Gripgo

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GRIPGO® (GRIPGO®)

Composition:

Active substances: paracetamol, anhydrous caffeine, phenylephrine hydrochloride, chlorpheniramine maleate;

One tablet contains: paracetamol 500 mg, anhydrous caffeine 30 mg, phenylephrine hydrochloride 10 mg, chlorpheniramine maleate 2 mg;

Excipients: microcrystalline cellulose, sodium croscarmellose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, biconvex, capsule-shaped tablets.

Pharmacotherapeutic group.

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

Pharmacological Properties

Pharmacodynamics

Grippo® is a combined medicinal product whose action is determined by the components contained in its composition.

Paracetamol is an analgesic-antipyretic agent possessing antipyretic and analgesic properties, which are associated with its effect on the hypothalamic thermoregulatory center and its ability to inhibit prostaglandin synthesis.

Caffeine is an alkaloid belonging to the methylxanthine group, exerting a stimulant effect on the central nervous system, primarily on the cerebral cortex, respiratory and vasomotor centers. It increases mental and physical performance, reduces drowsiness and feelings of fatigue, and diminishes the effects of agents that depress the central nervous system. It enhances the analgesic effect of paracetamol.

Phenylephrine hydrochloride is a sympathomimetic agent that reduces swelling of the nasal mucosa and paranasal sinuses, as well as the severity of exudative manifestations, thereby improving nasal breathing. It predominantly stimulates alpha-adrenergic receptors, resulting in vasoconstriction, reduced permeability of peripheral blood vessels, and decreased production of mucus secretion.

Chlorpheniramine maleate is an antihistamine agent with antiallergic activity. It competitively blocks histamine H1-receptors and prevents the development of histamine-mediated effects, relieving rhinorrhea, nasal itching, lacrimation, and eye irritation.

Pharmacokinetics

Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract (GI 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; 20–30% may bind at concentrations occurring during acute intoxication. It is primarily excreted by the kidneys in the form of conjugated metabolites.

Caffeine and its water-soluble salts are rapidly absorbed in the intestine (including the large intestine) and quickly distributed to all organs and tissues of the body. Protein binding in blood (to albumins) is 25–36%.
The elimination half-life from plasma is approximately 5–10 hours. The majority is demethylated and oxidized. About 10% is excreted unchanged by the kidneys. Caffeine and its metabolites are excreted renally (in adults, 1–2% of caffeine is excreted unchanged).

Phenylephrine hydrochloride has low bioavailability due to uneven absorption and the effect of monoamine oxidase in the GI tract and liver during the "first-pass" metabolism. It is excreted by the kidneys in the form of metabolites. Acidification of urine accelerates its elimination from the body.

Chlorpheniramine maleate is slowly absorbed from the GI tract; maximum plasma concentration is reached within 2.5–6 hours. Approximately 70% is bound to plasma proteins. Bioavailability ranges from 25% to 50% of the administered dose. Chlorpheniramine undergoes extensive first-pass metabolism in the liver and is significantly metabolized in the liver, forming desmethyl- and didesmethylchlorpheniramine metabolites. Chlorpheniramine is distributed throughout the body and crosses the blood-brain barrier. The drug and its metabolites are primarily excreted unchanged in the urine within 4–6 hours. Elimination depends on urine pH and the extent of excretion. In children, more rapid and extensive absorption, elimination, and shorter half-life are observed.

Clinical characteristics.

Indications.

Treatment of symptoms of influenza and other acute respiratory viral infections: fever, headache, nasal congestion, rhinitis, sinusitis, sore throat, muscle pain, and cough.

Contraindications.

• Hypersensitivity to any component of the medicinal product, other xanthine derivatives (theophylline, theobromine), opioids, antihistamines, sympathomimetic amines, Stevens–Johnson syndrome.

• Severe cardiovascular diseases, including unstable angina, decompensated heart failure, arrhythmias and conduction disorders, congenital prolonged QT interval or prolonged use of drugs that prolong the QT interval, arrhythmias, bradycardia, severe atherosclerosis, including coronary arteries, predisposition to vascular spasm, severe forms of ischemic heart disease; severe arterial hypertension, acute phase of myocardial infarction, organic cardiovascular diseases, thrombosis, thrombophlebitis.

• Severe hepatic dysfunction (including congenital hyperbilirubinemia; Gilbert’s syndrome).

• Severe renal dysfunction.

• Prostate disorders (prostate adenoma with difficult urination, acute urinary retention in prostate hypertrophy, prostate hyperplasia, bladder neck obstruction).

• Gastrointestinal disorders (peptic ulcer of the stomach and duodenum in the stage of exacerbation, stenosing ulcer of the stomach and duodenum, pyloroduodenal obstruction; acute pancreatitis).

• Epilepsy.

• Blood disorders (including severe anemia; leukopenia; hematopoietic disorders).

• Endocrine disorders (hyperthyroidism, diabetes mellitus, pheochromocytoma, thyrotoxicosis, phenylketonuria).

• Respiratory system disorders (including bronchial asthma; chronic bronchitis; chronic obstructive pulmonary disease; emphysema; risk of respiratory failure).

• Closed-angle glaucoma, elevated intraocular pressure.

