Coldrex c

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT COLDREX C (COLDREX C)

Composition:

Active substances: 1 capsule contains paracetamol 200 mg; ascorbic acid 150 mg; caffeine 25 mg; chlorpheniramine maleate 2.5 mg;

Excipients: lactose monohydrate; gelatin; glyceryl tristearate; titanium dioxide (E 171); quinoline yellow (E 104); erythrosine (E 127).

Pharmaceutical form. Hard capsules.

Main physicochemical properties: hard gelatin capsules, size 1, cap: yellow opaque, body: white opaque; capsule contents: powder ranging from white to yellowish-brown.

Pharmacotherapeutic group.
Paracetamol combinations without psycholeptics. ATC code N02BE51.

Pharmacological properties.

Paracetamol is an analgesic and antipyretic (pain-relieving and fever-reducing agent). Its effect is based on the inhibition of prostaglandin synthesis in the central nervous system. Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Maximum plasma concentration is reached within 30–60 minutes. The elimination half-life is 1–4 hours. It is uniformly distributed throughout all body fluids. Plasma protein binding is variable. It is excreted predominantly by the kidneys in the form of conjugated metabolites.

Chlorpheniramine maleate is a classical H1-antihistamine that exerts desensitizing and analgesic effects, reduces vascular and tissue permeability of the mucous membranes of the upper respiratory tract, and relieves itching in the eyes and nose.

Chlorpheniramine is well absorbed from the gastrointestinal tract; 69–72% of the drug is plasma protein-bound. Maximum plasma concentration is achieved within 2–6 hours. It is metabolized in the liver. Chlorpheniramine and its metabolites are excreted primarily by the kidneys.

Caffeine is a potent central nervous system stimulant. It enhances the analgesic effect of paracetamol, stimulates the respiratory and vasoconstrictor centers, promotes dilation of blood vessels in muscles, heart, and kidneys, causes constriction of vessels in abdominal organs and the brain, reduces platelet aggregation, increases diuresis, and enhances gastric secretory activity.

Ascorbic acid is an essential vitamin. It is known that ascorbic acid plays an important role in supporting the body's defense mechanisms against infection and is necessary for normal T-lymphocyte function and effective phagocytic activity of leukocytes. It normalizes capillary permeability.

Ascorbic acid is readily absorbed in the gastrointestinal tract. Approximately 25% is bound to blood proteins. It is metabolized in the liver, primarily to dehydroascorbic acid. Ascorbic acid and its metabolites are excreted in urine and bile. Excess ascorbic acid beyond the body's requirements is excreted in urine as metabolites.

Clinical characteristics.

Indications. For relief of cold symptoms.

Contraindications.

Hypersensitivity to paracetamol or any other component of the medicinal product; severe hepatic and/or renal function impairment, Gilbert's syndrome, Dubin-Johnson syndrome, congenital hyperbilirubinemia, glucose-6-phosphate dehydrogenase deficiency; alcoholism; blood disorders, marked anemia, leukopenia; coagulation disorders; thrombosis, thrombophlebitis; increased excitability, sleep disturbances; severe hypertension, marked increase in arterial pressure, predisposition to vascular spasm in organic cardiovascular diseases (including atherosclerosis), decompensated heart failure, severe cardiac conduction disorders and arrhythmias; epilepsy; hyperthyroidism; prostate hyperplasia, bladder neck obstruction; diabetes mellitus; closed-angle glaucoma; acute pancreatitis, gastric and duodenal ulcer in the stage of exacerbation, pyloroduodenal obstruction, myocardial infarction, paroxysmal tachycardia, hypersensitivity to other antihistamines; predisposition to thrombosis, age over 60 years.

Do not use concomitantly with monoamine oxidase inhibitors (MAOIs) and within 2 weeks after discontinuation of MAOIs; do not use with tricyclic antidepressants or β-blockers.

Interaction with other medicinal products and other forms of interaction.

Paracetamol.

