Gripomed® hot

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

Composition:

Active substances: paracetamol, ascorbic acid, pheniramine maleate;

1 sachet contains paracetamol 0.500 g, ascorbic acid 0.200 g, pheniramine maleate 0.025 g;

Excipients:

oral solution powder with lemon flavor: mannite (E 421), anhydrous citric acid (E 330), povidone, anhydrous trimagnesium dicitrate, aspartame (E 951), lemon flavoring;

oral solution powder with raspberry flavor: mannite (E 421), anhydrous citric acid (E 330), povidone, anhydrous trimagnesium dicitrate, aspartame (E 951), raspberry flavoring.

Pharmaceutical form. Powder for oral solution.

Main physicochemical characteristics:

oral solution powder with lemon flavor:

white to yellowish powder with lemon odor; yellowish specks may be present;

oral solution powder with raspberry flavor:

white to yellowish powder with raspberry odor; yellowish specks may be present.

Pharmacotherapeutic group.

Analgesics. Other analgesics and antipyretics. Anilides. Paracetamol combinations without psychotropic agents.

ATC code N02BE51.

Pharmacological Properties

Pharmacodynamics

Pharmacological effects due to the components of the drug:

• Pheniramine maleate — an H1-histamine receptor blocker, provides desensitizing action manifested by reduction of inflammatory response in the mucous membranes of the upper respiratory tract (improves nasal breathing, reduces rhinorrhea, sneezing, and lacrimation);
• Paracetamol exerts antipyretic and analgesic effects, which alleviate pain and fever (headache, myalgia);
• Ascorbic acid compensates for the body's requirement for vitamin C.

Pharmacokinetics

Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract after oral administration. Maximum plasma concentration of paracetamol is reached within 30–60 minutes after administration. Paracetamol is rapidly distributed into all tissues. Concentrations in blood, saliva, and plasma are similar. Plasma protein binding is weak. Paracetamol is primarily metabolized in the liver to form conjugates with glucuronic acid and sulfates. A minor metabolic pathway, catalyzed by cytochrome P450, leads to the formation of a reactive intermediate (N-acetylbenzoquinoneimine), which under normal conditions is rapidly detoxified by reduced glutathione and excreted in urine after conjugation with cysteine and mercapturic acid. However, in severe poisoning, the amount of this toxic metabolite increases. Paracetamol is excreted primarily in urine as metabolites. Approximately 90% of the administered dose is eliminated by the kidneys within 24 hours, mainly as glucuronide conjugates (60–80%) and sulfate conjugates (20–30%).

About 5% of the administered dose is excreted unchanged. The elimination half-life is approximately 2 hours.

In cases of severe renal impairment (creatinine clearance less than 10 ml/min), elimination of paracetamol and its metabolites is delayed.

In elderly patients, the capacity for conjugation is unchanged.

Pheniramine maleate is well absorbed from the gastrointestinal tract. It is primarily excreted by the kidneys.

Ascorbic acid is well absorbed from the gastrointestinal tract. It is primarily excreted in urine.

Clinical characteristics.

Indications.

Symptomatic treatment of colds, allergic rhinitis, influenza, rhinopharyngitis, manifested by chills, headache, runny nose, sneezing, and lacrimation.

Contraindications.

Hypersensitivity to components of the drug or to other antihistamines; severe hepatic dysfunction (>9 Child-Pugh score points) and/or renal impairment; phenylketonuria; congenital hyperbilirubinemia, including fructose intolerance; glucose-6-phosphate dehydrogenase deficiency; Gilbert’s syndrome; Dubin-Johnson syndrome; alcoholism; blood disorders; severe anemia; leukopenia; severe arterial hypertension; unstable angina pectoris; severe cardiac conduction disorders; acute phase of myocardial infarction; severe atherosclerosis; decompensated heart failure; hyperthyroidism; acute urinary retention due to prostatic hyperplasia; risk of urinary retention in urethral and prostate diseases; bladder neck obstruction; pyloroduodenal obstruction; gastric and duodenal ulcer in the stage of exacerbation; closed-angle glaucoma; thrombosis; thrombophlebitis; severe forms of diabetes mellitus; epilepsy; elderly age; acute pancreatitis; gastric and duodenal peptic ulcer in the stage of exacerbation.

Do not use the drug together with monoamine oxidase inhibitors (MAOIs) or within two weeks after discontinuation of MAOI therapy.

Contraindicated in patients taking tricyclic antidepressants or beta-blockers. Urinary stone disease (in case ascorbic acid intake exceeds 1 g per day).