• Glucose-6-phosphate dehydrogenase deficiency.

• Dubin–Johnson syndrome, Rotor syndrome.

• Alcoholism.

• Children under 12 years of age.

• Elderly age (over 60 years).

• Pregnancy or breastfeeding.

• Increased excitability, sleep disturbances, epilepsy.

• Concomitant use with:

  • monoamine oxidase inhibitors (MAOIs) and within 2 weeks after discontinuation of their use;
  • tricyclic antidepressants;
  • medicinal products that suppress or enhance appetite, and amphetamine-like psychostimulants;
  • vasodilators;
  • beta-blockers and other sympathomimetics.

Interaction with other medicinal products and other types of interactions.

Concomitant use of this medicinal product with other medicinal products containing paracetamol or other active substances present in the composition of Gripgo® should be avoided.

The interaction characteristics of the medicinal product are determined by the properties of its components.

For paracetamol.

The absorption rate of paracetamol may be increased by metoclopramide and domperidone and decreased by 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 does not have a significant effect.

Caution should be exercised when using paracetamol concomitantly with flucloxacillin, as such concomitant use has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, especially in patients with risk factors (see section "Special precautions for use").

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.

Concomitant use of paracetamol with zidovudine may lead to the development of neutropenia. Paracetamol reduces the effectiveness of diuretics.

Do not use concomitantly with alcohol.

For caffeine.

Caffeine, when used concomitantly, enhances the effect of analgesic-antipyretic drugs (improves bioavailability), xanthine derivatives, α- and β-adrenergic agonists, psychostimulants, thyrotropic agents, and ergotamine (improves gastrointestinal absorption of ergotamine).

Cimetidine, hormonal contraceptives, and isoniazid enhance the effect of caffeine.

Caffeine increases the likelihood of liver damage caused by hepatotoxic drugs.

Caffeine reduces the effect of opioid analgesics, anxiolytics, hypnotics, and sedatives; it acts as an antagonist of anesthetic agents and other drugs that suppress the central nervous system, a competitive antagonist of adenosine and ATP; it reduces lithium concentration in blood.

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

Caffeine reduces the hypotensive effect of guanethidine, which in turn increases the alpha-adrenergic stimulatory activity of phenylephrine. 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.

For phenylephrine hydrochloride.

Phenylephrine hydrochloride should not be used concomitantly with alpha-blockers, other antihypertensive agents, phenothiazine derivatives (e.g., promethazine), bronchodilator sympathomimetics, guanethidine, digitalis, Rauwolfia alkaloids, indomethacin, methyldopa, glucocorticosteroids; drugs affecting appetite, amphetamine-like psychostimulants, labor stimulants, anesthetics, ergot alkaloids, other central nervous system stimulants, theophylline.

Concomitant use of phenylephrine hydrochloride with indomethacin and bromocriptine may cause severe arterial hypertension. Concomitant use of phenylephrine hydrochloride with sympathomimetic amines, digoxin, and cardiac glycosides increases the risk of arrhythmias and myocardial infarction.

An increased vasoconstrictive effect of the drug may occur when used concomitantly with labor stimulants, and arrhythmias may occur when used with anesthetics. A significant increase in arterial pressure may occur with concomitant intravenous administration of ergot alkaloids.

Atropine sulfate blocks the reflex bradycardia caused by phenylephrine and increases the vasopressor response to phenylephrine. Concomitant use of phenylephrine with β-blockers may lead to arterial hypertension and excessive bradycardia with possible cardiac block. Use with caution together with thyroid hormones and drugs affecting cardiac conduction (cardiac glycosides, antiarrhythmic drugs). Concomitant use with drugs that cause potassium excretion, e.g., certain diuretics such as furosemide, may enhance hypokalemia and reduce arterial sensitivity to vasoactive agents such as phenylephrine.

Do not use together with other vasoconstrictive agents (regardless of the route of administration).

Concomitant use of phenylephrine and other sympathomimetics may lead to additive stimulation of the central nervous system to an extremely high level, accompanied by nervousness, irritability, and insomnia. Seizure attacks are also possible. In addition, concomitant use of other sympathomimetics with phenylephrine may lead to increased vasoconstrictive or cardiovascular effects of either of these medicinal products.

For chlorpheniramine maleate.

Chlorpheniramine maleate enhances the anticholinergic effect of atropine, spasmolytics, and central nervous system depressants (tranquilizers, barbiturates), antiparkinsonian drugs.

Do not use concomitantly with alcohol. Chlorpheniramine maleate, when used concomitantly with alcohol, potentiates the effects of each other.

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

Maprotiline (a tetracyclic antidepressant) and other anticholinergic drugs: the anticholinergic effect of these drugs or antihistamines such as chlorpheniramine may be intensified.

Special precautions for use.

Do not exceed the recommended doses.

Do not use sedatives and hypnotics simultaneously.

For paracetamol.

The medicinal product contains paracetamol; therefore, it should not be used together with other medicinal products containing paracetamol used, for example, to reduce fever, treat pain, flu or cold symptoms, or insomnia. Concurrent use with other paracetamol-containing products may lead to overdose. Paracetamol overdose may cause liver failure, which may require liver transplantation or may be fatal.

