Gripeks aktiv

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT GRIPEX® ACTIVE (GRIPEX ACTIVE)

Composition:

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

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

Excipients: maize starch, microcrystalline cellulose, calcium hydrogen phosphate, povidone, magnesium stearate, talc, sodium starch glycolate (type A), sunset yellow FCF (E 110), sodium croscarmellose.

Pharmaceutical form. Tablets.

Main physicochemical properties: orange or light orange tablets with speckles, elongated oval in shape, with a score line, and indentations "G" and "R" on the side with the score line.

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

Pharmacological Properties

The pharmacological effect is due to the action of all components of the drug.

Pharmacodynamics

Paracetamol acts as an analgesic and antipyretic agent. The analgesic and antipyretic effects of paracetamol are associated with its influence on the thermoregulatory center in the hypothalamus and its ability to inhibit prostaglandin synthesis.

Caffeine is a central nervous system stimulant. It stimulates the respiratory center, increasing the rate and depth of pulmonary oxygenation, enhances skeletal muscle tone, and reduces the threshold for hypercapnia. To achieve the same analgesic effect without caffeine, a dose approximately 40% higher would be required compared to when it is combined with caffeine. Thus, caffeine is used as an adjuvant to paracetamol.

Phenylephrine hydrochloride stimulates postsynaptic alpha-adrenergic receptors. It constricts pulmonary vessels and increases pulmonary arterial pressure. As a vasoconstrictor, it exerts an anticongestive effect: reduces edema and hyperemia of the nasal mucosa, diminishes exudative manifestations, and restores free breathing.

Chlorpheniramine maleate is an H1-blocker that inhibits the response of smooth muscle to histamine. It has antiallergic properties, reducing lacrimation and nasal itching.

Pharmacokinetics

Paracetamol is rapidly absorbed from the gastrointestinal tract and binds to plasma proteins. The plasma half-life ranges from 1 to 4 hours. It is metabolized in the liver, forming paracetamol glucuronide and sulfate. It is excreted by the kidneys primarily as conjugation products, with less than 5% excreted unchanged.

Caffeine and its water-soluble salts are rapidly absorbed in the intestine (including the colon). The plasma half-life is approximately 5 hours, and in some individuals up to 10 hours. The majority is demethylated and oxidized. About 10% is excreted unchanged by the kidneys.

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

Chlorpheniramine maleate is a component that reduces the typical effects of histamines, which is particularly important for preventing and relieving many allergic symptoms. It is absorbed relatively slowly from the gastrointestinal tract, with maximum plasma concentration reached 2.5 to 6 hours after oral administration. Bioavailability is low, ranging from 25% to 50% of the administered dose. Chlorpheniramine undergoes hepatic metabolism during first-pass metabolism. Chlorpheniramine maleate is extensively metabolized in the liver, forming desmethyl- and didesmethylchlorpheniramine metabolites. Approximately 70% of it binds to plasma proteins.

Chlorpheniramine distributes into all organs and tissues and crosses the blood-brain barrier. The unchanged component and its metabolites are primarily excreted in urine; excretion depends on urine pH and degree of ionization. Only traces are found in feces. The duration of action lasts from 4 to 6 hours.

Clinical characteristics.

Indications.

Symptomatic treatment of influenza and acute respiratory viral infections (ARVI) (fever, headache, rhinitis) in adults and children aged 12 years and older.

Contraindications.

The drug is contraindicated in patients with hypersensitivity to any of its components.

Alcoholism, prostatic hyperplasia, severe forms of atherosclerosis, arterial hypertension, acute pancreatitis and hepatitis, peripheral arterial thrombosis, decompensated heart failure; severe forms of ischemic heart disease, conduction disorders, ventricular tachycardia, closed-angle glaucoma, pronounced renal and hepatic dysfunction, bronchial asthma, chronic obstructive pulmonary disease (COPD), pheochromocytoma, hyperthyroidism, glucose-6-phosphate dehydrogenase deficiency, blood disorders, marked leukopenia, anemia, congenital hyperbilirubinemia, Dubin-Johnson syndrome, diabetes mellitus, increased intraocular pressure. Tendency to vascular spasm, difficulty in urination, bladder neck obstruction. Stenosing gastric and duodenal ulcers, pyloroduodenal obstruction; epilepsy, increased excitability, sleep disturbances, emphysema, acute myocardial infarction. Age over 60 years. Concurrent use with tricyclic antidepressants, β-blockers. Do not use together with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuation of MAOIs.