• When used concomitantly with drugs that delay gastric emptying (e.g., propantheline), absorption and, consequently, the efficacy of paracetamol may be reduced.
• When used concomitantly with drugs that accelerate gastric emptying (e.g., metoclopramide), absorption and, consequently, the efficacy of paracetamol may be increased.
• Concomitant use with azidothymidine (zidovudine) increases the risk of neutropenia. Therefore, Coldrex C should be used with azidothymidine only after consultation with a physician.
• Concomitant use with probenecid inhibits glucuronidation of paracetamol and leads to approximately a two-fold reduction in paracetamol clearance. The dose of paracetamol should be reduced when used concomitantly with probenecid.
• Salicylates may prolong the half-life of paracetamol.
• Caution is advised when used concomitantly with enzyme inducers.
• Repeated use of paracetamol over several weeks enhances the effect of anticoagulants.
• Cholestyramine reduces the absorption of paracetamol.
• The rate of paracetamol absorption may be increased when used with domperidone and decreased when used with cholestyramine.
• The anticoagulant effect of warfarin and other coumarins may be enhanced by long-term, regular daily use of paracetamol, increasing the risk of bleeding. Occasional use has no significant effect.
• Barbiturates reduce the antipyretic effect of paracetamol.
• Anticonvulsant drugs (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 effects of the drugs.
• Concomitant 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 this combination has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions").

Chlorpheniramine maleate.

Concomitant use of the drug with the following medicinal products may significantly increase the depressant effects of chlorpheniramine maleate: hypnotics; neuroleptics; tranquilizers.

Chlorpheniramine enhances the anticholinergic effects of atropine, spasmolytics, tricyclic antidepressants, and antiparkinsonian agents.

Concomitant use with centrally acting sedatives or alcohol potentiates the sedative effect.

Caffeine.

• Caffeine may reduce the sedative effect of barbiturates and antihistamines.
• Caffeine has a synergistic effect with sympathomimetics and thyroxine (increases heart rate).
• When used concomitantly with theophylline, it reduces the latter's elimination.
• Caffeine enhances the additive potential of ephedrine-type substances.
• When combined with broad-spectrum drugs (e.g., benzodiazepines), various unpredictable reactions may occur.
• Oral contraceptives, cimetidine, and disulfiram reduce caffeine metabolism in the liver; barbiturates and nicotine enhance it.
• Concomitant use of quinolone carboxylgyrase inhibitors may reduce the elimination of caffeine and its metabolite paraxanthine.
• Caffeine enhances the effect (improves bioavailability) of analgesic-antipyretics, potentiates the effects of xanthine derivatives, α- and β-adrenomimetics, and psychostimulants.
• Cimetidine, hormonal contraceptives, and isoniazid enhance the effects 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 adenosine triphosphate (ATP) preparations.
• Concomitant use of caffeine with ergotamine improves ergotamine absorption in the gastrointestinal tract; with thyrotropic agents, it enhances the thyroid effect.
• Caffeine reduces blood lithium concentration.

Ascorbic acid.

Absorption of ascorbic acid is reduced when used concomitantly with oral contraceptives, fruit or vegetable juices, and alkaline drinks. Orally administered ascorbic acid increases the absorption of penicillin, tetracycline, and iron; reduces the effectiveness of heparin and indirect anticoagulants; increases the risk of crystalluria during salicylate therapy. Concurrent intake of ascorbic acid and deferoxamine increases tissue iron toxicity, especially in cardiac muscle, which may lead to circulatory decompensation. Ascorbic acid increases the total clearance of ethanol. Quinolone derivatives, calcium chloride, salicylates, and corticosteroids, when used long-term, reduce ascorbic acid stores in the body.

Special precautions for use.

Before using the medicinal product, consult a physician if the patient is taking warfarin or similar agents with anticoagulant effects.

Paracetamol.

The medicinal product contains paracetamol; therefore, it should not be used concurrently with other medications containing paracetamol, such as those used for fever reduction, pain relief, flu and cold symptoms, or insomnia. Concurrent use with other paracetamol-containing products may lead to overdose. Paracetamol overdose can cause liver failure, which may require liver transplantation or may be fatal. Consult a physician regarding the possibility of using the product in patients with impaired kidney or liver function.

The risk of hepatotoxic effects of paracetamol is increased in patients with alcoholic liver disease. The product may affect laboratory test results for blood glucose and uric acid levels.

Patients who take analgesics daily for mild forms of arthritis should consult a physician.