Patients with liver or kidney disease should consult a physician before using this medicinal product.

It should be noted that patients with liver disease have an increased risk of hepatotoxic effects of paracetamol.

Cases of liver function impairment / liver failure have been reported in patients with reduced glutathione levels, such as in severe malnutrition, anorexia, low body mass index, chronic alcoholism, or sepsis.

Cases of 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 inadequate nutrition or other causes of glutathione deficiency (e.g., chronic alcoholism) who were treated with paracetamol at therapeutic doses for prolonged periods 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 monitoring of the patient's condition. Measurement of 5-oxoproline levels in urine may be helpful in identifying pyroglutamic acidosis as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

Patients with reduced glutathione levels are at increased risk of developing metabolic acidosis when taking paracetamol. 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.

If symptoms of illness do not resolve, consult a physician. Prolonged use without medical supervision may be hazardous.

The medicinal product should be used only when clearly necessary.

For chlorpheniramine maleate.

Alcohol consumption should be avoided during treatment, as alcohol enhances the sedative effect of chlorpheniramine maleate.

For phenylephrine hydrochloride.

Phenylephrine may cause increased heart rate, dizziness, or strong palpitations; patients should therefore be warned accordingly.

Use of the medicinal product may result in a positive analytical finding in doping control tests.

For caffeine.

When using the medicinal product, excessive consumption of coffee, strong tea, other stimulant beverages, and medicinal products containing caffeine should be avoided. This may cause sleep disturbances, tremor, tension, irritability, and palpitations.

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

In case of accidental overdose, immediate medical attention is required, even if the patient feels well.

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

Use during pregnancy or breastfeeding.

Grippo® is contraindicated during pregnancy. Breastfeeding should be discontinued during treatment with this medicinal product.

Effect on ability to drive and operate machinery.

During treatment, driving, operating machinery, and other potentially hazardous activities should be avoided.

Dosage and Administration

For adults and children aged 12 years and older, administer 1 tablet 3–4 times daily, with intervals between doses of at least 4 hours. The maximum daily dose is 4 tablets. The maximum duration of use without medical consultation is 3 days; continued use beyond this period should be under a physician's recommendation.

Children

The drug is contraindicated in children under 12 years of age.

Overdose

Symptoms

Below are the symptoms associated with overdose of individual components of the medicinal product Grippgo®.

Related to paracetamol

Paracetamol overdose can lead to liver failure, which may require liver transplantation or result in death. Clinical signs of liver damage typically appear 24–48 hours after overdose and peak at 4–6 days.

Symptoms within the first 24 hours include pallor, nausea, vomiting, anorexia, and abdominal pain. Asymptomatic presentation is also possible. Overdose of a single dose of paracetamol in adults and children may cause reversible or irreversible hepatocellular necrosis, leading to disturbances in glucose metabolism, metabolic acidosis, hepatocellular insufficiency, encephalopathy, hemorrhage, hypoglycemia, coma, and potentially fatal outcomes. Elevated levels of liver transaminases (aspartate aminotransferase, alanine aminotransferase), lactate dehydrogenase, bilirubin, and prolonged prothrombin time are observed 12–48 hours after ingestion. Liver injury is likely in adults who have ingested more than the recommended amount of paracetamol. It is believed that an increased amount of a paracetamol metabolite (normally detoxified by glutathione at therapeutic doses) irreversibly binds to liver tissue. Acute renal failure with acute tubular necrosis may present as severe lumbar pain, hematuria, and proteinuria, and can develop even in the absence of severe liver damage. Cardiac arrhythmias and acute pancreatitis have also been reported, usually accompanied by liver function abnormalities and hepatotoxicity.

With prolonged use of high doses, hematological side effects may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. Neurological effects may include dizziness, psychomotor agitation, and disorientation. Effects on the urinary system may include nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis).

Symptoms may be limited to nausea and vomiting and may not reflect the severity of overdose or risk of organ damage.

Risk factors for paracetamol overdose include:

• Long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, and other drugs that induce hepatic enzyme synthesis;
• Chronic alcohol abuse;
• Reduced glutathione levels, for example, due to malnutrition, fasting, cachexia, cystic fibrosis, or HIV.

Treatment: Immediate supportive and symptomatic therapy is required.

In case of overdose, prompt medical attention is essential. Treatment should be initiated immediately, and the patient should be taken to a hospital even in the absence of early symptoms, as liver damage may not develop immediately. Plasma paracetamol concentration should be measured at least 4 hours after ingestion (earlier concentrations are unreliable).

If an excessive dose of paracetamol (>150 mg/kg) was taken within the past hour, activated charcoal may be administered. Treatment with N-acetylcysteine or methionine may be beneficial. Symptomatic treatment should also be provided.

Related to phenylephrine hydrochloride and chlorpheniramine maleate

Symptoms of overdose due to phenylephrine and chlorpheniramine maleate include:

headache, hyperhidrosis, drowsiness, insomnia, behavioral changes, restlessness, irritability, tremor, seizures, hyperreflexia, dizziness, nausea, vomiting, tachycardia, arrhythmias, and extrasystoles.

