Tet 36.6® with acacia flavor

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Tet 36.6® with acacia flavour (Tet 36.6® with acacia flavour)

Composition:

Active substances: paracetamol, pheniramine maleate, ascorbic acid;

1 sachet contains: paracetamol 500 mg, pheniramine maleate 25 mg, ascorbic acid 200 mg;

Excipients: citric acid, sodium saccharin, acacia flavouring, white sugar, sucrose.

Pharmaceutical form. Powder for oral solution.

Main physicochemical properties: granular, free-flowing powder consisting of a mixture of white, pale-yellow granules with the smell of acacia.

Pharmacotherapeutic group. Other combination products used in colds. ATC code N02BE51.

Pharmacological properties.

Pharmacodynamics.

Pharmacological effects due to the components of the drug:

• Pheniramine maleate – an H1-histamine receptor blocker, provides a desensitizing effect manifested by reduction of inflammatory response in the mucous membranes of the upper respiratory tract (improvement of nasal breathing, reduction of rhinorrhea, sneezing, and lacrimation);
• Paracetamol exerts antipyretic and analgesic effects, alleviating pain and malaise (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 following 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, forming 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.

Excretion occurs mainly via urine, primarily 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.

Pheniramine maleate is well absorbed from the gastrointestinal tract. It is primarily excreted by the kidneys. The plasma half-life is 60–90 minutes.

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

Clinical Characteristics

Indications

Symptomatic treatment of colds, rhinitis, rhinopharyngitis, and influenza-like conditions characterized by runny nose, lacrimation, sneezing, sore throat, and/or headache.

Contraindications

Hypersensitivity to the components of the drug or to other antihistamines; severe impairment of liver and/or kidney function; congenital hyperbilirubinemia; glucose-6-phosphate dehydrogenase deficiency; alcoholism; blood disorders; marked anemia; leukopenia; severe arterial hypertension; unstable angina; severe cardiac conduction disorders; acute phase of myocardial infarction; severe atherosclerosis; decompensated heart failure; hyperthyroidism; acute urinary retention due to prostate hyperplasia; bladder neck obstruction; pyloroduodenal obstruction; active gastric or duodenal ulcer; closed-angle glaucoma; thrombosis; thrombophlebitis; severe forms of diabetes mellitus; epilepsy; elderly age; fructose intolerance, glucose/galactose malabsorption syndrome, or sucrase-isomaltase deficiency due to sucrose content; phenylketonuria.

Do not use concomitantly with monoamine oxidase inhibitors (MAOIs) or within two weeks after discontinuation of MAOIs. The drug is contraindicated in patients taking tricyclic antidepressants or β-blockers in urolithiasis, when ascorbic acid is administered in doses exceeding 1 g per day.

Interaction with other medicinal products and other forms of interaction

Unfavorable combinations

Due to the presence of pheniramine, ethanol enhances the sedative effect of H1-blockers. Therefore, patients should refrain from driving or operating machinery. During treatment, avoid consumption of alcoholic beverages and use of medicinal products containing ethanol.

Combinations requiring caution

Due to the presence of pheniramine, other sedative agents may cause central nervous system depression. These include: morphine derivatives (analgesics, antitussives, and substitution therapy), neuroleptics, barbiturates, benzodiazepines, non-benzodiazepine anxiolytics (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, drugs with anticholinergic (atropine-like) effects—such as imipramine-type antidepressants, most anticholinergic H1-blockers, anticholinergics, antiparkinsonian agents, atropine-like spasmolytics, disopyramide, phenothiazine neuroleptics, and clozapine—may increase the risk of adverse effects such as urinary retention, constipation, and dry mouth.

Concomitant use of paracetamol with oral anticoagulants may enhance anticoagulant effect and increase the risk of bleeding, particularly when paracetamol is taken at maximum doses (4 g/day) for at least four days. Regular monitoring of the international normalized ratio (INR) is recommended. If necessary, adjust the dose of the oral anticoagulant during and after paracetamol treatment.

Paracetamol may interfere with blood glucose measurements using the glucose oxidase-peroxidase method, leading to falsely elevated glucose levels, and may also affect blood urea measurements using phosphotungstic acid method.