Cases of liver dysfunction and liver failure have been reported in patients with reduced glutathione levels, such as those with severe malnutrition, anorexia, low body mass index, or chronic alcoholism.

In patients with severe infections such as sepsis, which are associated with reduced glutathione levels, the risk of metabolic acidosis increases during paracetamol administration. 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.

To avoid overdose, ensure that the maximum daily dose of paracetamol (4000 mg of paracetamol in patients weighing over 43 kg) is not exceeded, even when other paracetamol-containing medications are used.

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in critically ill patients, such as those with severe renal failure or sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g., chronic alcoholism), who were treated with therapeutic doses of paracetamol over a prolonged period or in combination with flucloxacillin.

If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol and close monitoring are recommended. Measurement of urinary 5-oxoproline levels may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

Ascorbic acid.

Renal and hepatic function, arterial pressure, and pancreatic function should be monitored during prolonged treatment or when high doses are administered. Treatment of patients with mild to moderate renal or hepatic impairment, epilepsy, benign prostatic hyperplasia, urinary disorders, or nephrolithiasis should be conducted with caution after consultation with a physician.

In patients with nephrolithiasis, the daily dose of ascorbic acid should not exceed 1 g. High doses of the medicinal product should not be prescribed to patients with increased blood coagulability.

Since ascorbic acid enhances iron absorption, its use in high doses may be hazardous in patients with hemochromatosis, thalassemia, polycythemia, leukemia, or sideroblastic anemia. Patients with high iron content in the body should use the product in minimal doses.

Concurrent use of the medicinal product with alkaline drinks reduces ascorbic acid absorption; therefore, it should not be taken with alkaline mineral water. Ascorbic acid absorption may also be impaired in intestinal dyskinesia, enteritis, or achylia.

Use with caution in patients with glucose-6-phosphate dehydrogenase deficiency.

Due to the stimulatory effect of ascorbic acid on corticosteroid hormone production, renal function and arterial pressure should be monitored when high doses of the medicinal product are used.

There is a risk of calcium oxalate stone formation when high doses of ascorbic acid are administered to patients predisposed to kidney stone formation. Ascorbic acid may affect the results of various laboratory tests, such as blood glucose, bilirubin, transaminase activity, lactate dehydrogenase, etc.

Caffeine.

During treatment with the product, excessive consumption of caffeine-containing beverages (e.g., coffee, tea) is not recommended, as it may cause dizziness, increased excitability, insomnia, restlessness, anxiety, irritability, headache, gastrointestinal disturbances, and tachycardia.

Do not exceed the recommended doses.

If headache becomes persistent, consult a physician.

Avoid concomitant use of other medications intended for symptomatic treatment of cold and flu, vasoconstrictive agents for rhinitis treatment, and other medicinal products containing paracetamol.

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

If symptoms of illness do not begin to improve within 3 days of treatment or if the condition worsens, consult a physician.

Important information about excipients.

The medicinal product contains lactose and therefore should not be used in patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy.

The use of the medicinal product is contraindicated during pregnancy, as epidemiological studies have shown an increased risk of central nervous system developmental disorders, craniofacial abnormalities, and childhood tumors associated with chlorpheniramine. Furthermore, one study reported an increased risk of retrolental fibroplasia in premature infants exposed to antihistamines during the last two weeks of pregnancy.

Breastfeeding.

Since it is unknown whether chlorpheniramine maleate is excreted in breast milk, nursing mothers should not breastfeed while being treated with this medicinal product.

Fertility.

Data on the effect on fertility are lacking.

Ability to affect reaction speed when driving or operating machinery.

During treatment, activities requiring heightened attention and rapid psychomotor responses should be avoided (see section "Adverse reactions" for nervous system and visual organ-related reactions).

Administration and Dosage

The product is intended for oral administration. The dose for adults and children aged 12 years and older is 2 capsules three times daily: in the morning, during the day, and in the evening, with an interval of at least 4 hours between doses. The product should be taken independently of food, with a sufficient amount of water.

The maximum duration of self-administration of the product is 3–5 days. When prescribed by a physician, the treatment course lasts 5–7 days.

Patients with mild to moderate hepatic and/or renal impairment. For patients with moderate impairment of liver and/or kidney function, the dose should be adjusted or the interval between doses increased.

