Combigrup hot sip®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT COMBIGRIP HOT SIP®

Composition:

Active substances: paracetamol, cetirizine hydrochloride, phenylephrine hydrochloride;

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

Excipients:

Combigrip Hot Sip with lemon flavor: colloidal anhydrous silicon dioxide, aspartame (E 951), mannitol (E 421), xanthan gum, tartrazine (E 102), lemon flavor, sucrose;

Combigrip Hot Sip with raspberry flavor: colloidal anhydrous silicon dioxide, aspartame (E 951), mannitol (E 421), xanthan gum, erythrosine (E 127), raspberry flavor, sucrose.

Pharmaceutical form. Powder for oral solution.

Main physicochemical properties:

Combigrip Hot Sip with lemon flavor: almost white powder with a pale yellow tint.

Combigrip Hot Sip with raspberry flavor: almost white powder with a pale pink tint.

Pharmacotherapeutic group.

Analgesics and antipyretics. Paracetamol combinations without psychotropic agents.

ATC code N02BE51.

Pharmacological Properties

Pharmacodynamics

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

The mechanism of action of paracetamol is associated with its influence 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 allergic reaction and reduces eosinophil migration and the release of inflammatory mediators, thereby suppressing the late-phase allergic response. Cetirizine has minimal activity at other receptors and thus does not cause undesirable anticholinergic or anti-serotonergic effects.

Phenylephrine hydrochloride is a relatively selective α1-adrenomimetic agent. It has weak activity at α2- and β-adrenergic receptors. Due to its vasoconstrictive effect, phenylephrine reduces nasal mucosal swelling and nasal secretions, thereby improving nasal breathing by facilitating airflow through the nasal passages. It is used to provide temporary relief from nasal congestion due to colds, acute respiratory viral infections, hay fever, and other allergic conditions.

Pharmacokinetics

Paracetamol is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations reached within 10–60 minutes. It is distributed into 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 primarily metabolized 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; administration with food does not reduce absorption but may slightly delay it. Peak 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 primarily excreted 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%. Peak plasma concentration is reached within 1–2 hours after administration. The elimination half-life from plasma is 2–3 hours. Following absorption, phenylephrine is extensively metabolized in the liver and excreted in the urine primarily as metabolites; less than 20% of the dose is excreted unchanged.

Clinical characteristics.

Indications.

Treatment of symptoms associated with acute respiratory viral infections, influenza, and allergic rhinitis (elevated body temperature, nasal discharge, nasal mucosa swelling, body aches, headache).

Contraindications.

Hypersensitivity to the active substances, hydroxyzine, any piperazine derivatives in history, or to other components of the drug; severe hepatic or renal impairment; 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; use in patients treated with monoamine oxidase inhibitors (MAOIs) and within 2 weeks after discontinuation of such therapy.

Interaction with other medicinal products and other forms of interaction.

Paracetamol

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

Diuretics: reduced effectiveness of diuretics.

Medicinal products that stimulate hepatic microsomal enzymes (e.g., barbiturates, monoamine oxidase inhibitors, tricyclic antidepressants, anticonvulsants), hepatotoxic agents: 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 this combination has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions for use").

The drug should not be used concomitantly with alcohol.

Cetirizine hydrochloride

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

Ritonavir: in a multiple-dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), exposure to cetirizine increased by approximately 40%, while ritonavir disposition was slightly affected (-11%) with concomitant cetirizine use.

Sedatives: no data indicate enhanced effects of sedatives when used at therapeutic doses. However, concomitant use of these agents 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 used concomitantly with cimetidine, glipizide, diazepam, and pseudoephedrine showed no evidence of adverse pharmacodynamic interactions.

Studies with cetirizine used concomitantly 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.

The extent of cetirizine absorption is not reduced when taken with food, although the rate of absorption is delayed by 1 hour.

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

Phenylephrine hydrochloride.

Monoamine oxidase inhibitors (MAOIs): enhanced cardiac and hypertensive effects of phenylephrine. The drug should not be used in patients being treated with monoamine oxidase inhibitors and within 2 weeks after discontinuation of such therapy.

Sympathomimetic amines: increased risk of cardiovascular adverse reactions.

Antihypertensive agents (e.g., β-blockers, debrisoquine, 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 for use.

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 continuous, the patient should consult a physician.

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

Consult a doctor before using the drug in case of liver or kidney disorders, 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 accompanied by 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. If these symptoms occur, seek immediate medical attention.

Cases of metabolic acidosis with a high anion gap due to 5-oxoprolinuria (pyroglutamic acidosis) have been reported in patients with severe conditions such as severe renal failure and sepsis, as well as in patients with malnutrition or other causes of glutathione deficiency (e.g., chronic alcoholism) who received 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.

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

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

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.

Use during pregnancy or breastfeeding.

The drug should not be used during pregnancy or breastfeeding.

Ability to affect reaction speed when driving or operating 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: take 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

This medicine is intended for children aged 12 years and older.

Overdose

Symptoms of paracetamol overdose

Hepatic damage 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 that induce liver enzymes; chronic 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 damage.

Symptoms within the first 24 hours include pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage may become apparent 12–48 hours after overdose. Disturbances in glucose metabolism 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 present 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.

Symptoms of cetirizine hydrochloride overdose

Symptoms observed after significant overdose of cetirizine are mainly related to effects on the central nervous system or to effects suggestive of 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.

Symptoms of phenylephrine hydrochloride overdose

Overdose of phenylephrine may lead to arterial hypertension with reflex bradycardia, nervousness, headache, dizziness, insomnia, nausea, vomiting, tachycardia, palpitations, allergic reactions, mydriasis, acute attack of angle-closure glaucoma (particularly in patients with pre-existing angle-closure glaucoma), dysuria, and urinary retention (particularly in patients with bladder obstruction). In severe cases, confusion, hallucinations, seizures, and arrhythmias may occur. However, in case of overdose of the combination product, the toxic dose of paracetamol will be reached much earlier than toxic effects of phenylephrine become apparent.

Treatment

The patient should be immediately taken 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 the overdose or the risk of organ damage.

Treatment includes symptomatic and supportive measures. If the excessive dose was taken within the last hour, gastric lavage and administration of activated charcoal are indicated. Plasma paracetamol concentration should be measured at least 4 hours 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. The efficacy of the paracetamol antidote decreases sharply after this time. If required, N-acetylcysteine should be administered intravenously 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 setting.

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.

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

Immune system, skin and subcutaneous tissue disorders: hypersensitivity reactions, including anaphylaxis, anaphylactic shock, pruritus, skin and mucous membrane rashes (including erythematous and generalized rashes), urticaria, angioneurotic edema, local drug eruptions, multiform exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), edema.

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

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

General disorders: increased fatigue, asthenia, malaise, edema.

Investigations: weight gain.

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 for use"). 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 any suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua

Shelf life.

4 years.

Storage conditions.

Store in 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 pack.

Supply category.

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