Related to chlorpheniramine maleate

Overdose of chlorpheniramine maleate may result in a clinical picture ranging from CNS depression to excitation (restlessness and seizures). Anticholinergic (atropine-like) symptoms may occur, including mydriasis, photophobia, dryness of skin and mucous membranes, elevated body temperature, and intestinal atony. CNS depression may be accompanied by respiratory depression and cardiovascular disturbances.

Related to caffeine

Symptoms of caffeine overdose include dehydration, hyperthermia, tinnitus, epigastric pain, increased frequency of urination, extrasystoles, tachycardia, rapid breathing, arrhythmia, and effects on the central nervous system (dizziness, insomnia, excitement, irritability, psychomotor agitation, mood disturbances, anxiety, tremor, vomiting, seizures, convulsions, agitation, restlessness, delirium, and increased tactile or pain sensitivity).

Treatment of overdose

In case of overdose, prompt medical assistance is required. The patient should be taken to a hospital immediately, even if early symptoms are absent. Symptoms may be limited to nausea and vomiting and may not reflect the severity of overdose or risk of organ damage. Administration of activated charcoal should be considered if an excessive dose of paracetamol was ingested within the past 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 after paracetamol ingestion, but the maximum protective effect is achieved when administered within 8 hours. The efficacy of the antidote decreases significantly after this time. If required, intravenous N-acetylcysteine should be administered according to the established dosing regimen. In the absence of vomiting, oral methionine may be used as an appropriate alternative, particularly in remote areas outside a hospital setting.

Side effects.

Immune system side effects: hypersensitivity reactions, including anaphylaxis, skin itching, hyperemia, rash on skin and mucous membranes (usually generalized, erythematous, or urticarial rash), anaphylactic shock, angioedema, Stevens-Johnson syndrome (including other forms of exudative multiform erythema), toxic epidermal necrolysis, acute generalized exanthematous pustulosis.

Nervous system and psychiatric disorders: psychomotor agitation and disorientation, restlessness, behavioral changes, fear, anxiety, irritability, sleep disturbances, insomnia, drowsiness, dizziness, confusion, hallucinations, depressive states, tremor, tingling and heaviness in extremities, tinnitus, headache, dizziness, coma, convulsions, increased excitability, epileptic seizures, dyskinesia.

Respiratory system side effects: bronchospasm in patients sensitive to aspirin and other NSAIDs, nasal congestion, throat irritation, hoarseness, pharyngitis.

Eye disorders: visual disturbances and accommodation disorders, mydriasis, increased intraocular pressure, dry eyes.

Gastrointestinal side effects: decreased appetite, nausea, vomiting, dry mouth, hypersalivation, heartburn, epigastric discomfort and pain, exacerbation of peptic ulcer disease, bloating, diarrhea, constipation.

Hepatobiliary system side effects: liver function disturbances, elevated liver transaminase activity (usually without jaundice), hepatonecrosis (with high-dose use), hepatotoxicity.

Endocrine system side effects: hypoglycemia, up to hypoglycemic coma. With prolonged high-dose use, damage to the islet apparatus of the pancreas may occur (hyperglycemia, glucosuria) and impaired glycogen synthesis, potentially leading to diabetes mellitus.

Metabolism and nutrition side effects: disturbances in zinc and copper metabolism, metabolic acidosis with high anion gap.

Blood and lymphatic system side effects: anemia, including hemolytic anemia, bruising or bleeding; sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), thrombocytosis, hyperproteinaemia, erythropenia, neutrophilic leukocytosis.

With prolonged high-dose use, aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia are possible.

Renal and urinary system side effects: with high-dose use – nephrotoxicity (including papillary necrosis), urinary dysfunction, urinary retention and difficulty urinating, dysuria, interstitial nephritis, increased creatinine clearance, increased excretion of sodium and calcium, sterile pyuria, renal colic.

With prolonged high-dose use, damage to the glomerular apparatus of the kidneys, crystalluria, and formation of urate, cystine, and/or oxalate stones in the kidneys and urinary tract are possible.

Cardiovascular side effects: arterial hypertension, tachycardia or reflex bradycardia, arrhythmia, dyspnea, chest pain, myocardial dystrophy (dose-dependent effect with prolonged use), rapid heartbeat.

Other side effects: general weakness, increased sweating; possible false elevation of blood uric acid levels when measured by the Bittner method; slight increase in urinary levels of 5-hydroxyindoleacetic acid, vanillylmandelic acid, and catecholamines.

Description of individual side effects.

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.

Reporting suspected side effects.

Reporting of suspected side effects after drug registration is highly important. It enables continuous monitoring of the benefit-risk balance of the drug. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected side effects and lack of drug efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

4 tablets per blister; 1 blister per cardboard package № 4 (4×1).

4 tablets per blister; 50 blisters per cardboard package № 200 (4×50).

10 tablets per blister; 1 blister per cardboard package № 10 (10×1).

10 tablets per blister; 1 blister per cardboard package № 10.

10 cardboard packages per cardboard box № 100 (10×1×10).

10 tablets per blister; 10 blisters per cardboard package № 100 (10×10).

Dispensing category.

Over-the-counter – № 4 (4×1), № 10 (10×1) in blisters.

