doses (2400 mg per day), slightly increases the risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Hypersensitivity reactions have been reported, which may manifest as:

non-specific allergic reactions and anaphylaxis;
respiratory tract reactivity, such as asthma, asthma exacerbation, bronchospasm, dyspnea;
various skin reactions, for example, pruritus, urticaria, angioedema, and less frequently – exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

The patient should immediately discontinue the use of the medicinal product in case of any of the above-mentioned manifestations and inform their physician.

Adverse reactions observed during the use of ibuprofen are listed by organ systems and frequency of occurrence. The frequency of adverse reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated based on available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Infections and parasitic diseases.

Very rare: exacerbation of infection-related inflammation.

If signs of infection occur or worsen during treatment, the patient is advised to seek immediate medical attention. It is necessary to determine whether anti-infective/antibacterial therapy is indicated.

Aseptic meningitis symptoms, including nuchal rigidity, headache, nausea, vomiting, fever, or altered consciousness, have been observed in patients with autoimmune diseases such as systemic lupus erythematosus and mixed connective tissue disease during ibuprofen use.

Blood and lymphatic system disorders.

Very rare: blood disorders (anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis). Initial symptoms include fever, sore throat, oral ulcers, influenza-like symptoms, severe fatigue, unexplained bleeding, and bruising.

In such cases, patients should be advised to discontinue use of this medicinal product and consult a physician.

Regular blood monitoring is necessary during prolonged therapy.

Immune system disorders.

Uncommon: hypersensitivity reactions, including urticaria and pruritus;

Very rare: severe hypersensitivity reactions, symptoms of which may include facial, tongue, and laryngeal swelling, dyspnea, tachycardia, arterial hypotension, anaphylactic reactions, angioedema, or severe shock; asthma exacerbation, bronchospasm.

Psychiatric disorders.

Very rare: psychotic reactions, depression.

Nervous system disorders.

Uncommon: headache, dizziness, insomnia, anxiety, irritability, or fatigue.

Eye disorders.

Uncommon: visual disturbances.

Ear and labyrinth disorders.

Rare: tinnitus, hearing loss.

Cardiac disorders.

Very rare: palpitations, heart failure, myocardial infarction.

Frequency not known: Kounis syndrome.

Vascular disorders.

Very rare: arterial hypertension, vasculitis;

Frequency not known: edema.

Gastrointestinal disorders.

Common: dyspepsia, heartburn, abdominal pain, nausea, vomiting, flatulence, diarrhea, constipation, and minor gastrointestinal blood loss, which may exceptionally lead to anemia;

Uncommon: peptic ulcer, perforation or gastrointestinal bleeding, ulcerative stomatitis, exacerbation of colitis and Crohn's disease, gastritis;

Very rare: esophagitis, pancreatitis, formation of intestinal diaphragm-like structures.

The patient must immediately discontinue the use of the medicinal product and consult a physician if upper abdominal pain, melena, or hematemesis occurs.

Hepatobiliary disorders.

Very rare: liver function abnormalities, liver damage, particularly during prolonged therapy, liver failure, acute hepatitis.

Skin and subcutaneous tissue disorders.

Uncommon: various skin rashes;

Very rare: severe skin adverse reactions (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis), alopecia.

In some cases, varicella may be a source of serious skin and soft tissue infections;

Frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome); acute generalized exanthematous pustulosis; photosensitivity reactions.

Renal and urinary disorders.

Rare: acute kidney function impairment, papillary necrosis, particularly with prolonged use, associated with increased serum urea levels;

Very rare: edema, especially in patients with arterial hypertension or renal insufficiency, nephrotic syndrome, interstitial nephritis, which may be accompanied by acute kidney injury. Therefore, kidney function should be monitored regularly.

Investigations.

Rare: decreased hemoglobin levels.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 capsules in a blister, 1 blister per carton.

10 capsules in a blister, 3 blisters per carton.

12 capsules in a blister, 3 blisters per carton.

Prescription status. Over-the-counter.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's address and location of operations.

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua

Termedol