Tetramol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TETRAMOL (TETRAMOL)

Composition:

Active substances: paracetamol, ibuprofen, caffeine;

1 capsule contains 325 mg of paracetamol, 200 mg of ibuprofen, and 30 mg of caffeine;

Excipients: talc, colloidal anhydrous silicon dioxide, sodium lauryl sulfate, gelatin, candurin (titanium dioxide (E 171), potassium aluminosilicate (E 555)).

Dosage form. Capsules.

Main physicochemical properties. Hard gelatin capsules. The body and cap of the capsule are white, pearly. The capsule content is a mixture of crystalline and amorphous white powder. The presence of lumps is acceptable.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Paracetamol combinations without psychotropic agents. ATC code N02BE51.

Pharmacological properties.

Pharmacodynamics.

A combined medicinal product whose action is determined by the components included in its composition. The drug exerts analgesic (pain-relieving), anti-inflammatory, and antipyretic effects. It inhibits the synthesis of prostaglandins. It reduces joint pain at rest and during movement, decreases morning stiffness and joint swelling, and promotes an increase in range of motion.

Caffeine enhances the analgesic effect of ibuprofen and paracetamol, improves work capacity, and reduces fatigue and drowsiness.

Pharmacokinetics.

Paracetamol

Paracetamol is rapidly and almost completely absorbed in the gastrointestinal tract (GI tract). Maximum plasma concentration is reached within 30–60 minutes after administration, and the elimination half-life from plasma is 1–4 hours after administration of therapeutic doses. In cases of severe hepatic insufficiency, the half-life increases to 5 hours. In renal insufficiency, the half-life does not increase; however, since renal excretion is limited, the dose of paracetamol should be reduced.

Paracetamol crosses the blood-brain barrier and also passes into breast milk in lactating women.

ibuprofen

Ibuprofen is rapidly absorbed from the gastrointestinal tract after administration. Maximum plasma concentration is reached within 45 minutes after intake; maximum concentration in synovial fluid is reached within 3 hours after intake. Ibuprofen is metabolized in the liver and excreted by the kidneys in unchanged form and as metabolites. The elimination half-life is approximately 2 hours.

Caffeine

After oral administration, caffeine is rapidly absorbed. Maximum plasma concentrations are reached approximately within 20–60 minutes, and the elimination half-life is approximately 4 hours.

Clinical characteristics.

Indications.

Pain of varying intensity:

• dysmenorrhea and menstrual pain;
• headache;
• neuralgia;
• myalgia;
• arthralgia;
• toothache.

Elevated body temperature (fever in influenza and colds).

As part of combination therapy for postoperative pain and alleviation of symptoms in rheumatoid arthritis and osteoarthritis.

Contraindications.

Hypersensitivity to paracetamol, ibuprofen, caffeine, or to any other component of the drug; peptic ulcer disease, including in medical history (two or more distinct episodes of peptic ulcer exacerbation or gastrointestinal bleeding); gastrointestinal bleeding or perforation in history associated with previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs); acute pancreatitis; severe impairment of liver and/or kidney function; congenital hyperbilirubinemia; glucose-6-phosphate dehydrogenase deficiency; alcoholism; blood disorders; severe anemia; leukopenia; thrombosis; thrombophlebitis; conditions of increased excitation; sleep disorders; severe arterial hypertension; organic cardiovascular diseases; closed-angle glaucoma; epilepsy; hyperthyroidism; decompensated heart failure; cardiac conduction disorders; severe atherosclerosis; tendency to vascular spasm; ischemic heart disease; prostate hypertrophy; severe forms of diabetes mellitus; allergic reaction (e.g., bronchial asthma, rhinitis, Quincke's edema) following administration of acetylsalicylic acid or other NSAIDs; concomitant use of the drug with NSAIDs; advanced age of the patient.

Do not use together with monoamine oxidase inhibitors (MAOIs), cyclooxygenase-2 inhibitors, or within 2 weeks after discontinuation of their use; contraindicated in patients taking tricyclic antidepressants or beta-blockers. Gilbert's syndrome. Patient age under 12 years. Contraindicated during pregnancy or breastfeeding.

Interaction with other medicinal products and other types of interactions.

Concomitant use of paracetamol with metoclopramide and domperidone may enhance paracetamol absorption, while cholestyramine may reduce absorption.

With long-term continuous use of paracetamol, the anticoagulant effect of warfarin and other coumarins may be enhanced, increasing the risk of bleeding.

NSAIDs may potentiate the effects of anticoagulants such as warfarin and reduce the efficacy of antihypertensive drugs or diuretics.

Concomitant use of other NSAIDs increases the risk of adverse reactions.

Corticosteroids may increase the risk of gastrointestinal adverse reactions.

Drug intake may lead to increased serum lithium concentration.

Concomitant use with methotrexate may lead to poisoning.

Barbiturates reduce the antipyretic effect of paracetamol.

Anticonvulsants (including phenytoin, barbiturates, carbamazepine), which stimulate hepatic microsomal enzyme activity, may enhance the hepatotoxic effect of paracetamol due to increased conversion of the drug into hepatotoxic metabolites. Concomitant use of paracetamol with hepatotoxic agents increases the hepatotoxic potential of the drugs. Simultaneous use of high doses of paracetamol with isoniazid increases the risk of hepatotoxic syndrome. Paracetamol reduces the effectiveness of diuretics. Do not use concomitantly with alcohol.

Caution is advised when using paracetamol concomitantly with flucloxacillin, as such combined use has been associated with metabolic acidosis with high anion gap, particularly in patients with risk factors (see section "Special precautions").

Concomitant use of caffeine with MAO inhibitors may cause dangerous elevation of blood pressure. Caffeine enhances the effect (improves bioavailability) of analgesic-antipyretic agents, potentiates the effects of xanthine derivatives, alpha- and beta-adrenergic agonists, and psychostimulants.