By prescription only – № 200 (4×50), № 100 (10×10), № 100 (10×1×10) in blisters.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of business activity.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.

INSTRUCTION

for medical use of medicinal product

GRIPGO®

(GRIPGO®)

Composition:

Active substances: paracetamol, anhydrous caffeine, phenylephrine hydrochloride, chlorpheniramine maleate;

Each tablet contains: paracetamol 500 mg, anhydrous caffeine 30 mg, phenylephrine hydrochloride 10 mg, chlorpheniramine maleate 2 mg;

Excipients: microcrystalline cellulose, sodium croscarmellose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, biconvex, capsule-shaped tablets.

Pharmacotherapeutic group.

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

Pharmacological Properties

Pharmacodynamics

Grippo® is a combined medicinal product whose action is determined by the components contained in its composition.

Paracetamol is an analgesic-antipyretic agent that has antipyretic and analgesic properties due to its effect on the hypothalamic thermoregulatory center and its ability to inhibit prostaglandin synthesis.

Caffeine is an alkaloid from the methylxanthine group that exerts a stimulating effect on the central nervous system, primarily on the cerebral cortex, respiratory and vasomotor centers, increases mental and physical performance, reduces drowsiness, fatigue, and counteracts the effects of agents that depress the central nervous system. It enhances the analgesic effect of paracetamol.

Phenylephrine hydrochloride is a sympathomimetic agent that reduces swelling of the nasal mucosa and paranasal sinuses, as well as the severity of exudative manifestations, thereby improving nasal breathing. It predominantly stimulates alpha-adrenergic receptors, resulting in vasoconstriction, reduced permeability of peripheral blood vessels, and decreased production of mucus secretion.

Chlorpheniramine maleate is an antihistamine agent with anti-allergic activity. It competitively blocks histamine H1-receptors and prevents the effects of histamine, thereby relieving rhinitis, nasal itching, lacrimation, and eye irritation.

Pharmacokinetics

Paracetamol is rapidly and almost completely absorbed in the gastrointestinal tract (GI tract). Maximum plasma concentration is reached within 30–60 minutes. The elimination half-life is 1–4 hours. It is evenly distributed in all body fluids. Plasma protein binding is variable; from 20 to 30% may bind at concentrations occurring during acute intoxication. It is primarily excreted by the kidneys in the form of conjugated metabolites.

Caffeine and its water-soluble salts are rapidly absorbed in the intestine (including the large intestine) and quickly distributed to all organs and tissues of the body. Plasma protein binding (to albumins) is 25–36%.
The elimination half-life from plasma is approximately 5–10 hours. The majority is demethylated and oxidized. About 10% is excreted unchanged by the kidneys. Caffeine and its metabolites are excreted renally (in adults, 1–2% of caffeine is excreted unchanged).

Phenylephrine hydrochloride has low bioavailability due to uneven absorption and the effect of monoamine oxidase in the GI tract and liver during the "first pass." It is excreted by the kidneys in the form of metabolites. Acidification of urine accelerates its elimination from the body.

Chlorpheniramine maleate is slowly absorbed from the GI tract; maximum plasma concentration is reached within 2.5–6 hours. Approximately 70% binds to plasma proteins. Bioavailability ranges from 25% to 50% of the administered dose. Chlorpheniramine undergoes metabolism during the "first pass" in the liver and is extensively metabolized in the liver, forming desmethyl- and didesmethylchlorpheniramine metabolites. Chlorpheniramine is distributed throughout the body and crosses the blood-brain barrier. The drug and its metabolites are primarily excreted in urine unchanged within 4–6 hours. Elimination depends on urine pH and the extent of excretion. In children, more rapid and extensive absorption, elimination, and shorter half-life are observed.

Clinical characteristics.

Indications.

Treatment of symptoms of influenza and other acute respiratory viral infections: fever, headache, nasal congestion, rhinitis, sinusitis, sore throat, muscle pain, and cough.

Contraindications.

• Hypersensitivity to any component of the medicinal product, other xanthine derivatives (theophylline, theobromine), opioids, antihistamines, sympathomimetic amines, Stevens–Johnson syndrome.

• Severe cardiovascular diseases, including unstable angina, decompensated heart failure, rhythm and conduction disorders, congenital prolonged QT interval or prolonged use of drugs that prolong the QT interval, arrhythmias, bradycardia, severe atherosclerosis including coronary arteries, predisposition to vascular spasm, severe forms of ischemic heart disease; severe arterial hypertension, acute phase of myocardial infarction, organic cardiovascular diseases, thrombosis, thrombophlebitis.

• Severe hepatic dysfunction (including congenital hyperbilirubinemia; Gilbert’s syndrome).

• Severe renal dysfunction.

• Prostate disorders (prostate adenoma with difficult urination, acute urinary retention in prostate hypertrophy, prostate hyperplasia, bladder neck obstruction).

• Gastrointestinal disorders (gastric and duodenal ulcer in the stage of exacerbation, stenosing gastric and duodenal ulcer, pyloroduodenal obstruction; acute pancreatitis).

• Epilepsy.

• Blood disorders (including severe anemia; leukopenia; hematopoietic disorders).

