Combigrup ezy drink

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT COMBIGRIP EASY DRINK

Composition:

Active substances: paracetamol, cetirizine hydrochloride, phenylephrine hydrochloride;

One 5 g sachet contains: paracetamol 500 mg, cetirizine hydrochloride 10 mg, phenylephrine hydrochloride 10 mg;

Excipients:

Combigrip Easy Drink with lemon flavour: colloidal anhydrous silicon dioxide, aspartame (E 951), mannitol (E 421), xanthan gum, tartrazine (E 102), lemon flavouring, sucrose;

Combigrip Easy Drink with raspberry flavour: colloidal anhydrous silicon dioxide, aspartame (E 951), mannitol (E 421), xanthan gum, erythrosine (E 127), raspberry flavouring, sucrose.

Pharmaceutical form. Oral soluble powder.

Main physicochemical properties:

Combigrip Easy Drink with lemon flavour: almost white powder with a pale yellow tint.

Combigrip Easy Drink with raspberry flavour: almost white powder with a pale pink tint.

Pharmacotherapeutic group.

Analgesics and antipyretics. Paracetamol, combinations without psychotropic agents.

ATC code N02B E51.

Pharmacological properties.

Pharmacodynamics.

Paracetamol exerts analgesic, antipyretic, and weak anti-inflammatory effects.

The mechanism of action of paracetamol is associated with the drug's effect on the thermoregulatory center in the hypothalamus, its ability to inhibit the synthesis of prostaglandins and inflammatory mediators (kinins, serotonin), and an increase in the pain sensitivity threshold.

Cetirizine hydrochloride is a potent antihistamine and a selective H1-receptor antagonist. It inhibits the histamine-mediated early phase of the allergic reaction and also reduces eosinophil migration and the release of inflammatory mediators, thereby attenuating the late-phase allergic response. Cetirizine has virtually no effect on other receptors and thus does not cause undesirable anticholinergic or anti-serotonergic effects.

Phenylephrine hydrochloride is a relatively selective α1-adrenomimetic agent. It exerts weak effects on α2- and β-adrenergic receptors. Due to its vasoconstrictive effect, phenylephrine reduces nasal mucosal swelling, decreases nasal secretions, and improves nasal breathing by facilitating airflow through the nose. It is used for temporary relief of nasal congestion associated with the common cold, acute respiratory viral infections, hay fever, and other allergic conditions.

Pharmacokinetics.

Paracetamol is rapidly absorbed from the gastrointestinal tract; maximum plasma concentration is reached within 10–60 minutes. It is distributed in most body tissues. At normal therapeutic concentrations, only a small fraction of paracetamol binds to plasma proteins. The elimination half-life from plasma is 1–3 hours. Paracetamol is metabolized primarily in the liver and excreted by the kidneys mainly as glucuronide and sulfate conjugates; less than 5% of the dose is excreted unchanged.

Cetirizine hydrochloride is rapidly absorbed from the gastrointestinal tract; absorption is not reduced when taken with food, although it may be slightly delayed. Maximum plasma concentration (approximately 0.3 mcg/mL) is achieved within 30–60 minutes after a 10 mg dose of cetirizine. The terminal elimination half-life is 6.7–10.7 hours in adults and 6.1–7.1 hours in children. Cetirizine is excreted predominantly unchanged in the urine. In patients with mild to moderate renal impairment, the elimination half-life increases to 19–21 hours. Approximately 90% of cetirizine is bound to plasma proteins.

Phenylephrine hydrochloride is readily absorbed after oral administration; however, due to extensive presystemic metabolism, primarily in enterocytes, systemic bioavailability is only about 40%. Maximum plasma concentration is reached within 1–2 hours after administration. The elimination half-life from plasma is 2–3 hours. After absorption, phenylephrine undergoes extensive biotransformation in the liver and is excreted in the urine primarily as metabolites; less than 20% of the dose is excreted unchanged.

Clinical characteristics.

Indications.

Combigrin Easy Drink is used for the treatment of symptoms associated with acute respiratory viral infections, influenza, and allergic rhinitis (elevated body temperature, nasal congestion, swelling of the nasal mucosa, body aches, headache).

Contraindications.

Hypersensitivity to the active substances, hydroxyzine, any piperazine derivatives in medical history, or to any other component of the drug; severe impairment of liver or kidney function; congenital hyperbilirubinemia; Gilbert’s syndrome; glucose-6-phosphate dehydrogenase deficiency; alcoholism; blood disorders (including severe anemia, leukopenia); arterial hypertension; cardiovascular diseases; hyperthyroidism; diabetes mellitus; closed-angle glaucoma; benign prostatic hyperplasia; pheochromocytoma; concomitant use with monoamine oxidase inhibitors (MAOIs) and within a 2-week period after discontinuation of such therapy; children under 12 years of age.

Interaction with other medicinal products and other forms of interaction.