Cimetidine, hormonal contraceptives, and isoniazid enhance the effect of caffeine. Caffeine reduces the effect of opioid analgesics, anxiolytics, hypnotics, and sedatives; it acts as an antagonist of anesthetic agents and other drugs that depress the central nervous system (CNS), and as a competitive antagonist of adenosine and ATP preparations. Concomitant use of caffeine with ergotamine improves ergotamine absorption from the gastrointestinal tract; with thyroid-stimulating agents – increases thyroid effect. Caffeine reduces lithium concentration in blood.

Should not be used in combination with:

acetylsalicylic acid, unless a lower dose of acetylsalicylic acid (not exceeding 75 mg per day) has been prescribed by a physician, as this may lead to adverse effects;

NSAIDs. Since this may lead to increased frequency of adverse effects.

Use ibuprofen with caution in combination with:

antihypertensive agents (ACE inhibitors and angiotensin II antagonists) and diuretics: NSAIDs may reduce the efficacy of diuretics and other antihypertensive drugs. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with reduced kidney function), concomitant use of an ACE inhibitor or angiotensin II antagonist with cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, such combinations should be prescribed with caution, especially in elderly patients. If long-term treatment is necessary, adequate hydration of the patient should be ensured, and monitoring of renal function should be considered at the beginning of combination therapy and periodically thereafter. NSAIDs may reduce the therapeutic effect of these drugs. Diuretics may increase the risk of nephrotoxic effects of NSAIDs.

Anticoagulants. NSAIDs may increase the therapeutic effect of anticoagulants such as warfarin.

Antiplatelet agents and selective serotonin reuptake inhibitors. Increased risk of gastrointestinal bleeding.

Cardiac glycosides. May exacerbate heart failure, reduce glomerular filtration rate, and increase plasma levels of glycosides.

Cyclosporines. Some data suggest a possible interaction increasing the risk of nephrotoxicity.

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

Tacrolimus. Increased risk of nephrotoxicity.

Lithium and methotrexate. Evidence suggests potential elevation of lithium and methotrexate plasma levels.

Zidovudine. Evidence suggests increased risk of hemarthrosis and hematoma in HIV-infected patients receiving concomitant treatment with zidovudine and ibuprofen.

Quinolone antibiotics. Concomitant use increases the risk of seizures.

Sulfonylurea derivatives. Possible potentiation of effect.

Special precautions for use.

In patients with impaired liver function, as well as in those taking paracetamol for a prolonged period, regular liver function tests are recommended. If a patient is taking warfarin or similar anticoagulant agents, medical advice must be sought before using the drug. Patients who regularly take analgesics for mild forms of arthritis should consult a physician before using the medication.

In patients with severe infections such as sepsis, associated with reduced glutathione levels, the use of paracetamol may increase the risk of metabolic acidosis. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Immediate medical attention should be sought if these symptoms occur.

When paracetamol is used concomitantly with oral anticoagulants at high doses, prothrombin time should be monitored. Alcohol consumption should be avoided during treatment. Patients should be warned not to take other medications containing paracetamol simultaneously.

Paracetamol intake may affect laboratory test results for blood uric acid and glucose levels.

The drug should be used only under medical supervision in patients with impaired liver or kidney function.

Paracetamol is hepatotoxic at high doses (exceeding 6 g per day). However, hepatotoxic effects may also occur at significantly lower doses in cases of alcohol consumption, use of hepatic enzyme inducers, or other substances with hepatotoxic potential.

Caution is advised when paracetamol is used concomitantly with flucloxacillin due to an increased risk of high anion gap metabolic acidosis, particularly in patients with severe renal insufficiency, sepsis, malnutrition, or other causes of glutathione deficiency (e.g., chronic alcoholism), as well as when maximum daily doses of paracetamol are administered. Close monitoring of the patient is recommended, including measurement of urinary 5-oxoproline levels.

The initiation of treatment should be approached with caution (after consultation with a physician) in patients who have previously experienced elevated blood pressure, fluid retention, or edema during NSAID therapy.

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

Cardiovascular and cerebrovascular effects. Clinical trials and epidemiological data indicate that the use of ibuprofen, especially at high doses (2400 mg daily) and with prolonged treatment, may lead to arterial thrombotic complications (myocardial infarction or stroke). Overall, epidemiological data do not suggest that low-dose ibuprofen (below 1200 mg daily) increases the risk of myocardial infarction. Long-term treatment in patients with uncontrolled hypertension, congestive heart failure, diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be prescribed by a physician only after careful consideration. Long-term NSAID therapy in patients with significant cardiovascular risk factors (such as hypertension, hyperlipidemia, diabetes, smoking) should be prescribed only after thorough evaluation.

Cases of Kounis syndrome have been reported in patients receiving ibuprofen therapy. 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.

Bronchospasm may occur in patients with current bronchial asthma or allergic conditions, or with a history of bronchospasm.

Systemic lupus erythematosus and systemic connective tissue diseases increase the risk of aseptic meningitis.

Chronic inflammatory bowel diseases (ulcerative colitis, Crohn's disease) may be exacerbated.

Symptoms of elevated blood pressure and/or heart failure related to severe liver dysfunction may be intensified and/or fluid retention may occur.

Renal effects. Prolonged use of NSAIDs may lead to dose-dependent reduction in prostaglandin synthesis and may provoke renal failure. Patients at high risk include those with impaired kidney or liver function, heart disorders, those taking diuretics, and elderly patients. Renal function should be monitored in such patients.

Hepatic effects. Impaired liver function. Liver diseases increase the risk of liver damage from paracetamol. The risk of overdose is higher in patients with non-cirrhotic alcoholic liver disease.