Do not use in children under 15 years of age.

Special precautions.

In case of high body temperature or prolonged fever persisting for 5 days during treatment, or if signs of superinfection appear, consult a physician to determine the appropriateness of continuing the drug.

Use with caution in patients with diabetes mellitus.

Alcohol enhances the sedative effect of pheniramine maleate and the hepatotoxicity of paracetamol.

Ascorbic acid may alter results of laboratory tests (blood glucose, bilirubin, transaminase activity).

Risk of primarily psychological dependence may occur when exceeding recommended doses or during prolonged treatment.

To prevent overdose, avoid using medications containing paracetamol.

For adults with body weight over 50 kg, the total daily dose of paracetamol should not exceed 4 g.

Warnings.

Consumption of alcoholic beverages or use of sedatives (especially barbiturates) increases the sedative effect of pheniramine maleate; therefore, avoid using these substances during treatment.

Very rare cases of serious skin reactions have been reported. Patients should be informed about early signs of such serious skin reactions, such as rash or other manifestations of hypersensitivity. If these occur, discontinue the drug.

The medicinal product contains aspartame (E 951), a source of phenylalanine, which poses a risk for patients with phenylketonuria. The product also contains mannitol (E 421), which may have a mild laxative effect.

Interaction with other medicinal products and other forms of interaction.

Unwanted combinations.

Due to the presence of pheniramine, ethanol enhances the sedative effect of H1-blockers; therefore, refrain from driving vehicles or operating machinery. Avoid consumption of alcoholic beverages and use of medicinal products containing ethanol during treatment.

Combinations requiring caution.

Due to the presence of pheniramine, other sedative agents may cause central nervous system depression, including: morphine derivatives (analgesics, antitussives, and substitution therapy), neuroleptics, barbiturates, benzodiazepines; anxiolytics other than benzodiazepines (e.g., meprobamate); hypnotics, sedative antidepressants (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), sedative H1-blockers, centrally acting antihypertensives, baclofen, and thalidomide.

Due to the presence of pheniramine, medicinal products with anticholinergic (atropine-like) effects—such as imipramine antidepressants, most anticholinergic H1-blockers, anticholinergics, antiparkinsonian agents, atropine-like spasmolytics, disopyramide, phenothiazine neuroleptics, and clozapine—may add undesirable anticholinergic effects such as urinary retention, constipation, and dry mouth.

Combinations requiring cautious use.

Concomitant use with oral anticoagulants may increase their effect and elevate the risk of bleeding when paracetamol is used at maximum doses (4 g/day) for at least 4 days. Regular monitoring of INR (International Normalized Ratio) is recommended. If necessary, adjust the dose of oral anticoagulant during and after paracetamol treatment.

Paracetamol intake may affect blood glucose measurement results using glucose oxidase-peroxidase methods, leading to abnormally high concentrations.

Paracetamol intake may affect blood urea measurement results using phosphotungstic acid method.

The absorption rate of paracetamol may increase when used concomitantly with metoclopramide and domperidone, and decrease when used with cholestyramine. The anticoagulant effect of warfarin and other coumarins, with increased risk of bleeding, may be enhanced during long-term concomitant use of paracetamol. Occasional use has no significant effect.

Barbiturates reduce the antipyretic effect of paracetamol.

Anticonvulsants (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 isoniazid increases the risk of hepatotoxic syndrome.

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

Paracetamol reduces the effectiveness of diuretics.

Do not use concomitantly with alcohol.

Ascorbic acid enhances intestinal iron absorption, increases levels of ethinylestradiol, penicillins, and tetracyclines; decreases blood levels of antipsychotic drugs and phenothiazine derivatives. Glucocorticoids reduce body stores of ascorbic acid. Concurrent use of ascorbic acid and deferoxamine increases tissue iron toxicity, especially in cardiac muscle, potentially leading to circulatory decompensation. It should be administered only 2 hours after deferoxamine injection. High doses of ascorbic acid reduce the effectiveness of tricyclic antidepressants. Absorption of ascorbic acid is reduced when used concomitantly with oral contraceptives, fruit or vegetable juices, or alkaline drinks.

Special precautions for use.

Patients with liver or kidney disease should consult a physician before using this medication. Medical advice is also necessary if the patient is taking warfarin or similar anticoagulant drugs. It should be noted that patients with alcoholic necrotic liver damage have an increased risk of hepatotoxic effects of paracetamol; the drug may affect laboratory test results for blood glucose and uric acid levels. In patients with severe infections such as sepsis, which are associated with reduced glutathione levels, paracetamol use 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.