Special precautions.

Before prescribing the medication, it is essential to confirm that the underlying cause of cough has been identified and that reducing cough intensity will not increase the risk of clinical or physiological complications. Use with caution in patients with persistent or chronic cough due to smoking or pulmonary emphysema, when cough is associated with excessive sputum production, and in patients with congenital long QT interval or those taking medications that may prolong the QT interval for prolonged periods.

Consult a physician regarding the possibility of using the drug in patients with renal or hepatic impairment. Consult a physician before use if the patient is taking warfarin or similar drugs with anticoagulant effects.

Alcohol consumption must be avoided during treatment, as it enhances the sedative effect of chlorpheniramine maleate and increases the hepatotoxicity of paracetamol.

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

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. Immediate medical attention should be sought if these symptoms occur.

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 malnutrition or other sources of glutathione deficiency (e.g., chronic alcoholism) who were treated with paracetamol at therapeutic doses for prolonged periods or in combination with flucloxacillin. If HAGMA 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 useful in identifying pyroglutamic acidosis as the primary cause of HAGMA in patients with multiple risk factors.

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

Do not exceed the recommended doses.

Do not take the drug with other products containing paracetamol.

If symptoms persist, consult a physician.

If headache becomes persistent, consult a physician.

Caffeine reduces the effect of sedatives and narcotic drugs. Excessive consumption of beverages containing caffeine (such as coffee, tea) is not recommended during treatment, as it may lead to sleep disturbances, tremors, and discomfort behind the sternum due to palpitations.

Phenylephrine may cause increased pulse rate, dizziness, or strong palpitations; patients should be warned about this.

Use with caution in epilepsy.

Use with caution in hepatic and renal diseases, arterial hypertension, and compensated heart failure.

The use of the drug may result in a positive analytical finding in doping control tests.

Interaction with other medicinal products and other types of interactions.

Avoid simultaneous use of the drug with other medicinal products containing paracetamol or other active ingredients present in Gripex Active.

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

Gripex Active potentiates the effects of monoamine oxidase inhibitors (MAOIs), sedatives, and ethanol. In addition, MAOIs and furazolidone used concomitantly with Gripex Active may cause agitation, hypertensive crisis, and hyperpyrexia (due to chlorpheniramine 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 Gripex Active and glucocorticoids. Paracetamol, a component of the drug, reduces the effectiveness of diuretics and increases the risk of hepatotoxic reactions when used concomitantly with barbiturates, diphenyl, carbamazepine, rifampicin, and other inducers of microsomal liver enzymes, as well as anticonvulsants. The absorption rate of paracetamol may increase when used concomitantly with metoclopramide and domperidone, and decrease when used concomitantly with cholestyramine. Simultaneous use of paracetamol with azidothymidine (zidovudine) 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. Single doses do not show significant effects. Concurrent use of paracetamol with nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk of renal complications. Concurrent use of paracetamol with hepatotoxic agents increases the toxic effects of drugs on the liver. Barbiturates reduce the antipyretic effect of paracetamol. Anticonvulsant drugs (including phenytoin, barbiturates, carbamazepine), which stimulate microsomal liver enzyme activity, may enhance the hepatotoxic effects of paracetamol by increasing its conversion to hepatotoxic metabolites.

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

Paracetamol should be used with caution when administered concomitantly with flucloxacillin, as their combined use has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, especially in patients with risk factors (see section "Special precautions").

One of the components of the drug—phenylephrine hydrochloride—exhibits adrenomimetic effects when used with tricyclic antidepressants; concurrent use with haloperidol increases the risk of ventricular arrhythmia. Gripex Active reduces the hypotensive effect of guanethidine, which in turn enhances the α-adrenomimetic activity of phenylephrine hydrochloride. Phenylephrine may cause adverse reactions when combined with indomethacin and bromocriptine (severe arterial hypertension). The use of phenylephrine hydrochloride with sympathomimetic amines, digoxin, and cardiac glycosides increases the risk of arrhythmias and myocardial infarction. Alkaloids of Rauwolfia reduce the therapeutic effect of phenylephrine hydrochloride; β-adrenoblockers (phentolamine), phenothiazines, furosemide, and other diuretics counteract vasoconstriction. Phenylephrine may reduce the effectiveness of beta-blockers and other antihypertensive drugs (reserpine, methyldopa, etc.), increasing the risk of arterial hypertension and other cardiovascular adverse reactions.

