Coldivel

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT COLDBEL

Composition:

Active substances: paracetamol, caffeine, phenylephrine hydrochloride, pheniramine maleate;

1 tablet contains: paracetamol 500 mg, caffeine 30 mg, phenylephrine hydrochloride 10 mg, pheniramine maleate 2 mg;

Excipients: maize starch, gelatin, lactose monohydrate, povidone, talc, magnesium stearate, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), Ponceau 4R (E 124) dye.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: oval-shaped, two-layer tablet (white layer/pink layer), with an imprint on both sides. Pink specks may be present in the white layer, and white specks may be present in the pink layer.

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

Pharmacological properties.

A combination drug with antipyretic, analgesic, vasoconstrictor, anti-inflammatory, and antiallergic effects, which are determined by the components included in the medicinal product.

Pharmacodynamics.

Paracetamol exerts analgesic and antipyretic effects. The analgesic effect is due to its inhibitory influence on prostaglandin synthesis. The antipyretic effect is mediated through the action on the hypothalamic thermoregulatory center.

Pheniramine maleate is an H\textsubscript{1}-histamine receptor blocker. It inhibits the biological effects of histamine, helps reduce cold symptoms and manifestations of allergic rhinitis and sinusitis, improves nasal breathing, reduces rhinorrhea, and relieves sneezing and lacrimation.

Caffeine is a central nervous system stimulant; it stimulates the respiratory and vasomotor centers, enhances cardiac activity and increases myocardial contraction force, reduces fatigue and drowsiness.

Phenylephrine hydrochloride stimulates alpha-adrenergic receptors of vascular smooth muscles, thereby producing a vasoconstrictive effect, which leads to a reduction in edema and hyperemia of the mucous membranes of the upper respiratory tract and nasal sinuses.

Clinical characteristics.

Indications.

Symptomatic treatment of colds, influenza, and acute respiratory viral infections accompanied by chills, hyperthermia, headache, rhinitis, and nasal congestion.

Contraindications.

• Hypersensitivity to any component of the drug, hypersensitivity to other xanthine derivatives (theophylline, theobromine), or to other parabens (methylparahydroxybenzoate and propylparahydroxybenzoate);
• Severe coronary atherosclerosis;
• Severe form of ischemic heart disease;
• Decompensated heart failure;
• Unstable angina, acute phase of myocardial infarction, severe cardiac conduction disorders;
• Severe arterial hypertension;
• Marked impairment of kidney and liver function, including hepatic and renal insufficiency;
• Pyloroduodenal obstruction, gastric and duodenal ulcer in the stage of exacerbation, acute pancreatitis;
• Epilepsy;
• Thrombosis, thrombophlebitis;
• Bronchial asthma;
• Chronic obstructive pulmonary disease;
• Pheochromocytoma;
• Hyperthyroidism;
• Glucose-6-phosphate dehydrogenase deficiency;
• Blood disorders;
• Marked leukopenia;
• Anemia;
• Congenital hyperbilirubinemia, Gilbert’s syndrome, Rotor’s syndrome;
• Dubin-Johnson syndrome;
• Diabetes mellitus;
• Prostate hyperplasia;
• Increased intraocular pressure;
• Closed-angle glaucoma;
• Alcoholism;
• Advanced age;
• Do not use concomitantly with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuation of MAOIs;
• Concurrent use with tricyclic antidepressants or beta-blockers;
• Rare hereditary forms of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency;
• Hematopoietic disorders;
• Conditions of increased excitation, sleep disturbances;
• Severe cardiovascular diseases;
• Organic cardiovascular diseases, predisposition to vascular spasm;
• Bladder neck obstruction;
• Stenosing duodenal ulcer, acute hepatitis;
• Risk of respiratory failure;
• Do not use in patients with phenylketonuria;
• Not recommended for patients with increased blood coagulation, predisposition to thrombosis;
• Do not use concomitantly with drugs that suppress or stimulate appetite, or with amphetamine-like psychostimulants.

Special precautions.

Cases of metabolic acidosis with a high anion gap (high anion gap metabolic acidosis (HAGMA)) due to pyroglutamic acidosis have been reported in patients with severe conditions such as severe renal failure and sepsis, or in patients with poor nutrition or other sources of glutathione deficiency (e.g., chronic alcoholism), who were treated with therapeutic doses of paracetamol over a prolonged period or with a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with careful monitoring. 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.

