Citramon maxi®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CITRAMON MAXI® (Citramon MAXI)

Composition:

Active substances: paracetamol, caffeine, acetylsalicylic acid;

One tablet contains: paracetamol 250 mg, caffeine 65 mg, acetylsalicylic acid 250 mg;

Excipients: hydroxypropylcellulose low-substituted, citric acid anhydrous, pregelatinized starch, microcrystalline cellulose, stearic acid.

Pharmaceutical form. Tablets.

Main physicochemical properties: elongated tablets with a biconvex surface, white or almost white in color. Grayish specks may be present.

Pharmacotherapeutic group. Analgesics. Other analgesics and antipyretics. Acetylsalicylic acid, combinations without psychotropic agents. ATC code N02B A51.

Pharmacological properties.

Pharmacodynamics.

The medicinal product exerts analgesic, antipyretic, and anti-inflammatory effects. The components contained in the medicinal product enhance each other's effects.

The antipyretic effect of acetylsalicylic acid is mediated via the central nervous system by inhibiting the synthesis of prostaglandins PGF2 in the hypothalamus in response to the action of endogenous pyrogens. The analgesic effect has both peripheral and central origins: the peripheral effect results from inhibition of prostaglandin synthesis in inflamed tissues; the central effect results from action on hypothalamic centers. Acetylsalicylic acid also reduces platelet aggregation.

Paracetamol exerts analgesic, antipyretic, and very weak anti-inflammatory effects, which are related to its action on the thermoregulatory center in the hypothalamus and its weak ability to inhibit prostaglandin synthesis in peripheral tissues.

Caffeine stimulates the central nervous system. It also enhances positive conditioned reflexes, stimulates motor activity, reduces the effects of sedatives and narcotic substances, and enhances the effects of analgesics and antipyretic agents.

Pharmacokinetics.

Acetylsalicylic acid

Rapidly and completely absorbed after oral administration. It is predominantly hydrolyzed in the gastrointestinal tract, liver, and blood to salicylate, which is then metabolized primarily in the liver.

Paracetamol

After oral administration, paracetamol is absorbed in the gastrointestinal tract, and peak plasma concentrations are reached within 30–120 minutes. Paracetamol is metabolized in the liver and is excreted mainly in the urine as glucuronide and sulfate conjugates. Less than 5% is excreted as unchanged paracetamol. The elimination half-life is 1–4 hours. At usual therapeutic concentrations, plasma protein binding is insignificant but proportional to increasing concentrations.

A minor hydroxylated metabolite, normally formed in the liver in very small amounts and detoxified primarily by conjugation with hepatic glutathione, may accumulate in cases of paracetamol overdose and cause liver damage.

Caffeine

Maximum caffeine concentration is observed between 5 and 90 minutes after administration of Citramon Maxi**®** on an empty stomach. Data on its presystemic metabolism are lacking. In adult patients, caffeine is almost completely metabolized in the liver, and its elimination rate is individual. The mean elimination half-life from plasma is 4.9 hours, with a range of 1.9–12.2 hours. Caffeine is uniformly distributed in all body fluids. Plasma protein binding averages 35%.

Caffeine is almost entirely metabolized via oxidation, demethylation, and acetylation, and is excreted in the urine. The main metabolites are 1-methylxanthine, 7-methylxanthine, and 1,7-dimethylxanthine (paraxanthine). Among minor metabolites are 1-methyluric acid and 5-acetylamino-6-formylamino-3-methyluracil (AMFU).

The medicinal product contains a low concentration of the three active substances, thus avoiding saturation of elimination processes with the associated risks of prolonged half-life and toxicity. Pharmacokinetic data for the fixed combination of acetylsalicylic acid, paracetamol, and caffeine correspond to the pharmacokinetic profiles established for each substance individually or for the combination of each analgesic with caffeine. Critical drug interactions between acetylsalicylic acid, paracetamol, and caffeine, or an increased risk of interactions with other medicinal products upon concomitant use, remain unknown.

Clinical characteristics.

Indications.

Emergency treatment of headache and migraine attacks with or without aura.

Contraindications.