• Endocrine disorders (hyperthyroidism, diabetes mellitus, pheochromocytoma, thyrotoxicosis, phenylketonuria).

• Respiratory disorders (including bronchial asthma; chronic bronchitis; chronic obstructive pulmonary disease; emphysema; risk of respiratory failure).

• Closed-angle glaucoma, increased intraocular pressure.

• Glucose-6-phosphate dehydrogenase deficiency.

• Dubin–Johnson syndrome, Rotor syndrome.

• Alcoholism.

• Age under 12 years.

• Elderly age (over 60 years).

• Pregnancy or breastfeeding.

• Increased excitability, sleep disturbances, epilepsy.

• Concomitant use with:

  • monoamine oxidase inhibitors (MAOIs) and within 2 weeks after discontinuation of their use;
  • tricyclic antidepressants;
  • medicinal products that suppress or increase appetite, and amphetamine-like psychostimulants;
  • vasodilators;
  • beta-blockers and other sympathomimetics.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of this medicinal product with other medicinal products containing paracetamol or other active ingredients present in the composition of Gripgo® should be avoided.

The interaction profile of the medicinal product is determined by the properties of its components.

For paracetamol.

The absorption rate of paracetamol may be increased by metoclopramide and domperidone and decreased by 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 does not have a significant effect.

Caution is advised when using paracetamol concomitantly with flucloxacillin, as such combination is associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, especially in patients with risk factors (see section "Special precautions for use").

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 effect of the drugs.

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

Concomitant use of paracetamol with zidovudine may lead to the development of neutropenia. Paracetamol reduces the effectiveness of diuretics.

Do not use concomitantly with alcohol.

For caffeine.

Caffeine enhances the effect of analgesic-antipyretic drugs (improves bioavailability), xanthine derivatives, α- and β-adrenergic agonists, psychostimulants, thyrotropic agents, and ergotamine (ergotamine absorption from the gastrointestinal tract is improved) when used concomitantly.

Cimetidine, hormonal contraceptives, and isoniazid enhance the effect of caffeine.

Caffeine increases the likelihood of liver damage caused by hepatotoxic drugs.

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, as a competitive antagonist of adenosine and ATP; it reduces lithium concentration in blood.

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

Caffeine reduces the antihypertensive effect of guanethidine, which in turn increases the alpha-adrenergic stimulatory activity of phenylephrine. Caffeine enhances the effect of indirect anticoagulants (coumarin derivatives). Metoclopramide increases, and cholestyramine reduces, the absorption rate of caffeine. Antidepressants, antiparkinsonian and antipsychotic drugs, phenothiazine derivatives increase the risk of urinary retention, dry mouth, and constipation. Glucocorticoids increase the risk of glaucoma.

For phenylephrine hydrochloride.

Phenylephrine hydrochloride should not be used concomitantly with alpha-blockers, other antihypertensive agents, phenothiazine derivatives (e.g., promethazine), bronchodilator sympathomimetics, guanethidine, digitalis, Rauwolfia alkaloids, indomethacin, methyldopa, glucocorticosteroids; appetite-affecting drugs, amphetamine-like psychostimulants, labor stimulants, anesthetics, ergot alkaloids, other central nervous system stimulants, theophylline.

Concomitant use of phenylephrine hydrochloride with indomethacin and bromocriptine may cause severe arterial hypertension. Concomitant use of phenylephrine hydrochloride with sympathomimetic amines, digoxin, and cardiac glycosides increases the risk of arrhythmias and myocardial infarction.

Vasoconstrictive effect of the drug may be enhanced when used concomitantly with labor stimulants, and arrhythmias may occur when used with anesthetics. Significant increase in blood pressure may occur with concomitant intravenous administration of ergot alkaloids.

Atropine sulfate blocks reflex bradycardia caused by phenylephrine and increases the vasopressor response to phenylephrine. Concomitant use of phenylephrine with β-adrenergic blockers may lead to arterial hypertension and excessive bradycardia with possible cardiac block. Use with caution together with thyroid hormones, drugs affecting cardiac conduction (cardiac glycosides, antiarrhythmic drugs). Concomitant use with drugs causing potassium excretion, e.g., certain diuretics such as furosemide, may enhance hypokalemia and reduce arterial sensitivity to vasoconstrictor agents such as phenylephrine.

Do not use together with other vasoconstrictive agents (regardless of the route of administration).

Concomitant use of phenylephrine and other sympathomimetics may lead to additive stimulation of the central nervous system to an extremely high level, accompanied by nervousness, irritability, and insomnia. Seizure attacks are also possible. In addition, concomitant use of other sympathomimetics with phenylephrine may lead to increased vasoconstrictive or cardiovascular effects of either of these medicinal products.

For chlorpheniramine maleate.

Chlorpheniramine maleate enhances the anticholinergic effect of atropine, spasmolytics, and central nervous system depressants (tranquilizers, barbiturates), antiparkinsonian drugs.

Do not use concomitantly with alcohol. Chlorpheniramine maleate and alcohol potentiate each other’s effects when used concomitantly.

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

Mianserin (tetracyclic antidepressant) and other drugs with anticholinergic activity: the anticholinergic effect of these drugs or antihistamines such as chlorpheniramine may be enhanced.