Effects on female fertility. Limited data suggest that drugs inhibiting cyclooxygenase/prostaglandin synthesis may affect ovulation. However, this effect is reversible and ceases after discontinuation of treatment. Prolonged use of ibuprofen (doses of 2400 mg daily and treatment duration exceeding 10 days) may impair female fertility and is therefore not recommended for women attempting to conceive. This medication should be discontinued in women who are unable to conceive or undergoing infertility evaluation.

Gastrointestinal (GI) effects. NSAIDs should be used cautiously in patients with chronic inflammatory bowel diseases (e.g., ulcerative colitis, Crohn's disease), as these conditions may be exacerbated. Cases of gastrointestinal bleeding, perforation, and ulcers, which may be fatal, have been reported and may occur at any stage of NSAID therapy, regardless of the presence of warning symptoms or a history of severe GI disorders.

The risk of gastrointestinal bleeding, perforation, and ulcers increases with higher NSAID doses, particularly in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, and in elderly patients. Such patients should start treatment with the lowest possible doses. Caution is advised when treating patients receiving concomitant medications that may increase the risk of gastropathy or bleeding, such as oral corticosteroids or anticoagulants (e.g., warfarin) or antiplatelet agents (e.g., acetylsalicylic acid). For long-term treatment in these patients, as well as in patients requiring concomitant low-dose acetylsalicylic acid or other drugs increasing GI risk, combined therapy with misoprostol or proton pump inhibitors should be considered.

Patients with a history of gastrointestinal disorders, particularly elderly patients, should be informed about any unusual gastrointestinal symptoms (especially bleeding), particularly gastrointestinal bleeding at the beginning of treatment. If gastrointestinal bleeding or ulceration occurs in patients receiving ibuprofen, treatment should be discontinued immediately.

Skin and subcutaneous tissue. Serious skin adverse reactions (SSARs) have been reported with NSAID (ibuprofen) use, including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal (see section "Adverse reactions"). Most such reactions occur within the first month. If signs or symptoms suggestive of these reactions appear, ibuprofen should be discontinued immediately and alternative therapy considered (if necessary).

Prolonged and high-dose use of analgesics may lead to medication-overuse headache, which cannot be treated by increasing the drug dose. Long-term and uncontrolled use of analgesics may result in chronic kidney injury with risk of renal failure (analgesic nephropathy).

One capsule of this medication contains approximately the same amount of caffeine as a cup of coffee. When using Tetrаmol, intake of caffeine-containing medications, food, and beverages should be limited, as excessive caffeine may cause nervousness, irritability, insomnia, and occasionally tachycardia.

Consult a physician before using the medication.

If symptoms persist, consult a physician.

Do not take this medication simultaneously with other products containing paracetamol, ibuprofen, or caffeine.

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

Use during pregnancy or breastfeeding.

Contraindicated during pregnancy or breastfeeding.

From the 20th week of pregnancy, ibuprofen use may cause oligohydramnios due to fetal renal dysfunction. If ibuprofen is used for several days starting from the 20th week of pregnancy, antenatal monitoring for oligohydramnios may be advisable.

Ability to affect reaction speed when driving or operating machinery.

If adverse reactions affecting the nervous system occur during treatment, patients should refrain from driving or operating machinery.

Method of Administration and Dosage.

For adults and adolescents aged 16 years and older, take 1–2 capsules 4 times daily depending on the intensity of pain and physician's recommendation. The daily dose should not exceed 6 capsules. For children aged 12 to 16 years: 1 capsule 1–2 times daily. The capsule should be swallowed whole, without chewing, with sufficient fluid (a glass of water). The usual duration of treatment is 3–7 days. If no improvement occurs during this period, the treatment should be re-evaluated.

Maximum duration of use in children without medical consultation – 3 days.

The interval between doses should be at least 4 hours.

Do not exceed the recommended dose.

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

Children.

The drug should not be used in children under 12 years of age.

Overdose.

Prolonged use of high doses may lead to aplastic anemia, thrombocytopenia, pancytopenia, agranulocytosis, neutropenia, and leukopenia. High-dose intake may cause central nervous system (CNS) disturbances (dizziness, psychomotor agitation, disorientation and attention deficits, insomnia, tremor, nervousness, restlessness), and urinary system disorders – nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis).

In case of overdose, symptoms may include increased sweating, psychomotor agitation or CNS depression, drowsiness, impaired consciousness, cardiac arrhythmias, tachycardia, extrasystoles, tremor, hyperreflexia, and seizures.

Paracetamol overdose symptoms. Liver damage is possible in adults who have ingested 10 g or more of paracetamol, and in children who have ingested more than 150 mg/kg body weight. In patients with risk factors (chronic use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs inducing liver enzymes; alcohol abuse; glutathione system deficiency, e.g., due to malnutrition, HIV infection, fasting, cystic fibrosis, cachexia), ingestion of 5 g or more of paracetamol may lead to liver damage.

Within the first 24 hours: pallor, nausea, vomiting, anorexia, and abdominal pain, hepatonecrosis, elevated liver transaminase activity, and increased prothrombin index. Liver damage may become evident 12–48 hours after ingestion of excessive doses. Disturbances in glucose metabolism and metabolic acidosis, as well as hemorrhages, may occur. In severe poisoning, liver failure may progress to encephalopathy, coma, and may be fatal. Acute renal failure with acute tubular necrosis may develop even in the absence of severe kidney damage. Cardiac arrhythmias and pancreatitis have also been reported.

Treatment. Immediate medical assistance is required in case of overdose, even if symptoms are absent. Symptoms may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage. Activated charcoal treatment should be considered if the excessive paracetamol dose was taken within 1 hour. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier concentrations are unreliable).

Treatment with N-acetylcysteine may be administered within 24 hours after paracetamol ingestion, but maximum protective effect is achieved when administered within 8 hours after ingestion. The efficacy of the antidote decreases sharply after this time. If necessary, N-acetylcysteine should be administered intravenously according to current guidelines. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside the hospital.