• Hypersensitivity to components of the drug, hypersensitivity to other xanthine derivatives (theophylline, theobromine), or to other salicylates;
• Bronchial asthma, urticaria, or rhinitis induced by salicylates or other NSAIDs in medical history;
• Congenital hyperbilirubinemia, severe renal or hepatic insufficiency, Gilbert’s syndrome, congenital glucose-6-phosphate dehydrogenase deficiency;
• Severe renal insufficiency or impaired kidney function (GFR < 30 mL/min/1.73 m²);
• Blood disorders, hemophilia, hemorrhagic diathesis, hypoprothrombinemia, anemia, leukopenia, increased tendency to bleeding, thrombosis, thrombophlebitis, hemorrhagic diseases;
• Active gastrointestinal ulcers, gastrointestinal bleeding, surgical procedures associated with significant blood loss;
• Severe cardiovascular diseases, including arrhythmias, paroxysmal tachycardia, marked atherosclerosis, severe form of ischemic heart disease, pronounced heart failure, acute myocardial infarction, severe arterial hypertension, portal hypertension, predisposition to vascular spasm;
• Conditions of increased excitability, sleep disorders, elderly age, alcoholism, glaucoma, hyperthyroidism, acute pancreatitis, prostatic hypertrophy, severe forms of diabetes mellitus;
• Third trimester of pregnancy;
• Concomitant use with monoamine oxidase inhibitors (MAOIs), as well as within 2 weeks after discontinuation of MAOIs;
• Combination with methotrexate at doses of 15 mg/week or higher.

Interaction with other medicinal products and other forms of interactions.

Possible interactions of active substances.

Acetylsalicylic acid (ASA)

Paracetamol

Caffeine

Effect on laboratory test results:

• The use of high doses of acetylsalicylic acid may affect the results of several clinical chemistry laboratory tests.
• The use of paracetamol may affect the results of uric acid determination when the analysis is performed using phosphotungstic acid reagent, and the results of glycemia determination when the analysis is performed using glucose oxidase/peroxidase method.
• Caffeine may counteract the effect of dipyridamole on myocardial blood flow and thus affect the results of this test. It is recommended to discontinue caffeine intake 24 hours before starting this test.

Special precautions for use

Before using the medicinal product, consult a physician.

Do not exceed the recommended doses of the medicinal product. For short-term use only.

Combined preparations containing acetylsalicylic acid, paracetamol, and caffeine should not be used concomitantly with other NSAIDs or specific cyclooxygenase-2 inhibitors, as this may increase the risk of adverse reactions.

Patients with hepatic or renal functional impairment require either a reduced dose or an increased interval between doses. In patients with impaired renal or liver function, the dosing interval should be no less than 8 hours.

During prolonged use of the medicinal product, occult blood in the stool should be monitored to detect potential ulcerogenic effects.

Alcoholic beverages should be avoided during treatment with Citramon Maxi® because alcohol in combination with paracetamol may cause liver damage.

Cases of hepatic dysfunction/failure have been reported in patients with reduced glutathione levels, such as those suffering from severe infections (e.g. sepsis), anorexia, low body mass index, or chronic alcohol abuse.

Caution is required when paracetamol is used concomitantly with flucloxacillin due to an increased risk of high anion gap metabolic acidosis, particularly in patients with severe renal impairment, 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 patients is recommended, including measurement of urinary 5-oxoproline levels.

The use of medicinal products containing acetylsalicylic acid during surgical procedures (including dental surgery) increases the risk of bleeding or exacerbation of bleeding due to the inhibition of platelet aggregation, which persists for some time after administration of acetylsalicylic acid. The medicinal product should be discontinued 4–8 days prior to surgery to reduce the risk of excessive bleeding.

Patients should inform their physician in advance about the use of Citramon Maxi®.

Citramon Maxi® may cause bronchospasm and induce asthma exacerbations (so-called analgesic intolerance or analgesic-induced asthma) or other hypersensitivity reactions.

Bronchospasm or asthma attacks may occur in patients with allergic conditions, including bronchial asthma, allergic rhinitis, urticaria, pruritus, mucosal edema, nasal polyposis, especially when combined with chronic respiratory tract infections, or in patients with hypersensitivity to nonsteroidal anti-inflammatory drugs. Therefore, NSAIDs are contraindicated in these patients.

Acetylsalicylic acid, a component of the medicinal product, may reduce the excretion of uric acid from the body, potentially triggering an acute attack of gout.

During treatment with the medicinal product, excessive consumption of caffeine-containing beverages (e.g. coffee, tea) is not recommended, as this may cause sleep disturbances, tremor, feelings of tension, irritability, and retrosternal discomfort due to palpitations.