The absorption rate of paracetamol may be increased by concomitant administration with metoclopramide or domperidone, and decreased by cholestyramine. Barbiturates reduce the antipyretic effect of paracetamol.

Anticonvulsants (including phenytoin, barbiturates, and carbamazepine), which stimulate hepatic microsomal enzyme activity, may enhance the hepatotoxic effect of paracetamol by increasing its conversion into hepatotoxic metabolites. Concomitant use of paracetamol with isoniazid increases the risk of hepatotoxic syndrome. Paracetamol reduces the efficacy of diuretics.

Paracetamol should be used with caution concomitantly with flucloxacillin, as co-administration has been associated with metabolic acidosis with a high anion gap due to 5-oxoproline (pyroglutamic acid) accumulation, particularly in patients with risk factors (see section "Special precautions for use").

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

Special precautions for use

In case of high body temperature or prolonged fever persisting for 5 days despite using the drug, or if signs of superinfection appear, consult a physician to determine whether continued use of the drug is appropriate.

Use with caution in patients with diabetes mellitus.

Alcohol enhances the sedative effect of pheniramine maleate and increases the hepatotoxic potential of paracetamol.

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

The risk of developing primarily psychological dependence may occur when recommended doses are exceeded or with prolonged treatment.

To prevent overdose, check and exclude all medications containing paracetamol.

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

Precautionary measures

Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoproline (pyroglutamic acid) accumulation have been reported in patients with severe underlying conditions such as severe renal insufficiency and sepsis, or in patients with malnutrition or other sources 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 HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with careful monitoring. Measurement of 5-oxoproline levels in urine may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

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

Each sachet contains 12 g of sucrose, which should be taken into consideration by patients with diabetes mellitus or those on a low-sugar diet.

Use during pregnancy or breastfeeding

Since the effect of the drug on pregnancy or breastfeeding has not been sufficiently studied, it should not be used during these periods.

Ability to affect reaction speed while driving or operating machinery

The drug may cause drowsiness; therefore, patients should refrain from driving vehicles or operating machinery during treatment.

Method of Administration and Dosage

For oral use. 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 sufficient amount of cold or warm water. The solution should be taken immediately after preparation. For patients with symptoms of a cold, it is preferable to take the warm solution in the evening. The interval between doses should be at least 4 hours.

Maximum duration of treatment is 5 days.

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

If symptoms of illness do not resolve or worsen, medical advice should be sought.

Children.

Do not use in children under 15 years of age.

Overdose.

Related to pheniramine. Overdose of pheniramine may cause seizures (especially in children), disturbances of consciousness, and coma.

Related to paracetamol. There is a risk of toxicity in elderly individuals and particularly in young children (therapeutic overdoses and accidental poisonings occur quite frequently). Paracetamol overdose can be fatal.

Symptoms: Nausea, vomiting, anorexia, pallor, increased sweating, and abdominal pain, which usually appear within the first 24 hours.

An overdose exceeding 10 g of paracetamol in a single dose in adults or 150 mg/kg body weight in a single dose in children may lead to hepatic cytolysis, which can result in complete and irreversible necrosis and hepatocellular failure, metabolic acidosis, encephalopathy, potentially progressing to coma and fatal outcome.

At the same time, elevated levels of liver transaminases, lactate dehydrogenase, and bilirubin are observed, along with increased prothrombin levels, which may manifest 12–48 hours after administration.

Emergency measures:

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

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

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

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

Endocrine system disorders: hypoglycemia up to hypoglycemic coma.

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

Cardiovascular system disorders: in isolated cases – tachycardia, myocardial dystrophy (dose-dependent effect with prolonged use), orthostatic hypotension.

Metabolism and nutrition disorders: disturbances in zinc and copper metabolism; frequency unknown (cannot be estimated from available data) – metabolic acidosis with high anion gap.

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

Skin disorders: eczema.

Eye disorders: dry eyes, mydriasis, accommodation disturbances.

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

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 for use"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

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

Shelf life. 2 years.

Storage conditions. Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging. 13.1 g in sachets, 5 or 10 sachets per carton.

Prescription status. Over-the-counter.

Manufacturer. Private Joint-Stock Company "Lekhim-Kharkiv".

Manufacturer's address and location of business activity.

36 Severina Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.