Chlorpheniramine enhances the anticholinergic effects of atropine, spasmolytics, tricyclic antidepressants, MAOIs, antiparkinsonian agents. Chlorpheniramine maleate enhances the effects of central nervous system depressants (tranquilizers, barbiturates), antiparkinsonian agents.

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

Concurrent 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.

Caffeine enhances the effect (improves bioavailability) of analgesic-antipyretic drugs, 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; 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 ATP preparations. When used concomitantly with ergotamine, caffeine improves ergotamine absorption from the gastrointestinal tract; with thyrotropic agents, it enhances thyroid effects. Caffeine reduces serum lithium concentration.

Special precautions.

Use during pregnancy or breastfeeding.

The drug is contraindicated during pregnancy or breastfeeding.

Ability to affect reaction rate when driving or operating machinery.

Since the drug may reduce psychomotor reaction speed in sensitive patients, which is necessary for performing potentially hazardous tasks, it is advisable to refrain from driving vehicles, operating machinery, or performing other activities requiring concentration of attention during treatment with this medicinal product.

Method of Administration and Dosage

The medication is intended for oral administration.

For adults and children aged 12 years and older: 1 tablet up to 4 times daily.

The interval between doses should be no less than 4 hours.

The duration of treatment should be determined by a physician.

Maximum duration of use without medical consultation – 3 days.

Do not exceed the recommended dose.

Do not take together with other medicinal products containing paracetamol.

Children.

The medication is contraindicated for children under 12 years of age.

Overdose.

Signs and symptoms of overdose, resulting from the properties of individual components of Gripex Aktiv, can be categorized as follows.

Symptoms of paracetamol overdose. Overdose is usually caused by paracetamol and manifests as pallor, anorexia, nausea, vomiting, abdominal pain, hepatonecrosis, elevated liver transaminase activity, and increased prothrombin index. In cases of overdose, excessive sweating, psychomotor agitation, or central nervous system depression may occur, as well as drowsiness, impaired consciousness, cardiac arrhythmias, tachycardia, extrasystoles, tremor, hyperreflexia, and seizures. Liver damage may become apparent 12–48 hours after overdose. Glucose metabolism disturbances and metabolic acidosis may also occur. In severe poisoning, liver failure may progress and lead to toxic encephalopathy with impaired consciousness, in some cases resulting in death. Acute kidney dysfunction 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. Liver injury is possible in adults who have ingested 10 g or more of paracetamol, and in children who have received more than 0.15 g/kg body weight of paracetamol. Ingestion of 5 g or more of paracetamol may lead to liver injury in patients with risk factors (long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs that induce liver enzymes; chronic excessive alcohol consumption; glutathione deficiency (digestive disorders, cystic fibrosis, HIV infection, fasting, cachexia)).

Symptoms of caffeine overdose. High doses of caffeine may cause headache, epigastric pain, vomiting, diuresis, rapid breathing, extrasystoles, tachycardia, or cardiac arrhythmia, and may affect the central nervous system (dizziness, insomnia, nervous excitation, irritability, emotional lability, anxiety, tremor, seizures). Clinically significant symptoms of caffeine overdose may also be associated with paracetamol-induced liver injury.

Symptoms of overdose related to potentiation of the anticholinergic effect of the antihistamine component and the sympathomimetic effect of phenylephrine. Drowsiness, possibly followed by excitation (especially in children); visual disturbances; nausea, vomiting, headache; circulatory disturbances; coma; behavioral changes; arterial hypertension; bradycardia; atropine-like psychosis. Overdose due to phenylephrine may cause excessive sweating, psychomotor agitation or central nervous system depression, pallor, dizziness, insomnia, cardiac arrhythmias, tachycardia, extrasystoles, tremor, hyperreflexia, irritability, and restlessness. In severe cases, impaired consciousness, hallucinations, seizures, and arrhythmias may occur.

In case of chlorpheniramine maleate overdose, the condition may range from depression to excitation (restlessness and seizures). Atropine-like symptoms may occur, including mydriasis, photophobia, dryness of skin and mucous membranes, elevated body temperature, and intestinal atony; central nervous system depression may be accompanied by respiratory disorders and cardiovascular dysfunction.