Concomitant use with other medicinal products containing paracetamol or other active ingredients present in the formulation should be avoided.

Patients with impaired renal or hepatic function, or those taking warfarin or similar anticoagulant agents, should consult a physician before using this drug.

Consider that the risk of hepatotoxic effects of paracetamol is increased in patients with alcoholic liver disease; the drug may affect laboratory test results for blood glucose and uric acid levels.

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

Do not exceed the recommended doses.

Alcohol consumption should be avoided during treatment with Coldibel.

Coldibel may cause a positive analytical result in doping control tests.

If high fever persists for 3 days or more, or recurs, or if pain persists for more than 5 days, medical advice should be sought.

If headache becomes persistent, consult a physician.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of the drug with other medicinal products containing paracetamol or other active ingredients present in the formulation should be avoided. Coldibel potentiates the effects of MAO inhibitors, beta-blockers, sedatives, and ethanol. In addition, MAO inhibitors and furazolidone, when used concomitantly with the drug, may cause excited states, hypertensive crisis, and hyperpyrexia (due to pheniramine maleate). Concurrent use with antidepressants, antiparkinsonian agents, neuroleptics may result in anticholinergic effects (manifested as dry mouth, urinary retention, constipation).

The risk of glaucoma increases with concomitant use of the drug with glucocorticosteroids. Paracetamol, one of the components of the drug, reduces the effectiveness of diuretics and increases the risk of hepatotoxic reactions when used concomitantly with barbiturates, phenytoin, carbamazepine, rifampicin, and other inducers of microsomal liver enzymes, as well as anticonvulsants.

Paracetamol should be used with caution when administered concomitantly with flucloxacillin, as such co-administration has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions").

The absorption rate of paracetamol may be increased when used concomitantly with metoclopramide and domperidone, and decreased when used with cholestyramine. The effect of paracetamol is enhanced when combined with codeine, ascorbic acid, scopolamine, chlorphenamine, propyphenazone, and caffeine. Concurrent use of paracetamol with azidothymidine may lead to neutropenia. The anticoagulant effect of warfarin and other coumarins is enhanced with prolonged regular use of paracetamol, increasing the risk of bleeding. Occasional use is not significant. Concurrent use of paracetamol with nonsteroidal anti-inflammatory drugs increases the risk of renal complications. Concurrent use of paracetamol with hepatotoxic agents increases the toxic effects of drugs on the liver.

One of the components of the drug, phenylephrine hydrochloride, exhibits adrenergic effects when used with tricyclic antidepressants; concomitant use with haloperidol increases the risk of ventricular arrhythmia. Coldibel reduces the antihypertensive effect of guanethidine, which in turn enhances the alpha-adrenergic stimulating activity of phenylephrine hydrochloride.

Phenylephrine contained in the drug may cause adverse reactions when combined with indomethacin and bromocriptine (severe arterial hypertension). Rauwolfia alkaloids reduce the therapeutic effect of phenylephrine.

Interaction of phenylephrine hydrochloride with MAO inhibitors causes a hypertensive effect; with sympathomimetic amines, digoxin, and cardiac glycosides – increases the risk of arrhythmias and myocardial infarction. Phenylephrine combined with other sympathomimetics increases the risk of adverse cardiovascular reactions, enhances arrhythmogenicity, and may reduce the effectiveness of β-blockers and other antihypertensive agents (reserpine, methyldopa), increasing the risk of arterial hypertension and adverse cardiovascular reactions.

Alpha-adrenergic blockers (phentolamine), phenothiazines, furosemide, and other diuretics counteract vasoconstriction. Concomitant use of phenylephrine hydrochloride with atropine may result in tachycardia. The drug reduces the antihypertensive action of guanethidine, which in turn increases the alpha-adrenergic stimulating activity of phenylephrine.

Pheniramine enhances the anticholinergic effects of atropine, spasmolytics, tricyclic antidepressants, maprotiline (tetracyclic antidepressant), MAO inhibitors, antiparkinsonian agents, antihistamines, and other anticholinergic drugs. Concurrent use with alcohol potentiates the effects of both.

Concomitant use with hypnotics, barbiturates, sedatives, neuroleptics, tranquilizers, anesthetics, narcotic analgesics enhances the effect of pheniramine maleate.