Do not exceed the recommended dose.

Do not take together with other medicinal products containing paracetamol.

Children.

The product is indicated for children aged 12 years and older.

Overdose.

Symptoms of overdose with the medicinal product Coldrex S are due to the effects of its individual components.

Paracetamol.

In patients with risk factors (long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs inducing liver enzymes; regular consumption of excessive amounts of ethanol; glutathione depletion (digestive disorders, cystic fibrosis, HIV infection, fasting, cachexia); elderly age), a single dose of 5 g or more of paracetamol in adults or 140 mg/kg in children may lead to liver damage.

Symptoms within the first 24 hours: pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage may become evident 12–48 hours after overdose. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, liver failure may progress to encephalopathy, hemorrhages, hypoglycemia, coma, and death; simultaneously, increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase, and bilirubin may occur, combined with prolonged prothrombin time, appearing 12–48 hours after ingestion. Acute renal failure with acute tubular necrosis may manifest as severe flank pain, hematuria, proteinuria, and may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have also been reported.

With prolonged use of the product in high doses, hematological disorders such as aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia may develop. With large doses, central nervous system effects may include dizziness, psychomotor agitation, and disorientation; urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis). In case of overdose, immediate medical assistance 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. Administration of activated charcoal should be considered if the excessive dose of paracetamol was ingested 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, intravenous N-acetylcysteine should be administered according to current guidelines. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside hospital settings.

Chlorpheniramine maleate.

After overdose, anticholinergic components cause symptoms similar to those caused by atropine: flushing, fixed dilated pupils, ataxia, tremor, fever, dry mouth, and constipation. Subsequently, signs of central nervous system intoxication may appear, with the condition varying from depressed to agitated: restlessness and seizures, photophobia, dry skin and mucous membranes, and intestinal atony. Final symptoms include coma, respiratory failure, and cardiovascular collapse.

Caffeine.

Large doses of caffeine (≥ 1 g) within a short period may cause intoxication symptoms: epigastric pain, vomiting, diuresis, rapid breathing, cardiovascular disturbances (tachycardia, myocardial damage, or cardiac arrhythmia), and effects on the central nervous system (insomnia, restlessness, nervous excitation, anxiety, dizziness, irritability, affective state, tremor, seizures). Clinically significant symptoms of caffeine overdose are also associated with liver damage caused by paracetamol. There is no specific antidote, but supportive measures such as beta-adrenergic antagonists may alleviate cardiotoxic effects. Gastric lavage is required, oxygen therapy is recommended, and diazepam should be administered in case of seizures. Symptomatic therapy.

Ascorbic acid.

Ascorbic acid is well tolerated. It is a water-soluble vitamin, and excess amounts are excreted in urine.

Symptoms. With prolonged use of high-dose vitamin C, suppression of pancreatic islet function may occur, requiring monitoring of pancreatic function. Overdose may lead to changes in renal excretion of ascorbic and uric acids during urine acidification, with a risk of precipitation of oxalate stones. After administration of large doses, the following may occur: epigastric pain, nausea, vomiting, diarrhea, itching, skin rashes, and increased excitability. There is a risk of hemolysis and kidney stone formation. After a single dose of ≥ 3 g, transient osmotic diarrhea and gastrointestinal disturbances may occur.

Treatment: gastric lavage, administration of alkaline drinks, activated charcoal, or other absorbents.

Adverse Reactions

In this section, the frequency of adverse reactions is defined as follows: very common (> 1/10); common (from > 1/100 to < 1/10); uncommon (from > 1/1000 to < 1/100); rare (from > 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data). Laboratory parameters.

Not known: the use of paracetamol may affect uric acid levels measured by phosphotungstic acid method and blood glucose levels measured by peroxidase oxidase method.

When ascorbic acid is used at the recommended dose, increased concentration of ascorbic acid in urine may interfere with accurate assessment of certain clinical-chemical parameters (glucose, uric acid, creatinine, inorganic phosphates, occult blood in feces). Thus, the reliability of test results based on colorimetric reactions may be altered.

Chlorpheniramine maleate may also reduce the intensity of reactions during skin allergy testing.