Paracetamol

Coumarin anticoagulants (e.g., warfarin): enhanced anticoagulant effect when paracetamol is used concomitantly over a long-term, daily basis. This increases the risk of bleeding. Occasional use does not show a significant effect.

Diuretics: reduced effectiveness of diuretics.

Drugs stimulating hepatic microsomal enzyme activity (e.g., barbiturates, monoamine oxidase inhibitors, tricyclic antidepressants, anticonvulsants), hepatotoxic drugs: increased hepatotoxicity of paracetamol.

Isoniazid: increased risk of hepatotoxic syndrome (when high doses of paracetamol are used).

Barbiturates: reduced antipyretic effect of paracetamol.

The absorption rate of paracetamol may be increased by metoclopramide and domperidone, and decreased by cholestyramine.

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

The drug should not be used concomitantly with alcohol.

Cetirizine hydrochloride

Theophylline: in a study of repeated administration of theophylline (400 mg once daily) and cetirizine, a slight (16%) reduction in cetirizine clearance was observed, while theophylline distribution was not affected by concomitant cetirizine intake.

Ritonavir: in a study of repeated administration of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), cetirizine exposure duration increased by approximately 40%, while ritonavir distribution was slightly reduced (–11%) with concomitant cetirizine intake.

Sedatives: no data on enhanced sedative effects when used at therapeutic doses. However, concomitant use with sedatives should be avoided.

Pharmacokinetic interaction studies have been conducted with cetirizine and pseudoephedrine, cimetidine, ketoconazole, erythromycin, and azithromycin; no pharmacokinetic interactions were observed.

Studies with cetirizine co-administered with cimetidine, glipizide, diazepam, and pseudoephedrine showed no evidence of adverse pharmacodynamic interactions.

Studies with cetirizine co-administered with azithromycin, erythromycin, ketoconazole, theophylline, and pseudoephedrine showed no evidence of adverse clinical interactions. Furthermore, concomitant use of cetirizine with macrolides or ketoconazole has never led to clinically significant changes on ECG.

Food intake does not affect the extent of cetirizine absorption but reduces the rate of its absorption.

No clinically significant interactions with alcohol (at blood alcohol levels of 0.5 g/L) have been observed when cetirizine is used at therapeutic doses. However, the drug should not be used concomitantly with alcohol.

Phenylephrine hydrochloride

Monoamine oxidase inhibitors (MAOIs): enhanced hypertensive effect of phenylephrine. The drug should not be administered to patients receiving MAOIs or within 2 weeks after discontinuation of such therapy.

Sympathomimetic amines: increased risk of cardiovascular adverse reactions.

Antihypertensive agents (e.g., β-blockers, debrisoquin, guanethidine, reserpine, methyldopa): reduced effectiveness of β-blockers and other antihypertensive drugs; increased risk of hypertension and other cardiovascular adverse reactions.

Tricyclic antidepressants (e.g., amitriptyline): increased risk of cardiovascular adverse reactions.

Cardiac glycosides (e.g., digoxin): increased risk of cardiac arrhythmias or myocardial infarction.

Special precautions.

Do not exceed the recommended doses of the drug.

Do not use the drug simultaneously with other products containing paracetamol.

If symptoms persist or headache becomes persistent, the patient should consult a physician.

Patients who take analgesics daily for mild forms of arthritis should consult a doctor before using this drug.

Consult a physician before using the drug in case of liver or kidney disease, or when taking anticoagulants.

In patients with non-cirrhotic alcoholic liver disease, the risk of hepatotoxic effects of paracetamol is increased.

In patients with severe infections such as sepsis, which are associated with reduced glutathione levels, the use of paracetamol may increase the risk of metabolic acidosis. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Immediate medical attention should be sought if these symptoms occur.

Cases of metabolic acidosis with a high anion gap (high anion gap metabolic acidosis (HAGMA)) resulting from pyroglutamic acidosis have been reported in patients with severe conditions such as severe renal failure and sepsis, or in patients with malnutrition and other causes of glutathione deficiency (e.g., chronic alcoholism), who were treated with paracetamol at therapeutic doses for prolonged periods or with a combination of paracetam0l and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with close monitoring of the patient. Measurement of urinary 5-oxoproline levels may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

Use the drug with caution in patients predisposed to urinary retention (e.g., spinal cord injury), in patients with occlusive vascular diseases (including Raynaud's phenomenon), in patients with chronic renal insufficiency (dose adjustment required), in elderly patients with renal impairment (possible reduction in glomerular filtration rate), in patients with epilepsy, and in patients at risk of seizures.

Antihistamines suppress skin allergy tests; therefore, administration of the drug should be discontinued at least 3 days before such testing.

If you have known intolerance to certain sugars, consult your doctor before taking this medicinal product.

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

The drug contains aspartame (a source of phenylalanine), which may be harmful to patients with phenylketonuria.

The drug contains mannitol, which may have a mild laxative effect.

Use during pregnancy or breastfeeding.