Caffeine enhances the effect (improves bioavailability) of analgesic-antipyretics, potentiates the effects of xanthine derivatives, alpha- and beta-adrenergic agonists, psychostimulants. Cimetidine, hormonal contraceptives, isoniazid enhance the effect 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, ATP. Concurrent use of caffeine with ergotamine improves absorption of ergotamine from the gastrointestinal tract; with thyrotropic agents – increases thyroid effect. Caffeine reduces blood concentration of lithium. Caffeine increases the likelihood of liver damage caused by hepatotoxic drugs.

Ototoxic and photosensitizing drugs, when used concomitantly, may enhance adverse effects.

Caffeine reduces the antihypertensive effect of guanethidine. Caffeine enhances the effect of indirect anticoagulants (coumarin derivatives). Metoclopramide increases, and cholestyramine decreases, the absorption rate of caffeine. Antidepressants, antiparkinsonian and antipsychotic drugs, phenothiazine derivatives increase the risk of urinary retention, dry mouth, and constipation. Glucocorticosteroids increase the risk of glaucoma development.

Special precautions for use.

Use during pregnancy or breastfeeding.

The use of this medicinal product is not recommended during pregnancy or breastfeeding.

Ability to affect reaction speed when driving vehicles or operating machinery.

It is not recommended to drive vehicles or operate potentially dangerous machinery during the use of this medicine.

In patients with severe infections such as sepsis, which are 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.

During treatment with this medicine, avoid excessive consumption of coffee, strong tea, other stimulant beverages, and medicinal products containing caffeine. This may cause sleep disturbances, tremor, tension, nervousness, irritability, and palpitations. Alcohol consumption should be avoided.

Use with caution in patients with compensated heart failure, in individuals with congenital prolonged QT interval or in cases of prolonged use of drugs that may prolong the QT interval, in patients at risk of seizures, in patients with chronic obstructive respiratory diseases, persistent or chronic cough due to smoking or pulmonary emphysema, when cough is associated with excessive sputum production. Use with caution in individuals predisposed to increased blood pressure.

During prolonged use, monitoring of peripheral blood counts and liver function should be performed.

Phenylephrine may cause increased pulse rate, dizziness, palpitations, and angina attacks; patients should be warned accordingly.

In case of accidental overdose, the patient must seek immediate medical attention, even if the condition appears stable.

Keep the medicine out of the sight and reach of children.

Method of Administration and Dosage.

Adults and children aged 15 years and older. The drug should be taken 1 tablet 3 times daily, 1–2 hours after meals. Swallow with sufficient amount of liquid. Intervals between doses should be 4–6 hours. Duration of treatment should not exceed 5 days.

Children. Not recommended for children under 15 years of age.

Overdose.

Symptoms of overdose are determined by the pharmacological effects of its components.

Symptoms caused by paracetamol.

Hepatic damage may occur 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 drugs inducing liver enzymes; chronic excessive alcohol consumption; glutathione deficiency (e.g. malnutrition, cystic fibrosis, HIV infection, fasting, cachexia)), ingestion of 5 g or more of paracetamol may lead to hepatic 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, hepatic failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and death. 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 damage. Cardiac arrhythmias and pancreatitis have also been reported.

With prolonged use of the drug in high doses, hematological side effects may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. Central nervous system (CNS) effects may include dizziness, psychomotor agitation, disorientation, sleep disturbances, cardiac arrhythmias, and pancreatitis. Urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, capsular necrosis).

Symptoms of overdose related to potentiation of the antihistaminic component's anticholinergic effects and phenylephrine's sympathomimetic action: drowsiness, possibly followed by excitation (especially in children); visual disturbances; nausea, vomiting, headache; circulatory disturbances; coma; seizures; behavioral changes; arterial hypertension; bradycardia; atropine-like psychosis.

Symptoms of phenylephrine hydrochloride overdose: dizziness, impaired consciousness, arrhythmias, tremor, hyperreflexia, irritability, restlessness.

Symptoms of overdose with pheniramine maleate – atropine-like symptoms may occur: mydriasis, photophobia, dryness of skin and mucous membranes, elevated body temperature, intestinal atony. CNS depression may be accompanied by respiratory depression and cardiovascular dysfunction (decreased pulse rate, decreased arterial pressure up to circulatory collapse).

Symptoms of caffeine overdose: headache, tremor, increased excitability and irritability, cardiac extrasystoles.

Large doses of caffeine may cause epigastric pain, vomiting, diuresis, rapid breathing, tachycardia or cardiac arrhythmia, and CNS effects (dizziness, insomnia, emotional lability, anxiety, tremor, seizures).