Treatment. In case of overdose, immediate medical assistance is required. The patient should be taken to a hospital immediately, even if no early symptoms of overdose are present. 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 an excessive dose of paracetamol was ingested within the past hour. Paracetamol plasma concentration should be measured 4 hours or later 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 after ingestion. The efficacy of the antidote decreases significantly after this time. If necessary, 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 in remote areas outside the hospital.

Adverse reactions.

In most cases, the drug is well tolerated. Adverse effects related to the components of the drug were rarely observed, usually as a result of prolonged use of the drug in high doses.

Paracetamol.

Gastrointestinal disorders: rarely – nausea, vomiting, decreased appetite, constipation, diarrhea or flatulence, epigastric discomfort. With long-term use of large doses – epigastric pain, hepatotoxic effect; hepatonecrosis (with high-dose use).

Blood and lymphatic system disorders: very rarely – hemolytic anemia, bruising or bleeding, methemoglobinemia (cyanosis, dyspnea, chest pain), thrombocytopenia; in isolated cases – aplastic anemia, pancytopenia, sulfhemoglobinemia, neutropenia, agranulocytosis, leukopenia.

Respiratory system disorders: bronchospasm in patients sensitive to acetylsalicylic acid and other NSAIDs.

Renal and urinary disorders: renal colic, aseptic pyuria, interstitial nephritis; very rarely – nephrotoxic effect, papillary necrosis, impaired urination, dysuria.

Immune system disorders: anaphylaxis, hypersensitivity reactions, including skin itching, skin and mucous membrane rashes (usually generalized rash, erythematous, urticaria), angioneurotic edema, multiform exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

Hepatobiliary disorders: liver function disturbances, increased liver enzyme activity, usually without jaundice development.

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

Other: in isolated cases – hypoglycemia, up to hypoglycemic coma, general weakness, increased sweating, visual disturbances, dry eyes. Increased creatinine clearance, increased excretion of sodium and calcium, nasal congestion, possible false increase in blood uric acid measured by the Wittner method; slight increase in 5-hydroxyindoleacetic acid, vanillylmandelic acid, and catecholamines in urine.

Caffeine.

Central nervous system disorders: rarely – headache, fear sensation, general weakness, dizziness; in isolated cases – psychomotor agitation and disorientation, insomnia, restlessness, irritability or nervousness, tremor, confusion, depressive states, tingling and heaviness in limbs, tinnitus, epileptic seizures, coma, anxiety, hallucinations, dyskinesia.

Cardiovascular disorders: in isolated cases – palpitations, tachycardia, arrhythmia, increased blood pressure (especially in patients with arterial hypertension).

Gastrointestinal disorders: rarely – nausea, vomiting, exacerbation of peptic ulcer.

Phenylephrine hydrochloride.

Nervous system disorders: rarely – headache, insomnia, dizziness, confusion.

Cardiovascular disorders: in isolated cases – tachycardia, reflex bradycardia, dyspnea, chest pain, increased blood pressure (especially in patients with arterial hypertension), arrhythmia.

Gastrointestinal disorders: nausea, diarrhea.

Chlorpheniramine maleate.

Gastrointestinal disorders: nausea, vomiting, epigastric pain, dry mouth or throat.

Eye disorders: very rarely – mydriasis, accommodation disorders, increased intraocular pressure.

Cardiovascular disorders: in isolated cases – tachycardia.

Central nervous system disorders: rarely – drowsiness, headache, tremor.

Renal and urinary disorders: very rarely – urinary retention and stranguria (difficult urination).

The excipient, yellow dye FCF (E 110), may cause allergic reactions.

Description of individual adverse reactions

Metabolic acidosis with high anion gap

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.

Shelf life. 4 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

4 tablets in a blister; in a cardboard box.

10 tablets in a blister; in a cardboard box.

12 tablets in a blister; in a cardboard box.

20 (10×2) tablets in blisters; in a cardboard box.

24 (12×2) tablets in blisters; in a cardboard box.

Prescription status. Over-the-counter.

Manufacturer.

Evertogen Life Sciences Limited.

Manufacturer's address and place of business.

Plot No S-8, S-9, S-13 & S-14, APIIC, Pharma Sez, Green Industrial Park, Polepally (V), Jadcherla (M), Mahabubnagar, In-509 301, India.

Marketing Authorization Holder.

Unilab, LP, USA.

Address of the Marketing Authorization Holder and/or its representative.

966 Hungerford Drive, Suite ZB, Rockville, Maryland 20850, USA.