Gripomed

INSTRUCTIONS FOR MEDICINAL USE OF THE MEDICINAL PRODUCT GRIPOMED® (GRIPOMED)

Composition:

Active substances: paracetamol, caffeine, chlorpheniramine maleate, ascorbic acid;

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

Excipients: calcium stearate, talc, stearic acid, colloidal anhydrous silicon dioxide, povidone, potato starch, sodium croscarmellose.

Pharmaceutical form. Capsules.

Main physicochemical characteristics: hard gelatin capsules with a blue opaque cap and a white opaque body, containing a white powder with a creamy shade.

Pharmacotherapeutic group. Paracetamol combinations without psychotropic agents.

ATC code N02BE51.

Pharmacological Properties.

Pharmacodynamics.

The drug has analgesic, antipyretic, anti-inflammatory, and desensitizing activity. The mechanism of action of the active ingredient — paracetamol — is due to inhibition of prostaglandin synthesis in the central nervous system.

Caffeine is a potent central nervous system stimulant that 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 brain, reduces platelet aggregation, increases diuresis and gastric secretory activity. Caffeine enhances and accelerates the pharmacotherapeutic effect of paracetamol.

Chlorpheniramine, by blocking histamine H1-receptors, exerts desensitizing and analgesic effects, reduces vascular-tissue permeability of the mucous membranes of the upper respiratory tract, and relieves itching in eyes and nose.

Ascorbic acid is an essential vitamin. It is known that ascorbic acid plays an important role in realizing the body's protective functions against infection and is necessary for normal functioning of T-lymphocytes and effective phagocytic activity of leukocytes. It normalizes capillary permeability. Ascorbic acid has antioxidant properties, promotes activation of the immune system, and increases resistance of the body to colds and respiratory infections.

Pharmacokinetics.

Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract, primarily from the upper intestinal segments. Plasma protein binding is about 25%. It is metabolized in the liver to form glucuronide and sulfate conjugates. It is excreted by the kidneys mainly as metabolites, with less than 5% excreted unchanged. Caffeine is well absorbed from the gastrointestinal tract and uniformly distributed throughout all body tissues. It readily crosses the blood-brain barrier. During biotransformation, it undergoes demethylation and oxidation. It is eliminated from the body in urine as metabolites, with a small portion (approximately 8%) excreted unchanged. Chlorpheniramine is well absorbed from the gastrointestinal tract; 69–72% of the drug binds to plasma proteins. Maximum plasma concentration is reached within 2–6 hours. It is metabolized in the liver to form dimethylchlorpheniramine and didesmethylchlorpheniramine. Chlorpheniramine and its metabolites are primarily excreted by the kidneys.

Ascorbic acid is well absorbed from the small intestine and readily penetrates into leukocytes and platelets, then into all tissues. Bioavailability is approximately 70%.

Plasma protein binding is 24%. It is mainly metabolized in the liver. It is excreted as metabolites and partially in unchanged form, primarily via the kidneys in urine, as well as in feces and sweat. It passes into breast milk.

Clinical characteristics.

Indications.

Symptomatic treatment of colds accompanied by elevated body temperature, headache, and nasal mucosa swelling (rhinitis).

Contraindications.

Hypersensitivity to the components of the drug or to other xanthine derivatives (theophylline, theobromine), congenital hyperbilirubinemia, Lapp lactase deficiency or glucose-galactose malabsorption, congenital glucose-6-phosphate dehydrogenase deficiency, fructose intolerance, Gilbert’s syndrome, Dubin-Johnson syndrome, blood disorders, leukopenia, anemia, blood dyscrasias, severe hepatic or renal dysfunction, marked arterial hypertension, severe cardiovascular diseases including cardiac arrhythmias, severe atherosclerosis, severe form of ischemic heart disease, hyperthyroidism, states of increased excitation, sleep disturbances, glaucoma, alcoholism, bronchial asthma, epilepsy. Thrombosis, predisposition to thrombosis, thrombophlebitis, diabetes mellitus, acute pancreatitis, peptic ulcer of the stomach and duodenum in the acute phase, urolithiasis, prostatic hyperplasia with obstructed urination, bladder neck obstruction, pyloroduodenal obstruction.

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

Advanced age. Pregnancy or breastfeeding period.

Interaction with other medicinal products and other types of interactions.

