Citramon extra

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CITRAMON EXTRA (Citramon Extra)

Composition:

Active substances: paracetamol, caffeine;

1 tablet contains: paracetamol 500 mg; caffeine 50 mg;

Excipients: microcrystalline cellulose, methylcellulose, sodium croscarmellose, povidone, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white, round-shaped tablets with a flat surface, beveled edges, and a score line.

Pharmacotherapeutic group. Analgesics and antipyretics. Paracetamol combinations without psychotropic agents. ATC code N02BE51.

Pharmacological properties.

Pharmacodynamics.

A combination medicinal product.

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

Caffeine increases reflex excitability of the spinal cord, stimulates respiratory and vasomotor centers, dilates blood vessels of skeletal muscles, brain, heart, and kidneys, reduces platelet aggregation; decreases drowsiness and fatigue, enhances mental and physical performance. In this combination, caffeine at a low dose practically does not exert a stimulatory effect on the central nervous system, but promotes normalization of cerebral vascular tone and accelerates blood flow.

Pharmacokinetics.

Paracetamol and caffeine are rapidly absorbed in the gastrointestinal tract and distributed into most body tissues. Plasma protein binding of paracetamol is minimal when administered at therapeutic doses.

Paracetamol and caffeine are metabolized primarily in the liver and excreted in urine as metabolites. The mean elimination half-life in plasma after oral administration is approximately 2.3 hours for paracetamol and approximately 4.9 hours for caffeine.

Clinical characteristics.

Indications.

The medicinal product exerts moderate analgesic and antipyretic effects. Indications for use include headache, including migraine, toothache, neuralgias, rheumatic pain, menstrual pain in women; for relief of symptoms of colds and influenza, sore throat.

Contraindications.

Hypersensitivity to paracetamol, caffeine, or any other component of the medicinal product in medical history; severe hepatic and/or renal impairment; congenital hyperbilirubinemia; glucose-6-phosphate dehydrogenase deficiency; alcoholism; blood disorders, pronounced anemia, leukopenia; states of increased excitation, sleep disorders, epilepsy; pronounced increase in blood pressure, organic cardiovascular diseases, including severe atherosclerosis, severe hypertension; decompensated heart failure, acute myocardial infarction, paroxysmal tachycardia, hyperthyroidism, acute pancreatitis, Gilbert's syndrome, severe forms of diabetes mellitus, glaucoma; age over 60 years.

Do not use concomitantly with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuation of MAOIs.

Contraindicated in patients taking tricyclic antidepressants or beta-blockers.

Interaction with other medicinal products and other forms of interactions.

Paracetamol

Concomitant use of paracetamol with hepatotoxic agents increases the toxic effect of the drug on the liver.

Barbiturates, rifampicin, salicylamide, antiepileptic drugs, carbamazepine, phenytoin, ethanol, phenylbutazone, tricyclic antidepressants and other stimulators of microsomal oxidation – these medicinal products increase the production of hydroxylated active metabolites affecting liver function, thereby increasing the risk of severe intoxication even with minor overdoses of the drug.

Barbiturates – reduce the antipyretic effect of paracetamol.

Paracetamol may reduce the bioavailability of lamotrigine, decreasing its effect due to probable induction of its hepatic metabolism.

Concomitant use of paracetamol and zidovudine increases the risk of developing neutropenia.

Inhibitors of microsomal oxidation (cimetidine) – reduce the risk of hepatotoxic effects of Citramon Extra.

Concomitant use of high doses of paracetamol with isoniazid increases the risk of hepatotoxic syndrome.

Metoclopramide and domperidone – increase absorption of paracetamol.

Ethanol – concomitant intake of paracetamol and ethanol increases the risk of hepatotoxic effects and acute pancreatitis.

Do not use concomitantly with alcohol.

Prolonged concomitant use of the medicinal product with acetylsalicylic acid or other nonsteroidal anti-inflammatory agents may lead to kidney damage.

Flucloxacillin – caution should be exercised when using paracetamol concomitantly with flucloxacillin, as this combination has been associated with metabolic acidosis with a high anion gap, especially in patients with risk factors (see section "Special precautions for use").

Coumarin derivatives (warfarin) – prolonged use of paracetamol increases the risk of bleeding. Single-dose administration does not produce a significant effect.

Cholestyramine – reduces absorption of paracetamol.

Under the influence of paracetamol, the elimination time of chloramphenicol increases fivefold.