The drug should not be used during pregnancy or breastfeeding.

Effect on ability to drive or operate machinery.

Patients who drive or operate machinery should not exceed the recommended doses and should take into account their individual response to the drug.

Method of Administration and Dosage

The contents of 1 sachet should be dissolved in a glass of hot water (but not boiling water) and taken orally.

For adults and children aged 12 years and older, use 1 sachet every 4–6 hours as needed to relieve symptoms, up to 4 times daily. The interval between doses should be no less than 4 hours. The single dose must not exceed 1 sachet. The treatment duration should not exceed 7 days.

Children

Do not use in children under 12 years of age.

Overdose

Paracetamol overdose symptoms

Hepatic injury may occur in adults who have ingested 10 g or more of paracetamol, and in children who have ingested more than 150 mg/kg body weight. In patients with risk factors (chronic use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs inducing liver enzymes; alcohol abuse; glutathione system deficiency, e.g. due to malnutrition, cystic fibrosis, AIDS, fasting, mucoviscidosis, cachexia), ingestion of 5 g or more of paracetamol may lead to hepatic injury.

Symptoms within the first 24 hours include pallor, nausea, vomiting, anorexia, and abdominal pain. Hepatic damage may become apparent 12–48 hours after overdose. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and may be fatal. Acute renal failure with acute tubular necrosis may manifest as severe lumbar pain, hematuria, proteinuria, and may develop even in the absence of severe liver injury. Cardiac arrhythmias and pancreatitis have also been reported.

Hydrochloride cetirizine overdose symptoms

Symptoms observed after significant cetirizine overdose are primarily related to effects on the central nervous system or effects indicating anticholinergic activity. Adverse effects reported after ingestion of doses at least 5 times higher than the recommended daily dose include confusion, diarrhea, dizziness, fatigue, headache, malaise, mydriasis, itching, restlessness, sedation, somnolence, stupor, tachycardia, tremor, and urinary retention.

Hydrochloride phenylephrine overdose symptoms

Phenylephrine overdose may lead to arterial hypertension with reflex bradycardia, nervousness, headache, dizziness, insomnia, nausea, vomiting, tachycardia, palpitations, allergic reactions, mydriasis, acute attack of closed-angle glaucoma (mainly if closed-angle glaucoma is already present), dysuria, and urinary retention (mainly if bladder obstruction is present). In severe cases, confusion, hallucinations, seizures, and arrhythmias may occur. However, in case of overdose of the combined preparation, the toxic dose of paracetamol will be reached much earlier than the toxic effects of phenylephrine become apparent.

Treatment

The patient should be immediately transported to a hospital, 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.

Treatment includes symptomatic and supportive measures. If the excessive dose was ingested within 1 hour, gastric lavage and administration of activated charcoal are indicated. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be administered within 24 hours after ingestion, but the maximum protective effect is achieved when administered within 8 hours after ingestion. The efficacy of the paracetamol antidote decreases sharply after this time. If necessary, intravenous N-acetylcysteine should be administered according to the established dosage regimen. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside the hospital.

Adverse Reactions.

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

Nervous system disorders: headache, dizziness, paresthesia, seizures, dysgeusia, dyskinesia, dystonia, loss of consciousness, tremor, amnesia, memory impairment.

Eye disorders: accommodation disorders, blurred vision, involuntary eye movements.

Ear and labyrinth disorders: vertigo.

Cardiac disorders: tachycardia, palpitations, cardiac arrhythmias, arterial hypertension.

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

Gastrointestinal disorders: abdominal pain, dry mouth, nausea, diarrhea, epigastric pain, vomiting.

Renal and urinary system disorders: dysuria, enuresis, urinary retention.

Endocrine system disorders: hypoglycemia, up to hypoglycemic coma.

Nutrition and metabolism disorders: increased appetite, metabolic acidosis with high anion gap with frequency "unknown" (cannot be estimated from available data).

Hepatobiliary disorders: liver function abnormalities (elevated levels of bilirubin and liver enzymes: transaminases, alkaline phosphatase, γ-glutamyl transferase), usually without development of jaundice.

Immune system, skin and subcutaneous tissue disorders: hypersensitivity reactions, including anaphylaxis, anaphylactic shock, pruritus, skin and mucosal rashes (including erythematous and generalized rash), urticaria, angioneurotic edema, local drug eruptions, erythema multiforme (including Stevens–Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), swelling.

Psychiatric disorders: somnolence, anxiety, aggression, confusion, depression, hallucinations, insomnia, tic, suicidal thoughts.

General disorders: increased fatigue, asthenia, malaise, edema, metabolic acidosis with high anion gap.

Investigations: increased body weight.

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.

Reporting of adverse reactions after drug registration is important. 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 drug efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

5 g of powder in sachets, 10 sachets 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/P & S-14/P TSIIC, Pharma SEZ, Green Industrial Park, Polepally (V), Jadcherla (M), Mahabubnagar, Telangana, IN-509 301, India