Paracetamol:

• when used concomitantly with drugs that delay gastric emptying (e.g., propantheline), absorption and thus effectiveness of paracetamol may be reduced;
• when used concomitantly with drugs that accelerate gastric emptying (e.g., metoclopramide), absorption and thus effectiveness of paracetamol may be increased;
• concomitant use with azidothymidine (zidovudine) increases the risk of neutropenia. Therefore, the drug should be used with azidothymidine only after consultation with a physician;
• concomitant use with probenecid inhibits glucuronidation of paracetamol and reduces paracetamol clearance by approximately 2-fold. Dose reduction of paracetamol is recommended when used concomitantly with probenecid;
• salicylates may prolong the half-life of paracetamol;
• caution is advised when used concomitantly with enzyme inducers and potentially hepatotoxic agents;
• repeated use of paracetamol over several weeks enhances the effect of anticoagulants;
• cholestyramine reduces paracetamol absorption;
• domperidone may increase the rate of paracetamol absorption, while cholestyramine may decrease it;
• anticonvulsant drugs (including phenytoin, barbiturates, carbamazepine), which stimulate hepatic microsomal enzyme activity, may enhance the hepatotoxic effect of paracetamol due to increased formation of hepatotoxic metabolites;
• anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol, increasing the risk of bleeding. Occasional use has no significant effect;
• barbiturates reduce the antipyretic effect of paracetamol;
• concomitant use of paracetamol with hepatotoxic agents increases hepatotoxic effects;
• 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 such 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 effect of chlorpheniramine maleate: hypnotics, tranquilizers.

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

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

Concomitant use of the drug with the following medicinal products may significantly increase the depressant effect of chlorpheniramine maleate: barbiturates; neuroleptics; anesthetics; narcotic analgesics; alcohol.

Caffeine:

• caffeine may reduce the sedative effect of barbiturates and antihistamines;
• caffeine has a synergistic effect with sympathomimetics and thyroxine (increases heart rate);
• concomitant use with theophylline reduces the latter’s elimination;
• caffeine enhances the additive potential of ephedrine-type substances;
• in combination with broad-spectrum agents (e.g., benzodiazepines), various unpredictable reactions may occur;
• oral contraceptives, cimetidine, and disulfiram reduce caffeine metabolism in the liver; barbiturates and nicotine enhance it;
• cimetidine, hormonal contraceptives, and isoniazid enhance the effect of caffeine;
• concomitant use of quinolone carboxylic hydrazide inhibitors may reduce elimination of caffeine and its metabolite paraxanthine;
• caffeine enhances the effect (improves bioavailability) of analgesic-antipyretic agents, potentiates effects of xanthine derivatives, α- and β-adrenergic agonists, and psychostimulants;
• 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, and as a competitive antagonist of adenosine and angiotensin-converting enzyme inhibitors;
• concomitant use of caffeine with ergotamine improves ergotamine absorption in the gastrointestinal tract; with thyrotropic agents, it enhances the thyroid effect;
• caffeine reduces serum lithium concentration.

Antidepressants, antiparkinsonian and antipsychotic agents, phenothiazine derivatives increase the risk of urinary retention, dry mouth, and constipation.

Concomitant use of caffeine with MAO inhibitors may cause dangerous elevation of blood pressure.

Ascorbic acid:

Absorption of ascorbic acid is reduced when used concomitantly with oral contraceptives, fruit or vegetable juices, or alkaline drinks. Orally administered ascorbic acid increases absorption of penicillin, tetracycline, and iron; reduces the effectiveness of heparin and indirect anticoagulants; increases the risk of crystalluria during salicylate therapy. Ascorbic acid may be taken only 2 hours after deferoxamine injection. Concomitant use of ascorbic acid and deferoxamine increases tissue iron toxicity, especially in cardiac muscle, which may lead to circulatory decompensation. Ascorbic acid increases total clearance of ethanol. Long-term use of quinolone derivatives, calcium chloride, salicylates, and corticosteroids reduces ascorbic acid reserves in the body.

Prolonged use of high doses in patients treated with disulfiram inhibits the disulfiram-alcohol reaction.

High doses of the drug reduce the effectiveness of tricyclic antidepressants.

Potential interactions between this drug and other agents should be considered: concomitant use with barbiturates (phenobarbital, bellaspon), antidepressants (amitriptyline, fluoxetine), or alcohol significantly increases the risk of hepatotoxicity.

The drug enhances the effect of central nervous system depressants (chlorpromazine, diazepam, imovan, etc.), accompanied by increased excitation, high temperature, and changes in respiratory and circulatory function.

Glucocorticosteroids increase the risk of glaucoma development.

Special precautions for use.

Do not exceed the recommended doses.

Do not take this medicine with other products containing paracetamol.

If symptoms do not improve, consult a physician.

If headache becomes persistent, consult a physician.

Consult a physician before use if the patient is taking warfarin or similar anticoagulant drugs; has impaired kidney or liver function; takes analgesics daily for mild forms of arthritis; or if there are signs of secondary infection, fever, worsening of symptoms, or development of further complications.