Caffeine overdose symptoms. Large doses of caffeine may cause rapid breathing, extrasystoles, dizziness, mood disturbances, epigastric pain, vomiting, diuresis, tachycardia or cardiac arrhythmia, and CNS stimulation (insomnia, restlessness, excitement, anxiety, syndrome of increased neuromuscular excitability, headache, tremor, seizures, nervousness, and irritability). Clinically significant symptoms of caffeine overdose may also be associated with liver damage caused by paracetamol.

Treatment. No specific antidote is available. However, supportive measures such as the use of beta-adrenergic antagonists may alleviate cardiotoxic effects.

Ibuprofen intoxication symptoms. In most patients participating in clinical trials, ingestion of a large amount of NSAIDs caused only nausea, vomiting, epigastric pain, or very rarely diarrhea. Tinnitus, headache, and gastrointestinal bleeding may also occur. In more severe poisoning, toxic CNS effects such as drowsiness, occasionally nervous agitation and disorientation, or coma may develop. Seizures are sometimes observed. Metabolic acidosis may occur in severe poisoning; prothrombin index may be elevated, possibly due to effects on blood clotting factors. Acute renal failure and liver damage may also occur. In patients with bronchial asthma, disease exacerbation may be observed. Doses exceeding 400 mg/kg in children may cause intoxication symptoms. In adults, the dose effect is less pronounced. The elimination half-life in overdose is 1.5–3 hours.

Treatment may be symptomatic and supportive, including airway management and monitoring of cardiac symptoms and vital signs until stabilization. Oral activated charcoal is recommended within 1 hour after ingestion of a potentially toxic dose. In cases of frequent or prolonged seizures, intravenous diazepam or lorazepam should be administered. Bronchodilators should be used for bronchial asthma treatment.

Adverse Reactions

The adverse reactions listed below are categorized according to MedDRA terminology.

Immune system disorders: hypersensitivity reactions such as urticaria and pruritus; severe hypersensitivity reactions including facial, tongue, and laryngeal edema, dyspnea, tachycardia, arrhythmia, hypotension or hypertension, anaphylaxis, Quincke's edema, hepatorenal syndrome, exacerbation of bronchial asthma, and bronchospasm.

Nervous system disorders: headache, dizziness, irritability, nervousness, depression, drowsiness, insomnia, anxiety, psychomotor agitation, emotional lability, seizures, paresthesia, aseptic meningitis; individual symptoms of which (nuchal rigidity, headache, nausea, vomiting, fever, or disorientation) may occur in patients with pre-existing autoimmune diseases such as systemic lupus erythematosus or mixed connective tissue disease.

Blood and lymphatic system disorders: hematopoietic disorders, agranulocytosis, anemia (including hemolytic and aplastic), decreased hematocrit and hemoglobin levels, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), leukopenia, neutropenia, pancytopenia, thrombocytopenia. Initial signs include: high fever, sore throat, oral ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding, and bruising.

Gastrointestinal disorders: abdominal pain, heartburn, ulcerative stomatitis, dyspepsia, and nausea; diarrhea, flatulence, constipation, and vomiting; pancreatitis, duodenitis, esophagitis, gastritis, peptic ulcer, gastrointestinal perforation, or gastrointestinal bleeding, which in some cases may lead to fatal outcomes, especially in elderly patients; exacerbation of ulcerative colitis and Crohn's disease.

Renal and urinary system disorders: acute renal failure; renal colic; papillary necrosis, particularly with prolonged use, associated with increased blood urea nitrogen and edema; cystitis; hematuria; interstitial nephritis; nephrotic syndrome; oliguria; polyuria; tubular necrosis; glomerulonephritis; sterile pyuria.

Sensory organ disorders: hearing disturbances, hearing loss, tinnitus, blurred vision, color vision disturbances, toxic amblyopia.

Respiratory system disorders: bronchospasm in patients hypersensitive to aspirin and other NSAIDs.

Cardiac disorders: heart failure, edema, Kounis syndrome.

Vascular disorders: arterial thrombosis (myocardial infarction or stroke).

Endocrine disorders and metabolic changes: hypoglycemia, up to hypoglycemic coma; decreased appetite; dryness of the mucous membranes of the eyes and mouth; rhinitis.

Hepatic disorders: liver dysfunction; elevated liver enzyme activity, hepatonecrosis (dose-dependent effect); liver failure during long-term treatment; hepatitis and jaundice may also occur.

Skin and subcutaneous tissue disorders: allergic skin reactions, rash, purpura, skin desquamation, pruritus, alopecia, photosensitivity; angioneurotic edema; severe skin adverse reactions (SSARs) (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis); drug-induced eosinophilia with systemic symptoms (DRESS syndrome); acute generalized exanthematous pustulosis (AGEP). If these symptoms occur, the patient must discontinue TETRAMOL immediately and seek medical attention without delay.

General disorders: malaise and fatigue.

Concomitant use of the medication at recommended doses with products containing caffeine may enhance caffeine-related adverse effects such as:

Psychiatric disorders: headache, dizziness, increased excitability, anxiety, irritability, tachycardia, restlessness, insomnia due to CNS stimulation;

Gastrointestinal tract: nausea caused by gastrointestinal irritation.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

6 capsules in blisters.

6 capsules per blister; 5 blisters per cardboard box.

10 capsules per blister; 3 blisters per cardboard box.

6 capsules per blister; 5 blisters per cardboard box; 10 cardboard boxes per cardboard carton.

Release category. Over-the-counter (without prescription).

Manufacturer.

JSC "Grindeks".

JSC "Grindeks".

Manufacturer's address and place of business.

53 Krustpils str., Riga, LV-1057, Latvia.

53 Krustpils str., Riga, LV-1057, Latvia.

INSTRUCTIONS

for medical use of the medicinal product

TETRAMOL

(TETRAMOL)

Composition:

Active ingredients: paracetamol, ibuprofen, caffeine;

1 capsule contains paracetamol 325 mg, ibuprofen 200 mg, caffeine 30 mg;

Excipients: talc, colloidal anhydrous silicon dioxide, sodium lauryl sulfate, gelatin, candurin (titanium dioxide (E 171), potassium aluminosilicate (E 555)).