Citramon Maxi® should not be taken concomitantly with anticoagulants or other medicinal products that inhibit platelet aggregation without medical supervision. Patients with coagulation disorders should be closely monitored. The product should be used with caution in cases of metrorrhagia or menorrhagia.

Patients should be warned not to take other medicinal products containing paracetamol simultaneously, due to the risk of severe liver damage in case of overdose. The risk of paracetamol toxicity may be increased in patients receiving other potentially hepatotoxic medicinal products or drugs that induce hepatic microsomal enzymes (e.g. rifampicin, isoniazid, chloramphenicol, sedatives, and antiepileptic drugs including phenobarbital, phenytoin, and carbamazepine).

The medicinal product may affect laboratory test results for blood glucose and uric acid levels.

The medicinal product should not be used without medical consultation for more than 5 days as an analgesic or more than 3 days as an antipyretic.

Acetylsalicylic acid may affect thyroid function test results by causing falsely low concentrations of levothyroxine (T4) or triiodothyronine (T3).

The medicinal product should not be used in patients who experience vomiting during >20% of migraine attacks or who require bed rest during >50% of migraine attacks.

If a patient does not experience relief from migraine after the first dose of 2 tablets, they should consult a physician.

Contraindicated in patients with bronchial asthma, increased bleeding tendency, and with particular caution during concomitant therapy with anticoagulants (coumarins and heparin), hepatic dysfunction, renal diseases, or concomitant anti-inflammatory therapy.

Use during pregnancy or breastfeeding

The medicinal product should not be used during pregnancy or breastfeeding.

Acetylsalicylic acid has teratogenic effects; when used during pregnancy, it may cause developmental abnormalities: during the first trimester – cleft palate; during the third trimester – inhibition of labor activity (inhibition of prostaglandin synthesis), closure of the fetal arterial duct leading to pulmonary vascular hyperplasia and pulmonary hypertension, impaired renal function potentially progressing to renal failure with oligohydramnios, prolonged bleeding time, and antiplatelet effects, which may occur even after very low doses.

Caffeine increases the risk of spontaneous abortion.

There is a potential risk of Reye's syndrome in infants following acetylsalicylic acid use. Therefore, the medicinal product is not recommended during breastfeeding.

Ability to affect reaction speed when driving or operating machinery

Due to possible adverse effects on the nervous system (dizziness, increased excitability, impaired orientation and attention), patients should avoid driving vehicles or operating machinery requiring high attention and rapid psychomotor reactions while using the medicinal product.

Method of Administration and Dosage.

For headache

The usual recommended dose is 1 tablet; an additional tablet may be taken with an interval of 4–6 hours between doses. In cases of more intense pain, 2 tablets may be taken. If necessary, 2 additional tablets may be taken, with an interval of 4–6 hours between doses.

Citramon Maxi® is intended for episodic use. When treating headache, the duration of use should not exceed 4 days.

For migraine:

At the onset of symptoms, take 2 tablets. If necessary, 2 additional tablets may be taken with an interval of 4–6 hours between doses.

Citramon Maxi® is intended for episodic use. When treating migraine, the duration of use should not exceed 3 days.

For both headache and migraine, the maximum daily dose of the medicinal product is 6 tablets (in 3 doses). This medicinal product should not be used for longer periods or in higher doses than recommended without consulting a physician.

Each dose should be taken with a full glass of water.

Do not take together with other medicinal products containing paracetamol.

Although the influence of liver and kidney diseases on the pharmacokinetics of Citramon Maxi® has not been studied, considering the mechanism of action of acetylsalicylic acid and paracetamol, liver and kidney disorders may worsen. This should be taken into account in patients with hepatic or renal insufficiency. For this reason, Citramon Maxi® is contraindicated in patients with severe hepatic or renal insufficiency and should be used with caution in patients with mild to moderate hepatic or renal insufficiency.

Citramon Maxi® should be used with caution in elderly patients, especially those with reduced body weight.

Children

The medicinal product should not be used in children due to the risk of developing Reye's syndrome (hyperpyrexia, metabolic acidosis, nervous system and psychiatric disturbances, vomiting, liver dysfunction) during hyperthermia associated with viral infections.

Overdose

Symptoms of paracetamol overdose

Hepatic injury 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 (long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other medicinal products inducing liver enzymes; regular consumption of excessive amounts of ethanol; glutathione depletion (digestive disorders, cystic fibrosis, HIV infection, starvation, cachexia)), ingestion of 5 g or more of paracetamol may lead to hepatic injury.