Do not exceed the recommended doses. If symptoms persist, consult a physician.

Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoproline (pyroglutamic acid) acidosis have been reported in critically ill patients, including those with severe renal impairment 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 monitoring of the patient's condition. Measurement of 5-oxoproline levels in urine may be useful in identifying pyroglutamic acidosis as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

This medication should be prescribed with particular caution to patients with disorders of iron metabolism (hemochromatosis, hemosiderosis, thalassemia).

Since ascorbic acid has a mild stimulating effect, it is not recommended to take this medication late in the day. Due to the stimulatory effect of ascorbic acid on corticosteroid hormone production, kidney function and blood pressure should be monitored when high doses are used.

Use this medication cautiously in patients with increased blood coagulability.

The drug should be prescribed with particular caution to patients with a history of nephrolithiasis (risk of hyperoxaluria and oxalate precipitation in the urinary tract after high-dose ascorbic acid intake).

Long-term use of high doses of ascorbic acid may accelerate its own metabolism, potentially leading to paradoxical vitamin deficiency after discontinuation of treatment. Recommended doses should not be exceeded.

Do not use simultaneously with other products containing vitamin C.

Absorption of ascorbic acid may be impaired in patients with intestinal motility disorders, enteritis, or achylia (suppressed gastric secretion).

It should be noted that high-dose vitamin C intake may alter certain laboratory test parameters (uric acid, creatinine, inorganic phosphates). Fecal occult blood testing may yield false-negative results.

Use during pregnancy or breastfeeding.

Since the effects of this medication on pregnancy or breastfeeding have not been sufficiently studied, it should not be administered during these periods.

Data on paracetamol

Standard reproductive and developmental toxicity studies using currently accepted assessment methods are lacking.

Current data on the effects of paracetamol in pregnant women indicate no disturbances in fetal development or fetotoxic/neonatal toxicity. Epidemiological studies on the neurodevelopment of children exposed to paracetamol in utero have yielded inconclusive results.

Studies on the effects of paracetamol have not revealed any risk to human fetal development or the course of pregnancy.

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

Data on ascorbic acid

Deficiency of ascorbic acid in the diet of pregnant women may be hazardous to the fetus; however, high-dose supplementation may also adversely affect fetal development.

Ascorbic acid is excreted into breast milk.

Data on pheniramine maleate

Currently, there are insufficient data from adequate studies on reproductive function or embryotoxic/fetotoxic effects of pheniramine maleate.

Ability to affect reaction speed when driving or operating machinery.

This medication may cause drowsiness, especially at the beginning of treatment. A significant effect on reaction speed is possible. Therefore, patients should refrain from driving or operating machinery while taking this medication.

Concomitant use of this medication with alcoholic beverages, alcohol-containing preparations, or other sedative agents increases these risks.

Dosage and Administration.

Take orally. Adults and children aged 15 years and older should take 1 sachet 2–3 times daily. The contents of the sachet should be dissolved in a glass of cold or warm water. Patients with symptoms of a cold should take the solution warm. The solution should be taken immediately after preparation. The interval between doses should be at least 4 hours. The maximum duration of treatment is 5 days.

For patients with severe renal impairment (creatinine clearance less than 10 mL/min), the interval between doses should be at least 8 hours.

Do not exceed the recommended dose.

Do not take together with other medicinal products containing paracetamol.

Children.

Do not use in children under 15 years of age.

Overdose.

Related to ascorbic acid.

Ascorbic acid is well tolerated. It is a water-soluble vitamin, and excess amounts are excreted in urine. However, prolonged use of high doses of vitamin C may suppress the function of the islet apparatus of the pancreas, requiring monitoring of pancreatic function. Overdose may lead to changes in renal excretion of ascorbic and uric acids during urine acidification, with a risk of precipitation of oxalate stones. High-dose ascorbic acid intake may cause vomiting, nausea, or diarrhea, which resolve after discontinuation of ascorbic acid.

Related to pheniramine.

Pheniramine overdose may cause seizures (especially in children), impaired consciousness, or coma.

Pheniramine overdose leads to anticholinergic-like symptoms: mydriasis, photophobia, dryness of skin and mucous membranes, hyperthermia, and intestinal atony. Central nervous system depression may result in respiratory and cardiovascular system dysfunction (bradycardia, arterial hypotension, collapse).

Related to paracetamol.