Pharmaceutical form. Capsules.

Main physicochemical properties: Hard gelatin capsules. The capsule body and cap are white, pearly. The capsule contents are a white crystalline and amorphous powder mixture. The presence of lumps is acceptable.

Pharmacotherapeutic group: Non-steroidal anti-inflammatory and antirheumatic agents. Paracetamol combinations without psychotropic agents. ATC code N02BE51.

Pharmacological Properties.

Pharmacodynamics.

A combined medicinal product, whose action is determined by the components included in its composition. The drug exerts analgesic (pain-relieving), anti-inflammatory, and antipyretic effects. It inhibits the synthesis of prostaglandins. It reduces joint pain at rest and during movement, decreases morning stiffness and joint swelling, and promotes an increase in range of motion.

Caffeine enhances the analgesic effect of ibuprofen and paracetamol, improves physical performance, and reduces fatigue and drowsiness.

Pharmacokinetics.

Paracetamol

Paracetamol is rapidly and almost completely absorbed in the gastrointestinal tract (GI tract). Maximum plasma concentration is reached within 30–60 minutes after administration, and the plasma half-life ranges from 1 to 4 hours after therapeutic doses. In cases of severe hepatic insufficiency, the half-life increases to 5 hours. In renal insufficiency, the half-life does not increase; however, since renal excretion is reduced, the dose of paracetamol should be decreased.

Paracetamol penetrates the blood-brain barrier and is also excreted into breast milk of lactating women.

Ibuprofen

Ibuprofen is rapidly absorbed from the gastrointestinal tract after administration. Maximum plasma concentration is achieved within 45 minutes after intake, while peak concentration in synovial fluid occurs 3 hours after administration. Ibuprofen is metabolized in the liver and excreted by the kidneys in unchanged form and as metabolites. The elimination half-life is approximately 2 hours.

Caffeine

After oral administration, caffeine is rapidly absorbed. Maximum plasma concentrations are reached approximately within 20–60 minutes, and the elimination half-life is approximately 4 hours.

Clinical characteristics.

Indications

Pain of varying intensity:

• dysmenorrhea and menstrual pain;
• headache;
• neuralgia;
• myalgia;
• arthralgia;
• toothache.

Elevated temperature (fever in influenza and colds).

As part of complex therapy for postoperative pain, and for alleviating symptoms of rheumatoid arthritis and osteoarthritis.

Contraindications

Hypersensitivity to paracetamol, ibuprofen, caffeine, or any other component of the drug; peptic ulcer disease, including in medical history (two or more distinct episodes of peptic ulcer exacerbation or bleeding); gastrointestinal bleeding or perforation in history associated with previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs); acute pancreatitis; severe hepatic and/or renal dysfunction; congenital hyperbilirubinemia; glucose-6-phosphate dehydrogenase deficiency; alcoholism; blood disorders; severe anemia; leukopenia; thrombosis; thrombophlebitis; states of increased excitation; sleep disorders; severe arterial hypertension; organic cardiovascular diseases; closed-angle glaucoma; epilepsy; hyperthyroidism; decompensated heart failure; cardiac conduction disorders; severe atherosclerosis; predisposition to vascular spasm; ischemic heart disease; prostate hypertrophy; severe forms of diabetes mellitus; allergic reactions (e.g., bronchial asthma, rhinitis, Quincke's edema) following administration of acetylsalicylic acid or other NSAIDs; concomitant use of the drug with NSAIDs; advanced age of the patient.

Do not use concurrently with monoamine oxidase inhibitors (MAOIs), cyclooxygenase-2 inhibitors, or within 2 weeks after discontinuation of such therapy; contraindicated in patients taking tricyclic antidepressants or beta-blockers. Gilbert's syndrome. Patient age under 12 years. Contraindicated during pregnancy or breastfeeding.

Interaction with other medicinal products and other types of interactions

Concomitant use of paracetamol with metoclopramide or domperidone may enhance paracetamol absorption, while cholestyramine may reduce absorption.

Long-term continuous use of paracetamol may potentiate the anticoagulant effect of warfarin and other coumarins, increasing the risk of bleeding.

NSAIDs may enhance the effect of anticoagulants such as warfarin and reduce the efficacy of antihypertensive agents or diuretics.

Concomitant use of other NSAIDs increases the risk of adverse effects.

Corticosteroids may increase the risk of gastrointestinal adverse reactions.

Drug intake may lead to increased serum lithium concentration.

Concomitant use with methotrexate may result in toxicity.

Barbiturates reduce the antipyretic effect of paracetamol.

Anticonvulsants (including phenytoin, barbiturates, carbamazepine), which stimulate hepatic microsomal enzyme activity, may enhance the hepatotoxic effect of paracetamol due to increased formation of hepatotoxic metabolites. Concomitant use of paracetamol with hepatotoxic agents increases the hepatotoxic effect of the drugs. Concurrent use of high-dose paracetamol with isoniazid increases the risk of hepatotoxic syndrome. Paracetamol reduces the effectiveness of diuretics. Do not use concurrently with alcohol.

Caution is advised when using paracetamol concomitantly with flucloxacillin, as such combination has been associated with metabolic acidosis with high anion gap, especially in patients with risk factors (see section "Special precautions").

Concomitant use of caffeine with MAO inhibitors may cause dangerous elevation of blood pressure. Caffeine enhances the effect (improves bioavailability) of analgesic-antipyretic agents, potentiates the effects of xanthine derivatives, alpha- and beta-adrenergic agonists, and psychostimulants.