Probenecid affects the plasma concentration of paracetamol and its excretion.

Paracetamol reduces the effectiveness of diuretics.

Caffeine

Concomitant use of caffeine with monoamine oxidase inhibitors (MAOIs) may cause a dangerous increase in blood pressure.

Caffeine enhances the effect (improves bioavailability) of analgesic-antipyretic agents, potentiates the effects of xanthine derivatives, α- and β-adrenergic agonists, psychostimulants.

Cimetidine, hormonal contraceptives, isoniazid – enhance the action of caffeine.

Caffeine reduces the effect of opioid analgesics, anxiolytics, hypnotics and sedatives, acts as an antagonist of anesthetic agents and other drugs that depress the central nervous system, and as a competitive antagonist of adenosine preparations, adenosine triphosphate (ATP).

Concomitant use of caffeine with thyrotropic agents increases the thyroid effect.

Caffeine decreases blood concentration of lithium.

Caffeine accelerates absorption of ergotamine.

Special precautions for use.

Consult a physician regarding the possibility of using the medicinal product in patients with impaired kidney or liver function.

It should be noted that in patients with liver disease, the risk of hepatotoxic effects of paracetamol is increased.

Alcoholic beverages must not be consumed during treatment. Paracetamol may be hepatotoxic at doses exceeding 6–8 g per day; however, adverse effects on the liver may also occur at significantly lower doses when alcohol is consumed, when hepatic enzyme inducers or other substances with hepatotoxic effects are used, or in patients with non-cirrhotic alcoholic liver disease. Prolonged alcohol consumption significantly increases the risk of hepatotoxic effects of paracetamol. In patients with impaired liver function, as well as in those taking high doses of paracetamol over a prolonged period, regular liver function tests are recommended.

Consult a physician before using the medicinal product if the patient is taking warfarin or similar anticoagulant agents. Restrictions on the use of the medicinal product in such patients are primarily due to the presence of paracetamol.

When treating with oral anticoagulants and simultaneously taking high doses of paracetamol, monitoring of prothrombin time is required.

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

Cases of impaired liver function/liver failure have been reported in patients with reduced glutathione levels, for example, in severe malnutrition, anorexia, low body mass index, chronic alcoholism, or sepsis. In patients with reduced glutathione levels, the use of paracetamol increases 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.

Caution is required when using paracetamol concomitantly with flucloxacillin due to an increased risk of high anion gap metabolic acidosis, especially 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 used. Careful monitoring, including measurement of 5-oxoproline in urine, is recommended.

During treatment with this medicinal product, excessive consumption of beverages containing caffeine (such as coffee, tea, and certain other drinks) is not recommended. This may lead to sleep disturbances, tremor, chest discomfort due to palpitations, tension, and irritability.

Do not exceed the recommended doses.

Do not take this medicinal product with other products containing paracetamol.

If symptoms persist, consult a physician.

If headaches become persistent, consult a physician.

Keep the medicinal product out of sight and reach of children.

Use during pregnancy or breastfeeding.

The use of this medicinal product during pregnancy is not recommended, as it increases the risk of spontaneous abortion associated with caffeine use.

Paracetamol and caffeine pass into breast milk but in clinically insignificant amounts when taken at recommended doses. The use of this medicinal product during breastfeeding is not recommended. Caffeine in breast milk may have a stimulating effect on infants during breastfeeding, but significant toxicity has not been observed.

Ability to affect reaction speed when driving or operating machinery.

Has no significant effect.

Method of Administration and Dosage

The medicinal product is intended for oral administration.

Adults and children aged 12 years and older: 1–2 tablets 4 times daily. The interval between doses should be at least 4 hours. Do not exceed 8 tablets (4000 mg paracetamol / 400 mg caffeine) within 24 hours. Do not exceed the recommended dose.

Do not use together with other medicinal products containing paracetamol.

The duration of treatment is determined by a physician.

Children

The medicinal product is not recommended for children under 12 years of age.

Overdose

Hepatic injury may occur in adults after ingestion of 10 g or more of paracetamol, and in children after ingestion of more than 150 mg/kg body weight.

Paracetamol overdose can cause liver failure, which may require liver transplantation or result in death.

In patients with risk factors (long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other medicinal products that induce liver enzymes; chronic excessive alcohol consumption; glutathione depletion (gastrointestinal disorders, cystic fibrosis, HIV infection, fasting, cachexia)), ingestion of 5 g or more of paracetamol may lead to hepatic injury.