Special precautions for use.

Do not exceed recommended doses.

Do not use sedatives and hypnotics simultaneously.

For paracetamol.

The medicinal product contains paracetamol; therefore, it should not be used together with other medications containing paracetamol, such as those used for fever reduction, pain relief, treatment of 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 result in death.

Patients with liver or kidney disease should consult a physician before using this product.

It should be noted that patients with liver disease have an increased risk of hepatotoxic effects of paracetamol.

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

Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoproline (pyroglutamic) acidosis have been reported in patients with severe conditions such as severe renal failure and sepsis, or in patients with inadequate nutrition or other causes of glutathione deficiency (e.g., chronic alcoholism) who were treated with paracetamol at therapeutic doses 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 monitoring of the patient. Measurement of urinary 5-oxoproline levels may be useful in identifying pyroglutamic acidosis as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

Patients with reduced glutathione levels are at increased risk of developing metabolic acidosis when taking paracetamol. 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.

If symptoms of illness do not resolve, consult a physician. Prolonged use without medical supervision may be dangerous.

The medicinal product should be used only when clearly necessary.

For chlorpheniramine maleate.

Alcohol consumption should be avoided during treatment, as alcohol enhances the sedative effect of chlorpheniramine maleate.

For phenylephrine hydrochloride.

Phenylephrine may cause increased heart rate, dizziness, or strong palpitations; patients should be warned accordingly.

Use of the product may result in a positive analytical finding in doping controls.

For caffeine.

When using this product, avoid excessive consumption of coffee, strong tea, other stimulant beverages, and medications containing caffeine. This may cause sleep disturbances, tremor, tension, irritability, and palpitations.

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

In case of accidental overdose, seek immediate medical attention, even if the patient feels well.

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

Use during pregnancy or breastfeeding.

Grippo® is contraindicated during pregnancy. Breastfeeding should be discontinued for the duration of treatment with this product.

Ability to affect reaction speed when driving or operating machinery.

During treatment, avoid driving, operating machinery, and other potentially hazardous activities.

Dosage and Administration.

For adults and children aged 12 years and older, the recommended dose is 1 tablet 3–4 times daily, with intervals between doses of at least 4 hours. The maximum daily dose is 4 tablets. The maximum duration of use without consulting a physician is 3 days; continued use should be under medical supervision.

Children.

The drug is contraindicated in children under 12 years of age.

Overdose.

Symptoms.

Below are the symptoms of overdose related to individual components of the medicinal product Grippgo®.

Associated with paracetamol.

Paracetamol overdose may cause liver failure, which could require liver transplantation or result in a fatal outcome. Clinical signs of liver damage typically appear 24–48 hours after overdose and peak at 4–6 days.

Symptoms within the first 24 hours include pallor, nausea, vomiting, anorexia, and abdominal pain. Overdose may also be asymptomatic initially. A single overdose of paracetamol in adults and children may cause reversible or irreversible hepatocellular necrosis, leading to disturbances in glucose metabolism, metabolic acidosis, hepatic insufficiency, encephalopathy, hemorrhage, hypoglycemia, coma, and potentially death. Elevated levels of liver transaminases (aspartate aminotransferase, alanine aminotransferase), lactate dehydrogenase, bilirubin, and prolonged prothrombin time are usually observed 12–48 hours after ingestion. Liver damage is likely in adults who have ingested more than the recommended amount of paracetamol. It is believed that an increased amount of a paracetamol metabolite (normally neutralized by glutathione at therapeutic doses) binds irreversibly to liver tissue. Acute renal failure with acute tubular necrosis may present as severe lumbar pain, hematuria, and proteinuria, and may develop even in the absence of severe liver injury. Cardiac arrhythmias and acute pancreatitis have also been reported, usually accompanied by liver function abnormalities and hepatotoxicity.

With prolonged use of high doses, hematological complications may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. Neurological effects may include dizziness, psychomotor agitation, and disorientation. Urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis).

Symptoms may be limited to nausea and vomiting or may not reflect the severity of the overdose or risk of organ damage.

Risk factors for paracetamol overdose include:

• Long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, and other drugs that induce liver enzyme synthesis;
• Chronic alcohol abuse;
• Reduced glutathione levels, e.g., due to malnutrition, fasting, cachexia, cystic fibrosis, or HIV.

Treatment: Immediate supportive and symptomatic therapy.

In case of overdose, urgent medical assistance is required. Treatment should be initiated immediately, and the patient should be taken to a hospital even if early symptoms are absent, as liver damage may not develop immediately. Plasma paracetamol concentration should be measured at least 4 hours after ingestion (earlier measurements are unreliable).

If an excessive dose of paracetamol (>150 mg/kg) was taken within the last hour, activated charcoal may be administered. Treatment with N-acetylcysteine or methionine may be beneficial. Symptomatic treatment should also be provided.

Associated with phenylephrine hydrochloride and chlorpheniramine maleate.

Symptoms of overdose due to phenylephrine and chlorpheniramine maleate include:

headache, hyperhidrosis, drowsiness, insomnia, behavioral changes, restlessness, irritability, tremor, seizures, hyperreflexia, dizziness, nausea, vomiting, tachycardia, arrhythmias, and extrasystoles.