In patients with severe infections such as sepsis, associated 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. Seek immediate medical attention if these symptoms occur.

Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoprolinuria (pyroglutamic acidosis) have been reported in patients with severe conditions such as severe renal failure and sepsis, as well as in patients with malnutrition or other causes 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 high anion gap metabolic acidosis due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with careful patient monitoring. Measurement of urinary 5-oxoproline levels may be helpful in identifying pyroglutamic acidosis as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

Prolonged use of high doses of analgesics may lead to medication-overuse headache. In such cases, increasing the dose of the medicine is not recommended.

As with other paracetamol-containing medicines, exceeding the recommended dose may result in acute liver injury, requiring immediate medical treatment.

Patients with alcoholic liver disease have an increased risk of hepatotoxic effects from paracetamol.

To avoid the risk of overdose, ensure that the maximum daily dose of paracetamol is not exceeded when using other paracetamol-containing medicines (for patients weighing over 43 kg – 4000 mg of paracetamol).

There is a risk of calcium oxalate kidney stone formation when high doses of ascorbic acid are used in patients predisposed to kidney stone formation.

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

Use with caution in patients with mild to moderate impairment of kidney or liver function, epilepsy, benign prostatic hyperplasia, urinary disorders, or nephrolithiasis, and only after consultation with a physician. When high doses are used or treatment is prolonged, monitor kidney and liver function, blood pressure, and pancreatic function.

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

If signs of illness do not begin to improve within 3 days of treatment or, conversely, if the condition worsens, medical advice should be sought.

Ascorbic acid may affect the results of various laboratory tests, for example, blood glucose, bilirubin, transaminase activity, lactate dehydrogenase, etc.

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 levels in the body should use the medicine at the lowest possible doses.

During treatment with this medicine, it is not recommended to consume excessive amounts of beverages containing caffeine (e.g., coffee, tea). This may cause sleep disturbances (insomnia), dizziness, increased excitability, restlessness, anxiety, irritability, headache, gastrointestinal disturbances, tachycardia, tremor, tension, and agitation.

Use during pregnancy or breastfeeding.

Gripomed®, capsules are contraindicated during pregnancy or breastfeeding.

Current data on the use of paracetamol in pregnant women indicate no disturbances in fetal development or fetotoxic/neonatal toxicity.

Epidemiological studies on the neurodevelopmental outcomes of children exposed to paracetamol in utero have shown inconclusive results.

Studies on paracetamol have not revealed any risk to human fetal development or pregnancy; however, consultation with a physician is necessary before using paracetamol during pregnancy, and it should be used at the lowest effective dose, for the shortest duration, and with the lowest possible frequency.

Paracetamol crosses the placental barrier and is excreted in breast milk.

Effect on ability to drive or operate machinery.

During treatment, activities requiring high attention, and rapid mental or motor reactions should be avoided (see section "Adverse reactions" regarding nervous system and visual disturbances).

Method of Administration and Dosage

The medication 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 medication should be taken regardless of meal times, swallowed with an adequate amount of water.

The maximum duration of self-administration is 3 days.

Under a physician's prescription, the treatment course may last 5–7 days.

Patients with mild to moderate hepatic and/or renal impairment

For patients with mild to moderate impairment of liver and/or kidney function, dosage adjustment or an increased interval between doses is recommended.

Do not exceed the recommended dose.

Do not take together with other medicinal products containing paracetamol.

Children. The medication is indicated for children aged 12 years and older.

Overdose.

Symptoms of overdose are caused by the action of each individual component of the medication.

Paracetamol

Hepatic 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 [long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs inducing liver enzymes; chronic excessive alcohol consumption; glutathione depletion (malnutrition, cystic fibrosis, HIV infection, fasting, cachexia)], ingestion of 5 g or more of paracetamol 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, hepatic failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and death. Acute renal failure with acute tubular necrosis may present as severe lumbar 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 high doses, hematological complications may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. High-dose intake may also cause the following reactions: from the central nervous system (CNS) – dizziness, psychomotor agitation, disorientation; from the urinary system – nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis).

In case of overdose, immediate medical assistance is required. The patient should be transported to a hospital immediately, even if early symptoms are absent. Symptoms may be limited to nausea and vomiting or may not reflect the severity of the overdose or the risk of organ damage. Activated charcoal treatment 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. Intravenous N-acetylcysteine should be administered as per current guidelines if required. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside hospital settings.

Chlorpheniramine maleate

Following overdose, anticholinergic components cause symptoms similar to those induced by atropine: mydriasis, photophobia, facial flushing, fixed dilated pupils, ataxia, tremor, fever, dry mouth, and constipation. Subsequently, signs of central nervous system intoxication may appear, with the condition ranging from depression to excitation – restlessness and seizures, photophobia, dryness of skin and mucous membranes, intestinal atony. This may progress to coma, respiratory failure, and cardiovascular collapse.