Symptoms within the first 24 hours post-overdose: pallor, nausea, vomiting, anorexia, and abdominal pain. Hepatic injury may become evident 12–48 hours after overdose and peak at 4–6 days. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and may be fatal. Acute renal failure with acute tubular necrosis may present as severe flank pain, hematuria, proteinuria, and may develop even in the absence of severe liver injury. Cardiac arrhythmias and pancreatitis have also been reported.

With prolonged use of the medicinal product in high doses, hematological disorders may develop, including aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. Central nervous system effects from high-dose intake may include dizziness, psychomotor agitation, and disorientation. Urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, cortical necrosis).

In case of overdose, prompt medical assistance is required. The patient should be immediately transported to a hospital, 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. If overdose is confirmed or suspected, the patient must be taken to the nearest medical facility capable of providing emergency medical care and qualified treatment. This must be done even in the absence of symptoms due to the risk of delayed hepatic injury.

Administration of activated charcoal should be considered if the excessive dose of paracetamol was ingested within 1 hour. Plasma paracetamol concentration should be measured at least 4 hours after ingestion (earlier measurements are unreliable). Treatment with N-acetylcysteine may be administered within 24 hours of paracetamol ingestion, but maximum protective effect is achieved when administered within 8 hours of ingestion. The efficacy of the antidote decreases sharply after this time. If required, intravenous N-acetylcysteine should be administered according to the recommended dosage. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside hospital settings.

Caffeine overdose may cause epigastric pain, vomiting, diuresis, rapid breathing, extrasystoles, tachycardia, or cardiac arrhythmia, and central nervous system effects (dizziness, insomnia, nervous excitation, irritability, emotional lability, anxiety, tremor, seizures). Clinically significant symptoms of caffeine overdose may also be associated with paracetamol-induced liver injury, which may occur when such quantities of the medicinal product are ingested that cause caffeine overdose. There is no specific antidote, but supportive measures such as administration of β-adrenoreceptor antagonists may alleviate cardiotoxic effects. Gastric lavage is necessary; oxygen therapy is recommended; diazepam is indicated for seizures. Symptomatic therapy.

Adverse Reactions

The adverse reactions listed below were identified during post-marketing surveillance. Since these reactions have been reported voluntarily and the patient population size is unknown, the frequency of these adverse reactions cannot be determined; however, they are likely to be rare (< 1/10,000).

Respiratory system, thoracic organs and mediastinum disorders: rhinitis, nasal congestion, bronchospasm in patients sensitive to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs.

Gastrointestinal disorders: nausea, vomiting, heartburn, epigastric pain, mild diarrheal effect.

Hepatobiliary disorders: increased liver enzyme activity, usually without development of jaundice, hepatotoxic effects, liver function disorders, liver failure, hepatonecrosis (dose-dependent effect), jaundice.

Renal and urinary disorders: nephrotoxic effects (including interstitial nephritis, papillary necrosis), aseptic pyuria.

Endocrine disorders: hypoglycemia, up to hypoglycemic coma.

Nervous system disorders: headache, nervousness, dizziness.

Psychiatric disorders: insomnia, restlessness, anxiety, irritability.

Cardiovascular disorders: tachycardia, arrhythmia, increased blood pressure, rapid heartbeat, edema.

Blood and lymphatic system disorders: thrombocytopenia, leukopenia, neutropenia, agranulocytosis, pancytopenia, anemia, aplastic anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, bruising or bleeding.

Immune system disorders: hypersensitivity reactions, including skin and mucous membrane rashes (usually generalized rash, erythematous rash), Stevens-Johnson syndrome, angioneurotic edema, anaphylaxis, anaphylactic shock, erythema multiforme, toxic epidermal necrolysis (Lyell's syndrome), acute generalized exanthematous pustulosis.

Skin and subcutaneous tissue disorders: pruritus, rash, sweating, purpura, urticaria.

Concomitant use of the medicinal product at recommended doses with products containing caffeine may enhance caffeine-related adverse effects such as dizziness, increased excitability, insomnia, restlessness, anxiety, irritability, headache, gastrointestinal disturbances, and rapid heartbeat.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 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 blister pack in a carton.

Dispensing category. Over-the-counter.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of operations.

13, Borispilska Street, Kyiv, 02093, Ukraine.