There is a risk of toxicity in elderly individuals and particularly in young children (therapeutic overdose and accidental poisoning occur quite frequently).

Paracetamol overdose can be fatal.

Symptoms.

Nausea, vomiting, anorexia, pallor, excessive sweating, and abdominal pain, usually appearing within the first 24 hours.

Acute renal failure with acute tubular necrosis may manifest as severe flank pain, hematuria, proteinuria, and may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have also been reported.

With prolonged use of high doses, hematological disorders such as aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia may develop. High-dose intake may cause central nervous system effects such as dizziness, psychomotor agitation, and disorientation; urinary system effects such as nephrotoxicity (renal colic, interstitial nephritis, cortical necrosis); and gastrointestinal effects such as hepatonecrosis.

A single ingestion of more than 10 g of paracetamol in adults or 150 mg/kg body weight in children causes hepatic cytolysis, which may lead to complete and irreversible necrosis, resulting in hepatocellular failure, metabolic acidosis, encephalopathy, coma, and potentially death.

Elevated levels of liver transaminases, lactate dehydrogenase, and bilirubin, along with increased prothrombin levels, may occur 12–48 hours after ingestion.

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 alcohol abuse; glutathione deficiency (due to malnutrition, cystic fibrosis, HIV infection, fasting, cachexia)], ingestion of 5 g or more of paracetamol may lead to liver damage.

Emergency measures:

• Immediate hospitalization;
• Determination of initial plasma paracetamol concentration;
• Immediate removal of the ingested drug by gastric lavage;
• Standard overdose treatment includes administration of the antidote N-acetylcysteine, either intravenously or orally; the antidote should be administered as early as possible, preferably within 10 hours of overdose;
• Methionine as symptomatic therapy.

Adverse Reactions

Blood and lymphatic system disorders: anemia, sulfhemoglobinemia, and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia; thrombosis, hyperprothrombinemia, erythrocytopenia, thrombocytopenia, agranulocytosis, thrombocytopenic purpura, neutrophilic leukocytosis, leukopenia, neutropenia, bruising or bleeding.

Immune system disorders: anaphylaxis, anaphylactic shock, hypersensitivity skin reactions including pruritus, skin and mucous membrane rashes (usually erythematous, urticarial), angioneurotic edema, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), including fatal outcomes.

Respiratory system disorders: bronchospasm in patients sensitive to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs.

Gastrointestinal disorders: dyspepsia, dry mouth, nausea, heartburn, vomiting, constipation, epigastric pain, diarrhea, liver function disturbances, increased liver enzyme activity (usually without jaundice), hepatonecrosis (dose-dependent effect).

Endocrine system disorders: hypoglycemia up to hypoglycemic coma.

Nervous system disorders: rarely – headache, dizziness, sleep disturbances, insomnia, somnolence, confusion, hallucinations, nervousness, tremor; sedation or in individual cases – coma, seizures, dyskinesia, behavioral changes, increased excitability; disturbances of balance and memory, inattention, especially in elderly patients.

Anticholinergic effects, e.g. dry mucous membranes, constipation, accommodation disturbances, mydriasis, palpitations, risk of urinary retention. Orthostatic hypotension.

Cardiovascular disorders: in isolated cases – tachycardia, myocardial dystrophy (dose-dependent effect with prolonged use), orthostatic hypotension, reflex bradycardia, dyspnea, increased blood pressure, arrhythmia.

Metabolism and nutrition disorders: disturbances in zinc and copper metabolism, hypokalemia.

Renal and urinary disorders: urinary retention and difficulty in urination, aseptic pyuria, renal colic.

Skin disorders: eczema.

Eye disorders: dry eyes, mydriasis, accommodation disturbances.

With prolonged use in high doses: damage to the glomerular apparatus of kidneys, crystalluria, formation of urate, cystine and/or oxalate kidney stones and in urinary tract; damage to the islet apparatus of the pancreas (hyperglycemia, glucosuria) and impaired glycogen synthesis up to the development of diabetes mellitus.

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

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

Adverse reactions associated with ascorbic acid: when used in doses exceeding 1 g per day – irritation of the gastrointestinal mucosa, renal failure, arterial hypertension.

Reporting suspected adverse reactions:

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

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.

5 g in sachets. 5 or 10 sachets per cardboard box.

Prescription status.

Over-the-counter.

Manufacturer.

JSC "CHEMICAL PHARMACEUTICAL PLANT "CHERVONA ZIRKA".

Manufacturer's address and place of business.

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