Cardiovascular system: not known: tachycardia, reflex bradycardia, dyspnea, chest pain, arrhythmia, arterial hypertension, palpitations.

Blood and lymphatic system disorders: very rare: anemia, sulfhemoglobinemia, hemolytic anemia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis, pancytopenia, aplastic anemia; at high doses – mild formation of methemoglobin, thrombocytopenic purpura, methemoglobinopathy, bruising, and bleeding.

Gastrointestinal system: common: dry mouth; very rare: nausea, vomiting, gastrointestinal complaints, discomfort and pain in the epigastric region, hypersalivation, decreased appetite, heartburn, diarrhea.

Endocrine system: hypoglycemia, up to hypoglycemic coma.

Hepatobiliary system: rare: liver function abnormalities; very rare: increased liver enzyme activity, usually without development of jaundice, hepatonecrosis (dose-dependent effect).

Very rare: liver injury may occur after prolonged use of higher doses or following overdose.

Immune system disorders: very rare: anaphylaxis, hypersensitivity reactions including skin itching, skin and mucous membrane rashes (usually generalized, erythematous rash, urticaria). For the active substance paracetamol, severe hypersensitivity reactions have been reported (angioneurotic edema, dyspnea, sweating attacks, nausea, hypotension progressing to circulatory failure and anaphylactic shock). Not known: cases of multiform exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome) have been observed in isolated cases temporally associated with the use of Coldrex C.

Nervous system disorders: very rare: dyskinesia; not known: headache, dizziness, psychomotor agitation and disorientation, restlessness, sedation, somnolence, insomnia, fear sensation, sleep disturbances, confusion, in individual cases – coma, convulsions, behavioral changes.

Renal and urinary system disorders: very rare: renal colic, interstitial nephritis, difficulty in urination. Kidney damage is possible after prolonged use of higher doses.

Respiratory system: very rare: respiratory hypersensitivity, bronchospasm in patients sensitive to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs).

Skin and subcutaneous tissue disorders: uncommon: allergic skin reactions (erythema, rash), which may be accompanied by fever (drug-induced fever) and mucosal damage, local medicamentous dermatitis. Very rare cases of serious skin reactions have been reported.

Metabolism and nutrition disorders: very rare: increased appetite; frequency not known: metabolic acidosis with high anion gap.

Description of selected adverse reactions

Metabolic acidosis with high anion gap

Cases of metabolic acidosis with high anion gap due to pyroglutamic acidosis have been observed during paracetamol use in patients with risk factors (see section "Special precautions"). Pyroglutamic acidosis may occur as a result of low glutathione levels in these patients.

Psychiatric disorders: very rare: psychotic reactions; not known: inner restlessness, insomnia.

Eye disorders: very rare: development of glaucoma (angle-closure glaucoma), visual and accommodation disturbances, dry eyes, mydriasis.

With long-term use at high doses the following may occur: damage to renal glomerular apparatus, formation of urate and/or oxalate kidney stones and urinary tract calculi, renal failure; damage to pancreatic islet apparatus (hyperglycemia, glucosuria) and impaired glycogen synthesis up to onset of diabetes mellitus; myocardial dystrophy; thrombocytosis, thrombosis, hyperthrombinemia, erythrocytopenia, neutrophilic leukocytosis, decreased capillary permeability (possible worsening of tissue trophism, increased blood pressure); hemolysis of erythrocytes in patients with glucose-6-phosphate dehydrogenase deficiency; oral dysbiosis; disturbances in zinc and copper metabolism.

Concomitant intake of the product at recommended doses with caffeine-containing products may enhance caffeine-related side effects such as dizziness, increased excitability, insomnia, restlessness, anxiety, irritability, headache, gastrointestinal disturbances, and tachycardia.

Reporting of suspected adverse reactions

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

Shelf life: 5 years.

Do not use the medicinal product after the expiry date.

Storage conditions

Store in original packaging at a temperature not exceeding 30 °C.

Keep out of reach and sight of children.

Packaging

10 capsules in a blister; 1 or 2 blisters per cardboard box.

Release category

Over-the-counter (without prescription).

Manufacturer

STADA Arzneimittel AG, Germany.

Manufacturer's address and location of business operations

Stadaweg 2–18, 61118 Bad Vilbel, Germany.