Cimetidine, hormonal contraceptives, and isoniazid enhance the effect of caffeine. Caffeine reduces the effect of opioid analgesics, anxiolytics, hypnotics, and sedatives; it acts as an antagonist to anesthetics and other agents that depress the central nervous system (CNS), and as a competitive antagonist to adenosine and ATP preparations. Concomitant use of caffeine with ergotamine improves ergotamine absorption from the gastrointestinal tract; with thyroid-stimulating agents, it enhances thyroid effect. Caffeine reduces lithium concentration in blood.

Do not use in combination with:

acetylsalicylic acid, unless a lower dose of acetylsalicylic acid (not exceeding 75 mg per day) has been prescribed by a physician, as this may lead to adverse effects;

NSAIDs. Since this may lead to increased frequency of adverse effects.

Use ibuprofen with caution in combination with:

antihypertensive agents (ACE inhibitors and angiotensin II antagonists) and diuretics: NSAIDs may reduce the efficacy of diuretics and other antihypertensive drugs. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with reduced renal function), concomitant use of ACE inhibitors or angiotensin II antagonists with cyclooxygenase-inhibiting agents may further deteriorate renal function, including possible acute renal failure, which is usually reversible. Therefore, such combinations should be prescribed cautiously, especially in elderly patients. In case of long-term treatment, adequate hydration should be ensured, and monitoring of renal function should be considered at the beginning of combined therapy and periodically thereafter. NSAIDs may reduce the therapeutic effect of these agents. Diuretics may increase the risk of nephrotoxic effects of NSAIDs.

Anticoagulants. NSAIDs may enhance the therapeutic effect of anticoagulants such as warfarin.

Antiplatelet agents and selective serotonin reuptake inhibitors. Increased risk of gastrointestinal bleeding.

Cardiac glycosides. May exacerbate heart failure, reduce glomerular filtration rate, and increase plasma levels of glycosides.

Cyclosporines. Some data suggest a possible interaction increasing the risk of nephrotoxicity.

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

Tacrolimus. Increased risk of nephrotoxicity.

Lithium and methotrexate. Evidence suggests potential elevation of lithium and methotrexate plasma levels.

Zidovudine. Evidence suggests increased risk of hemarthrosis and hematoma in HIV-infected patients receiving concomitant zidovudine and ibuprofen therapy.

Quinolone antibiotics. Concomitant use increases the risk of seizures.

Sulfonylurea group agents. Possible potentiation of effect.

Special precautions for use.

In patients with impaired liver function, as well as in those taking paracetamol for prolonged periods, regular liver function tests are recommended. If a patient is taking warfarin or similar anticoagulant agents, medical advice should be sought before using the drug. Patients who take analgesics daily for mild forms of arthritis should consult a physician before using the medication.

In patients with severe infections such as sepsis, which are associated with reduced glutathione levels, paracetamol intake may increase the risk of metabolic acidosis. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Immediate medical attention should be sought if these symptoms occur.

When oral anticoagulants are used concomitantly with high doses of paracetamol, prothrombin time should be monitored. Alcohol consumption should be avoided during treatment. Patients should be warned not to take other medications containing paracetamol simultaneously.

Paracetamol intake may affect laboratory test results for blood uric acid and glucose levels.

The drug should be used only under medical supervision in patients with impaired liver or kidney function.

Paracetamol is hepatotoxic at high doses (exceeding 6 g per day). However, adverse effects on the liver may also occur at significantly lower doses, particularly in cases of alcohol consumption, use of hepatic enzyme inducers, or other substances toxic to the liver.

Caution is advised when using paracetamol concomitantly with flucloxacillin due to an increased risk of metabolic acidosis with a high anion gap, especially in patients with severe renal insufficiency, sepsis, malnutrition, or other causes of glutathione deficiency (e.g., chronic alcoholism), as well as when maximum daily doses of paracetamol are administered. Close monitoring of the patient's condition is recommended, including measurement of urinary 5-oxoproline levels.

The initiation of treatment should be done cautiously (after consultation with a physician) in patients who have previously experienced elevated blood pressure, fluid retention, or edema during treatment with NSAIDs.

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to treat symptoms.

Cardiovascular and cerebrovascular effects. Clinical trials and epidemiological data indicate that the use of ibuprofen, particularly at high doses (2400 mg daily) and with prolonged treatment, may lead to arterial thrombotic complications (myocardial infarction or stroke). Overall, epidemiological data do not suggest that low-dose ibuprofen (below 1200 mg daily) increases the risk of myocardial infarction. Long-term treatment in patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be prescribed by a physician only after careful assessment. Long-term treatment with NSAIDs should be prescribed to patients with significant cardiovascular risk factors (such as hypertension, hyperlipidemia, diabetes, smoking) only after thorough consideration.

Cases of Kounis syndrome have been reported in patients receiving ibuprofen treatment. 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.

Bronchospasm may occur in patients with current bronchial asthma or allergic disorders, or with a history of bronchospasm.

Systemic lupus erythematosus and systemic connective tissue diseases increase the risk of aseptic meningitis.

Chronic inflammatory bowel diseases (ulcerative colitis, Crohn's disease) may worsen.

Symptoms of elevated blood pressure and/or heart failure due to severe liver dysfunction may intensify and/or fluid retention may occur.

Renal effects. Prolonged use of NSAIDs may lead to dose-dependent reduction in prostaglandin synthesis and provoke kidney failure. Patients at high risk include those with impaired kidney function, heart disorders, liver dysfunction, those taking diuretics, and elderly patients. Kidney function should be monitored in such patients.

Hepatic effects. Impaired liver function. Liver disease increases the risk of liver damage from paracetamol. The risk of overdose is higher in patients with non-cirrhotic alcoholic liver disease.