Early signs of overdose (very commonly nausea, vomiting, anorexia, pallor, lethargy, and sweating) usually resolve within the first 24 hours. Abdominal pain may be the first sign of hepatic injury, which typically does not manifest within the first 24–48 hours and may appear within 4–6 days after administration. Liver damage usually becomes evident within 72–96 hours after drug intake. Glucose metabolism disturbances and metabolic acidosis may also occur. Acute renal failure with acute tubular necrosis may develop, even in the absence of severe liver injury. Cardiac arrhythmias and pancreatitis have also been reported.

With prolonged use of the medicinal product in high doses, blood dyscrasias may develop, including aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. With large doses, central nervous system (CNS) effects may include dizziness, psychomotor agitation, and disorientation; urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, cortical necrosis).

Treatment: In case of overdose, prompt medical attention is required. The patient should be taken to hospital immediately, even if early symptoms of overdose are absent. Symptoms may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage. N-acetylcysteine should be administered intravenously or orally as soon as possible after drug intake. This antidote is most effective within the first 8 hours after overdose detection, as its efficacy gradually decreases thereafter. Treatment with N-acetylcysteine up to 24 hours after ingestion has been shown to remain effective. Administration of methionine more than 10 hours after paracetamol overdose is associated with more frequent and severe liver damage. Therefore, methionine should be administered within the first 10 hours after paracetamol intake. Absorption after oral administration of methionine may be reduced due to vomiting or concomitant use of activated charcoal.

Symptoms of acetylsalicylic acid overdose

Symptoms of mild salicylate intoxication include dizziness, tinnitus, hearing loss, sweating, diminished peripheral pulse, nausea and vomiting, dehydration, headache, and confusion. These effects may occur at plasma concentrations of acetylsalicylic acid between 150 and 300 µg/mL. These symptoms can be managed by reducing the dose or discontinuing treatment. More severe intoxication occurs at concentrations > 300 µg/mL. Symptoms of severe overdose include hyperventilation, fever, psychomotor agitation, ketosis, respiratory alkalosis, and metabolic acidosis. CNS depression may lead to coma. Cardiovascular collapse and respiratory failure are also possible. Rare manifestations include hematemesis, hyperpyrexia, hypoglycemia, hypokalemia, thrombocytopenia, prolonged PT/INR, intravascular coagulation, renal failure, and non-cardiogenic pulmonary edema. CNS symptoms such as confusion, disorientation, coma, and seizures are less commonly observed in adults than in children.

Treatment:

In suspected poisoning, the patient must be hospitalized. If there is suspicion that the patient has ingested > 120 mg/kg of salicylate within the past hour, repeated oral doses of activated charcoal should be administered. In patients who have ingested > 120 mg/kg of salicylate, plasma salicylate concentration should be measured, although the severity of poisoning cannot be determined by these values alone. Clinical and biochemical parameters must also be considered. Intravenous administration of sodium bicarbonate is effective in enhancing salicylate elimination from plasma when plasma concentrations exceed 500 µg/mL (350 µg/mL in children under 5 years of age). Forced diuresis should not be used, as it does not enhance salicylate elimination and may cause pulmonary edema. Hemodialysis or hemoperfusion are the treatments of choice in cases where plasma salicylate concentration exceeds 700 µg/mL, or lower in children and elderly patients, or in cases of severe metabolic acidosis.

Symptoms of caffeine overdose

Common symptoms: epigastric pain, vomiting, anxiety, nervousness, restlessness, insomnia, excitement, muscle twitching, confusion, tremor, and seizures. Hyperglycemia may also develop with excessive caffeine intake. Cardiovascular symptoms include tachycardia and arrhythmia. Symptoms can be controlled by reducing or discontinuing caffeine intake. The occurrence of clinically significant symptoms of caffeine overdose with this medicinal product may be associated with paracetamol-induced hepatotoxicity.

Adverse reactions.

When using the medicinal product, adverse reactions characteristic of medicinal products containing acetylsalicylic acid, paracetamol, or caffeine may occur in individual patients.

Most of the adverse reactions listed below are clearly dose-dependent and may manifest differently in each individual case.

Possible adverse reactions:

Below are the adverse effects reported from post-marketing surveillance (frequency unknown).