Caffeine

When large doses of caffeine (≥ 1 g) are taken within a short period, symptoms of intoxication may develop: epigastric pain, vomiting, diuresis, tachypnea, extrasystoles, cardiovascular disturbances (tachycardia or cardiac arrhythmia, myocardial damage), and central nervous system reactions (dizziness, insomnia, nervous excitation, irritability, affective disturbance, anxiety, confusion, tremor, seizures).

Treatment: There is no specific antidote; however, supportive measures such as the use of beta-adrenergic receptor antagonists may alleviate cardiotoxic effects. Gastric lavage is indicated, oxygen therapy should be administered, and diazepam should be used in case of seizures. Symptomatic therapy is required.

Ascorbic acid

Epigastric pain, nausea, vomiting, flatulence, diarrhea, pruritus, and skin rash, increased nervous system excitability. After a single dose of > 3 g, transient osmotic diarrhea and gastrointestinal disturbances may occur.

There is a risk of hemolysis and kidney stone formation.

With prolonged use at high doses, possible adverse effects include suppression of the islet apparatus of the pancreas, cystitis, glomerular apparatus damage in kidneys, crystalluria, myocardial dystrophy, disturbances in zinc and copper metabolism, thrombocytosis, erythrocytopenia, thrombosis, neutrophilic leukocytosis, and hypercoagulability.

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

Side effects

Discontinue use of the medication and seek immediate medical attention if any adverse reactions occur. Side effects of paracetamol are very rare (< 1/10,000).

Laboratory findings

Unknown: paracetamol may affect uric acid levels when measured using phosphotungstic acid reagent, and blood glucose levels when measured using peroxidase oxidase method.

When the recommended dose of ascorbic acid is used, increased urinary concentration of ascorbic acid may interfere with accurate assessment of certain clinical chemistry parameters (glucose, uric acid, creatinine, inorganic phosphates, occult blood in feces). Thus, the reliability of methods based on color reactions may be altered.

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

Immune system disorders:
Anaphylaxis, hypersensitivity reactions including skin and mucosal pruritus, skin rash (typically generalized rash, erythematous rash, urticaria), angioneurotic edema, multiform exudative erythema (including Stevens–Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), anaphylactic shock.

Skin and subcutaneous tissue disorders:
Allergic skin reactions (erythema, rash), which may be accompanied by fever (drug-induced fever), mucosal damage, localized medicamentous dermatitis, pruritus, urticaria.

Gastrointestinal disorders:
Dyspeptic symptoms including nausea, vomiting, epigastric discomfort and pain, heartburn, dry mouth, hypersalivation, decreased appetite, diarrhea.

Eye disorders:
Visual disturbances and accommodation disorders, mydriasis, increased intraocular pressure, development of glaucoma (angle-closure glaucoma), dry eyes.

Respiratory system disorders:
Bronchospasm in patients sensitive to aspirin and other nonsteroidal anti-inflammatory drugs.

Hepatobiliary disorders:
Liver function abnormalities, increased liver enzyme activity (usually without jaundice), hepatonecrosis (a dose-dependent effect).

Endocrine disorders:
Hypoglycemia, up to hypoglycemic coma.

Nervous system disorders:
Headache, tremor, paresthesia, fear, restlessness, irritability, psychomotor agitation and disorientation, dyskinesia, restlessness, sedation, drowsiness, sleep disturbances, insomnia, fear, anxiety, general weakness, dizziness, confusion, in isolated cases—coma, seizures, behavioral changes.

Psychiatric disorders:
Psychotic reactions, inner restlessness, insomnia.

Metabolism and nutrition disorders:
Metabolic acidosis with high anion gap (frequency unknown).

Cardiovascular disorders:
Tachycardia, reflex bradycardia, dyspnea, chest pain, arrhythmia, palpitations, arterial hypertension.

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

Renal and urinary disorders:
Nephrotoxicity, renal colic, interstitial nephritis, papillary necrosis, impaired urination, dysuria, urinary retention, and difficulty in micturition.

With prolonged 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 the development of diabetes mellitus; myocardial dystrophy; thrombocytosis, thrombus formation, 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.

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

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 in patients with risk factors taking paracetamol (see section "Special precautions"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Shelf life. 2 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 capsules per blister. 2 blisters per cardboard box.

Prescription status.

Over-the-counter (without prescription).

Manufacturer.

JSC “CHEMICAL PHARMACEUTICAL PLANT “CHERVONA ZIRKA”.

Manufacturer’s address and location of business activity.

1, Gordienkovskaya Street, Kharkiv, Kharkiv Oblast, 61010, Ukraine.