Effects on female fertility. Limited data suggest that drugs inhibiting cyclooxygenase/prostaglandin synthesis may affect ovulation. However, this effect is reversible and ceases after treatment ends. Long-term use (doses of 2400 mg daily and treatment duration exceeding 10 days) of ibuprofen may impair female fertility and is therefore not recommended for women trying to conceive. This medication should be discontinued in women who are unable to conceive or undergoing infertility evaluation.

Gastrointestinal (GI) effects. NSAIDs should be used cautiously in patients with chronic inflammatory bowel diseases (e.g., ulcerative colitis, Crohn's disease), as these conditions may worsen. Cases of gastrointestinal bleeding, perforation, and ulcers, which may be fatal, have been reported and can occur at any stage of NSAID treatment, regardless of prior warning symptoms or history of severe GI disorders.

The risk of gastrointestinal bleeding, perforation, and ulcers increases with higher NSAID doses, particularly in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, and in elderly patients. These patients should start treatment with the lowest possible doses. Caution is advised when treating patients receiving concomitant medications that may increase the risk of gastropathy or bleeding, such as oral corticosteroids or anticoagulants (e.g., warfarin) or antiplatelet agents (e.g., acetylsalicylic acid). For long-term treatment in these patients, as well as in those requiring concomitant low-dose acetylsalicylic acid or other drugs increasing GI risk, combined therapy with misoprostol or proton pump inhibitors should be considered.

Patients with a history of gastrointestinal disorders, particularly elderly patients, should be informed about any unusual GI symptoms (especially bleeding), particularly gastrointestinal bleeding at the beginning of treatment. If gastrointestinal bleeding or ulcers occur in patients receiving ibuprofen, treatment should be discontinued immediately.

Skin and subcutaneous tissue. Severe skin adverse reactions (SSARs), including exfoliative dermatitis, Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug-induced eosinophilia with systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP), have been reported with NSAID (ibuprofen) use, which may be life-threatening or fatal (see section "Adverse reactions"). Most such reactions occur within the first month. If signs or symptoms suggestive of these reactions appear, ibuprofen should be discontinued immediately and alternative treatment considered (if necessary).

Prolonged use of analgesics in high doses may cause headache that cannot be treated by increasing the drug dose. Long-term and uncontrolled use of analgesics may lead to chronic kidney damage with a risk of kidney failure (analgesic nephropathy).

One capsule of this medication contains approximately the same amount of caffeine as a cup of coffee. When using Tetramol, intake of caffeine-containing medications, food, and beverages should be limited, as excessive caffeine may cause nervousness, irritability, insomnia, and sometimes tachycardia.

Consult a physician before using the medication.

If symptoms persist, consult a physician.

Do not take the medication simultaneously with other products containing paracetamol, ibuprofen, or caffeine.

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

Use during pregnancy or breastfeeding.

Contraindicated during pregnancy or breastfeeding.

Starting from the 20th week of pregnancy, ibuprofen use may cause oligohydramnios due to fetal kidney dysfunction. If ibuprofen is used for several days starting from the 20th week of pregnancy, antenatal monitoring for oligohydramnios may be advisable.

Ability to influence reaction speed when driving or operating machinery.

If adverse reactions affecting the nervous system occur during treatment with the medication, patients should refrain from driving vehicles or operating machinery.

Dosage and Administration

For adults and adolescents aged 16 years and older: take 1–2 capsules 4 times daily, depending on the severity of pain and physician's recommendation. The daily dose should not exceed 6 capsules. For children aged 12 to 16 years: 1 capsule 1–2 times daily. The capsule should be taken whole, without chewing, and swallowed with sufficient fluid (a glass of water). The usual duration of treatment is 3–7 days. If no improvement occurs during this period, the treatment regimen should be reassessed.

Maximum duration of use in children without prior medical consultation is 3 days.

The interval between doses should be at least 4 hours.

Do not exceed the recommended dose.

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

Children.

The drug should not be administered to children under 12 years of age.

Overdose.

Prolonged use of high doses may lead to aplastic anemia, thrombocytopenia, pancytopenia, agranulocytosis, neutropenia, and leukopenia. High-dose intake may also cause central nervous system (CNS) disturbances (dizziness, psychomotor agitation, disorientation and attention deficits, insomnia, tremor, nervousness, anxiety), and urinary system disorders – nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis).

In cases of overdose, symptoms may include increased sweating, psychomotor agitation or CNS depression, drowsiness, impaired consciousness, cardiac arrhythmias, tachycardia, extrasystoles, tremor, hyperreflexia, and seizures.

Paracetamol overdose symptoms. Liver damage is possible in adults who have ingested 10 g or more of paracetamol, and in children who have received more than 150 mg/kg body weight. In patients with risk factors (chronic use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs inducing liver enzymes; alcohol abuse; glutathione system deficiency, e.g., due to gastrointestinal disorders, HIV infection, fasting, cystic fibrosis, or cachexia), ingestion of 5 g or more of paracetamol may result in liver damage.

Within the first 24 hours: pallor, nausea, vomiting, anorexia, and abdominal pain; hepatonecrosis; elevated liver transaminase activity; prolonged prothrombin index. Liver injury may become evident 12–48 hours after ingestion of excessive doses. Glucose metabolism disturbances and metabolic acidosis, as well as hemorrhages, may occur. In severe poisoning, liver failure may progress to encephalopathy, coma, and may be fatal. Acute renal failure with acute tubular necrosis may develop even in the absence of severe kidney damage. Cardiac arrhythmias and pancreatitis have also been reported.

Treatment. Immediate medical assistance is required in case of overdose, even if overdose symptoms are not present. Symptoms may be limited to nausea and vomiting and may not reflect the severity of overdose or risk of organ damage. Activated charcoal should be considered if the excessive paracetamol dose was ingested within the past hour. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier concentrations are unreliable).

Treatment with N-acetylcysteine may be administered within 24 hours after paracetamol ingestion, but maximum protective effect is achieved when administered within 8 hours after ingestion. The efficacy of the antidote decreases sharply after this time. If required, N-acetylcysteine should be administered intravenously according to current guidelines. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside hospital settings.