Adverse reactions associated with acetylsalicylic acid

Blood and lymphatic system disorders (frequency unknown): anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, bruising or bleeding; with prolonged use at high doses – aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis. Due to its antiplatelet effect, acetylsalicylic acid increases the risk of bleeding. Bleeding events observed include intraoperative hemorrhages, hematomas, genitourinary bleeding, epistaxis, gingival bleeding, gastrointestinal bleeding, and cerebral hemorrhage (particularly in patients with uncontrolled arterial hypertension and/or concomitant use of antihemostatic agents), which in isolated cases may be life-threatening. Bleeding may lead to acute and chronic post-hemorrhagic anemia/iron-deficiency anemia (due to so-called occult microbleeding), with corresponding laboratory findings and clinical symptoms such as asthenia and pallor of the skin.

Immune system disorders (frequency unknown): hypersensitivity reactions, including anaphylaxis and anaphylactic shock. In patients with individual hypersensitivity to salicylates, allergic skin reactions may occur, including symptoms such as skin hyperemia, sensation of warmth, rash, urticaria, swelling, pruritus, angioedema, rhinitis, and nasal congestion. In patients with bronchial asthma, increased frequency of bronchospasm may occur; allergic reactions ranging from mild to moderate severity may affect the skin, respiratory tract, gastrointestinal tract, and cardiovascular system, manifesting as rashes, urticaria, edema, and pruritus.

Metabolism and nutrition disorders (frequency unknown): sodium and fluid retention.

Endocrine system disorders: hypoglycemia, up to hypoglycemic coma.

Auditory and labyrinthine disorders (frequency unknown): temporary hearing loss, tinnitus.

Gastrointestinal disorders: dyspeptic symptoms, including nausea, vomiting, epigastric discomfort and pain, heartburn, abdominal pain; inflammation of the gastrointestinal tract, erosive-ulcerative lesions of the gastrointestinal tract, which in isolated cases may lead to gastrointestinal bleeding and perforation with corresponding laboratory and clinical manifestations; oral mucosal ulcers.

Hepatobiliary disorders: increased liver enzyme activity, usually without development of jaundice, hepatonecrosis (dose-dependent effect), transient hepatic insufficiency with elevated liver transaminase levels, Reye's syndrome.

Renal and urinary system disorders (frequency unknown): nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis), increased blood uric acid concentration.

Adverse reactions associated with paracetamol

Blood and lymphatic system disorders (rare): thrombocytopenia.

Skin and subcutaneous tissue disorders: pruritus, skin and mucosal rash (usually generalized rash, erythematous rash, urticaria), angioedema, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

Respiratory, thoracic and mediastinal disorders (rare): rhinitis, nasal congestion, dyspnea, bronchial asthma, bronchospasm in patients sensitive to ASA and other NSAIDs.

Hepatobiliary disorders (rare): liver function abnormalities.

General disorders: general weakness.

Adverse reactions associated with caffeine

Nervous system disorders (frequency unknown): headache, nervousness, anxiety, dizziness, tremor, paresthesia, tinnitus, visual disturbances, which may indicate overdose: insomnia, sleep disturbances, increased excitability, disorientation, irritability.

Cardiac disorders (frequency unknown): tachycardia, palpitations, arterial hypertension, arterial hypotension, arrhythmia.

Psychiatric disorders (frequency unknown): fear, insomnia, restlessness, anxiety, irritability, nervousness.

Gastrointestinal disorders (frequency unknown): gastrointestinal discomfort.

Additionally, for medicinal products containing similar active substances, the following adverse reactions have been reported (frequency unknown): arterial hypertension, anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, fear, excitement, sleep disturbances, gastrointestinal inflammation, hypoglycemia up to hypoglycemic coma, hepatonecrosis (dose-dependent effect), hypoperfusion, non-cardiogenic pulmonary edema.

To date, there are no data indicating that the extent or type of adverse effects associated with the individual active substances of this medicinal product increases or that their spectrum broadens when the combination product is used according to the instructions.

The increased risk of hemorrhagic complications may persist for 4–8 days after the last dose of acetylsalicylic acid. Severe hemorrhagic complications (e.g., intracranial hemorrhage) have been very rarely observed, particularly in patients with untreated arterial hypertension and/or concomitant anticoagulant therapy. In individual cases, such complications may be life-threatening.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives are encouraged to report all suspected adverse reactions and/or lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

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 tablets in a blister pack; 1, 2, or 5 blisters per carton.

Prescription status. Over-the-counter.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of business activity.

13 Borispilska Street, Kyiv, 02093, Ukraine.