Associated with chlorpheniramine maleate.

Overdose of chlorpheniramine maleate may result in a clinical state ranging from CNS depression to excitation (restlessness and seizures). Anticholinergic-like symptoms may occur, including mydriasis, photophobia, dry skin and mucous membranes, elevated body temperature, and intestinal atony. CNS depression may be accompanied by respiratory depression and cardiovascular disturbances.

Associated with caffeine.

Symptoms of caffeine overdose include dehydration, hyperthermia, tinnitus, epigastric pain, increased diuresis, extrasystoles, tachycardia, rapid breathing, arrhythmia, and effects on the central nervous system (dizziness, insomnia, excitement, irritability, psychomotor agitation, affective disturbances, anxiety, tremor, vomiting, seizures, convulsions, agitation, restlessness, delirium, and increased tactile or pain sensitivity).

Treatment of overdose.

In case of overdose, immediate medical assistance is required. The patient should be taken 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 risk of organ damage. Administration of activated charcoal should be considered if an excessive dose of paracetamol was ingested within the past 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 after paracetamol ingestion, but maximum protective effect is achieved when administered within 8 hours. The efficacy of the antidote decreases significantly after this period. Intravenous N-acetylcysteine should be administered according to the established dosing regimen if required. In the absence of vomiting, oral methionine may be used as an alternative, particularly in remote areas outside hospital settings.

Adverse Reactions.

Immune system disorders: hypersensitivity reactions, including anaphylaxis, pruritus, hyperemia, skin and mucous membrane rashes (usually generalized rash, erythematous, urticaria), anaphylactic shock, angioedema, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis, acute generalized exanthematous pustulosis.

Nervous system disorders and psychiatric disorders: psychomotor agitation and disorientation, restlessness, behavioral changes, fear, anxiety, irritability, sleep disturbances, insomnia, drowsiness, dizziness, confusion, hallucinations, depressive states, tremor, sensations of tingling and heaviness in limbs, tinnitus, headache, dizziness, coma, seizures, increased excitability, epileptic seizures, dyskinesia.

Respiratory system disorders: bronchospasm in patients sensitive to aspirin and other NSAIDs, nasal congestion, throat irritation, hoarseness, pharyngitis.

Eye disorders: visual disturbances and accommodation disorders, mydriasis, increased intraocular pressure, dry eyes.

Gastrointestinal disorders: decreased appetite, nausea, vomiting, dry mouth, hypersalivation, heartburn, epigastric discomfort and pain, exacerbation of peptic ulcer, flatulence, diarrhea, constipation.

Hepatobiliary disorders: liver function abnormalities, increased liver transaminase activity, usually without development of jaundice, hepatonecrosis (with high-dose use), hepatotoxicity.

Endocrine system disorders: hypoglycemia, up to hypoglycemic coma. With prolonged use in high doses, damage to the pancreatic islet apparatus (hyperglycemia, glucosuria) and impaired glycogen synthesis may occur, leading to the development of diabetes mellitus.

Metabolism and nutrition disorders: disturbances in zinc and copper metabolism, metabolic acidosis with high anion gap.

Blood and lymphatic system disorders: anemia, including hemolytic anemia, bruising or bleeding; sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), thrombocytosis, hyperproteinaemia, erythropenia, neutrophilic leukocytosis.

With prolonged use in high doses, aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia are possible.

Renal and urinary system disorders: with high-dose use – nephrotoxicity (including papillary necrosis), impaired urination, urinary retention and difficulty in urination, dysuria, interstitial nephritis, increased creatinine clearance, increased excretion of sodium and calcium, sterile pyuria, renal colic.

With prolonged use in high doses, damage to the glomerular apparatus of the kidneys, crystalluria, and formation of urate, cystine and/or oxalate calculi in the kidneys and urinary tract are possible.

Cardiovascular system disorders: arterial hypertension, tachycardia or reflex bradycardia, arrhythmia, dyspnea, chest pain, myocardial dystrophy (dose-dependent effect with prolonged use), rapid heartbeat.

Other: general weakness, increased sweating; possible false increase in blood uric acid levels when measured by the Bittner method; slight increase in urinary levels of 5-hydroxyindoleacetic acid, vanillylmandelic acid, and catecholamines.

Description of specific 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.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

4 tablets in a blister; 1 blister in a cardboard package № 4 (4×1).

4 tablets in a blister; 50 blisters in a cardboard package № 200 (4×50).

10 tablets in a blister; 1 blister in a cardboard package № 10 (10×1).

10 tablets in a blister; 1 blister in a cardboard package № 10.

10 cardboard packages in a cardboard box № 100 (10×1×10).

10 tablets in a blister; 10 blisters in a cardboard package № 100 (10×10).

Prescription category.

Over-the-counter – № 4 (4×1), № 10 (10×1) in blisters.

By prescription only – № 200 (4×50), № 100 (10×10), № 100 (10×1×10) in blisters.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of business operations.

Plot No. M-3, Indore Special Economic Zone, Phase-II, Pithampur, Distt. Dhar, Madhya Pradesh, Pin 454774, India.