Caffeine overdose symptoms. High doses of caffeine may cause rapid breathing, extrasystoles, dizziness, affective disturbances, epigastric pain, vomiting, diuresis, tachycardia or cardiac arrhythmia, and CNS stimulation (insomnia, restlessness, excitement, anxiety, increased neuromuscular excitability, headache, tremor, seizures, nervousness, and irritability). Clinically significant caffeine overdose symptoms may also be associated with paracetamol-induced liver damage.

Treatment. No specific antidote is available. However, supportive measures such as administration of beta-adrenergic antagonists may help alleviate cardiotoxic effects.

Ibuprofen intoxication symptoms. In most patients participating in clinical trials, ingestion of large amounts of NSAIDs caused only nausea, vomiting, epigastric pain, or very rarely diarrhea. Tinnitus, headache, and gastrointestinal bleeding may also occur. In more severe intoxication, toxic CNS effects may manifest as drowsiness, occasionally nervous agitation, disorientation, or coma. Seizures may occasionally be observed. Severe intoxication may lead to metabolic acidosis; prothrombin index may be elevated, possibly due to effects on blood coagulation factors. Acute renal failure and liver damage may also occur. In patients with bronchial asthma, disease exacerbation may be observed. Doses exceeding 400 mg/kg in children may cause intoxication symptoms. In adults, the dose effect is less pronounced. The elimination half-life in overdose is 1.5–3 hours.

Treatment may be symptomatic and supportive, including airway management and monitoring of cardiac symptoms and vital signs until stabilization. Oral administration of activated charcoal is recommended within 1 hour after ingestion of a potentially toxic amount of the drug. Intravenous diazepam or lorazepam should be administered in cases of frequent or prolonged seizures. Bronchodilators should be used for managing bronchial asthma.

Side effects

The following adverse reactions to the medicinal product are categorized according to MedDRA terminology.

Immune system disorders: hypersensitivity reactions such as urticaria and itching; severe hypersensitivity reactions including facial, tongue, and laryngeal swelling, dyspnea, tachycardia, arrhythmia, hypotension or hypertension, anaphylaxis, Quincke's edema (angioedema), hepatorenal syndrome, exacerbation of bronchial asthma, and bronchospasm.

Nervous system disorders: headache, dizziness, irritability, nervousness, depression, drowsiness, insomnia, anxiety, psychomotor agitation, emotional lability, convulsions, paresthesia, aseptic meningitis. Some of its symptoms (nuchal rigidity, headache, nausea, vomiting, fever, or disorientation) may occur in patients with pre-existing autoimmune diseases such as systemic lupus erythematosus or mixed connective tissue disease.

Blood and lymphatic system disorders: blood dyscrasias, agranulocytosis, anemia (including hemolytic and aplastic anemia), decreased hematocrit and hemoglobin levels, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), leukopenia, neutropenia, pancytopenia, thrombocytopenia. Initial signs include high fever, sore throat, oral ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding, and bruising.

Gastrointestinal disorders: abdominal pain, heartburn, ulcerative stomatitis, dyspepsia, and nausea; diarrhea, flatulence, constipation, and vomiting; pancreatitis, duodenitis, esophagitis, gastritis, peptic ulcer, gastrointestinal perforation, or gastrointestinal bleeding, which in some cases may lead to fatal outcomes, especially in elderly patients; exacerbation of ulcerative colitis and Crohn’s disease.

Renal and urinary system disorders: acute renal failure; renal colic; papillary necrosis, particularly with prolonged use, associated with increased blood urea levels and edema; cystitis; hematuria; interstitial nephritis; nephrotic syndrome; oliguria; polyuria; tubular necrosis; glomerulonephritis; sterile pyuria.

Sensory organ disorders: hearing disturbances, hearing loss, tinnitus or ringing in the ears, blurred vision, color vision disturbances, toxic amblyopia.

Respiratory system disorders: bronchospasm in patients sensitive to aspirin and other NSAIDs.

Cardiac disorders: heart failure, edema, Kounis syndrome.

Vascular disorders: arterial thrombosis (myocardial infarction or stroke).

Endocrine disorders and metabolic changes: hypoglycemia, up to hypoglycemic coma; decreased appetite; dryness of the mucous membranes of the eyes and mouth; rhinitis.

Hepatic disorders: liver dysfunction; elevated liver enzyme activity, hepatonecrosis (a dose-dependent effect); hepatic failure during long-term treatment; hepatitis and jaundice may occur.

Skin and subcutaneous tissue disorders: skin allergic reactions, rash, purpura, skin desquamation, pruritus, alopecia, photosensitivity; angioneurotic edema; severe skin adverse reactions (SSARs) (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis); drug-induced eosinophilia with systemic symptoms (DRESS syndrome); acute generalized exanthematous pustulosis (AGEP). If any of these symptoms occur, the patient must discontinue taking Tetramol and seek immediate medical attention.

General disorders: malaise and fatigue.

Concomitant use of the medicinal product at recommended doses with caffeine-containing products may enhance caffeine-related side effects such as:

Psychiatric disorders: headache, dizziness, increased excitability, anxiety, restlessness, tachycardia, nervousness, insomnia due to CNS stimulation;

Gastrointestinal tract: nausea caused by gastrointestinal irritation.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

6 capsules in blisters.

6 capsules per blister; 5 blisters per cardboard box.

10 capsules per blister; 3 blisters per cardboard box.

6 capsules per blister; 5 blisters per cardboard box; 10 cardboard boxes per cardboard carton.

Supply category. Over-the-counter (without prescription).

Manufacturer.

Dragenopharm Apoteker Pueschl GmbH.

Dragenopharm Apoteker Pueschl GmbH.

Manufacturer's address and place of business.

Goellstrasse 1, Tittmoning, Bavaria, 84529, Germany.