Treatment. Immediate medical intervention is required in case of overdose. The patient should be taken to hospital immediately, even if early symptoms 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 excessive paracetamol dose was taken within the past hour. Plasma paracetamol concentration should be measured at least 4 hours after ingestion (earlier measurements are unreliable). Treatment with N-acetylcysteine as an antidote to paracetamol may be administered within 24 hours after ingestion, but maximum protective effect is achieved when administered within 8 hours. The efficacy of the antidote decreases sharply after this time. If necessary, N-acetylcysteine should be administered intravenously according to the established dosage regimen. In the absence of vomiting, oral methionine may be used as an alternative in remote areas outside hospital settings.

General treatment: gastric lavage, symptomatic therapy, monitoring of respiratory and cardiovascular functions (adrenaline must not be used). In case of seizures, diazepam should be administered.

Adverse Reactions

Gastrointestinal system: decreased appetite, nausea, vomiting, constipation, diarrhea, flatulence, hypersalivation, heartburn. With prolonged use of significant doses of the drug – exacerbation of peptic ulcer, epigastric pain.

Cardiovascular system: tachycardia, reflex bradycardia, dyspnea, chest pain, increased blood pressure (especially in patients with arterial hypertension), myocardial dystrophy (dose-dependent effect with long-term use), palpitations, arrhythmia.

Central nervous system: behavioral changes, anxiety, sleep disturbances, drowsiness, hallucinations, headache, feelings of fear, general weakness, dizziness; psychomotor agitation and disorientation, insomnia, restlessness, irritability or nervousness, dyskinesia, tremor, confusion, depressive states, sensations of tingling and heaviness in limbs, tinnitus, epileptic seizures, coma.

Urinary system: urinary dysfunction, urinary retention and strangury (difficult urination); dysuria, interstitial nephritis, increased creatinine clearance, increased excretion of sodium and calcium, aseptic pyuria, renal colic, nephrotoxic effect, papillary necrosis, possible slight increase in 5-hydroxyindoleacetic acid, vanillylmandelic acid, and catecholamines in urine.

Blood system: disturbances in zinc and copper metabolism, anemia, including hemolytic anemia, bruising or bleeding, methemoglobinemia (cyanosis, dyspnea, chest pain), thrombocytopenia; in isolated cases – aplastic anemia, pancytopenia, sulfhemoglobinemia, neutropenia, agranulocytosis, leukopenia, thrombocytosis, hyperproteinaemia, erythropenia, neutrophilic leukocytosis, possible false increase in blood uric acid levels when measured by the Bittner method.

Eye organs system: mydriasis, accommodation disorders, increased intraocular pressure.

Immune system: anaphylaxis, hypersensitivity reactions including skin itching, rashes on skin and mucous membranes (usually generalized rash, erythematous rash, urticaria), angioneurotic edema, hyperemia; bronchial obstruction, multiform exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome); in isolated cases – anaphylactic shock.

Metabolism and nutrition: with unknown frequency (cannot be estimated from available data) – metabolic acidosis with high anion gap.

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

Hepatobiliary system: liver function disturbances, increased liver enzyme activity, usually without development of jaundice; hepatotoxicity, hepatic necrosis.

Other: nasal congestion, dryness in nose, dryness in mouth or throat, sore throat, hoarseness, vision disturbances, dry eyes, in isolated cases – increased sweating.

Description of specific adverse reactions

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

With prolonged use at high doses – damage to the glomerular apparatus of kidneys, crystalluria, formation of urate, cystine and/or oxalate stones in kidneys and urinary tract; damage to the islet apparatus of the pancreas with hyperglycemia up to hypoglycemic coma, glucosuria, and impaired glycogen synthesis leading to development of diabetes mellitus.

If any adverse reactions occur, the patient should discontinue the drug and consult a physician.

Shelf life. 3 years.

Storage conditions. Store in a dry, protected from light and inaccessible to children place at temperature not exceeding 25 °C.

Packaging. 12 tablets in a blister, 1 blister in a cardboard box; 4 tablets in a blister, 1 blister in a cardboard envelope.

Dispensing category. Over-the-counter.

Manufacturer. Precise Chemipharm Pvt. Ltd., India

Manufacturer's address and place of business.
Plot No. 215/1, 215/2, Khatvad Phata, At Post: Talegaon, Taluka-Dindori, Nashik-422 202, Maharashtra, India.