Tricitron extra

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRICYTRON EXTRA

Composition:

Active substances: 1 sachet contains 650 mg of paracetamol, 20 mg of pheniramine maleate, 10 mg of phenylephrine hydrochloride;

Excipients: sucrose, anhydrous citric acid, sodium citrate dihydrate, silicon dioxide, lemon flavor, tartrazine (E 102).

Pharmaceutical form. Oral solution powder.

Main physicochemical properties: Powder from white/almost white to light yellow color with lemon scent. Presence of soft lumps of more intense color is acceptable. Solution: When dissolved in hot water, forms a clear light yellow solution.

Pharmacotherapeutic group.

Analgesics and antipyretics. Paracetamol combinations without psychotropic agents.

ATC code N02B E51.

Pharmacological properties.

Pharmacodynamics.

A combination medication for the treatment of flu and cold symptoms.

Exerts antipyretic, decongestant, analgesic, and antiallergic effects.

Paracetamol provides analgesic, antipyretic, and weak anti-inflammatory effects, primarily mediated through inhibition of prostaglandin synthesis in the central nervous system. It does not affect platelet function or hemostasis.

Phenylephrine hydrochloride is a sympathomimetic amine that acts primarily directly on alpha-adrenergic receptors. When used in therapeutic doses to relieve nasal congestion, the drug does not exert a significant stimulatory effect on cardiac beta-adrenergic receptors or a significant effect on the central nervous system. It is a well-established nasal decongestant that acts via vasoconstriction, reducing swelling and hyperemia of the nasal mucosa.

Pheniramine maleate is an H1-receptor blocker, exerting antiallergic effects, reducing the severity of local exudative manifestations, decreasing lacrimation, rhinorrhea, and itching in the eyes and nose. Reduction of general allergic symptoms is associated with respiratory tract diseases and results in a moderate sedative effect. It also exerts antimuscarinic effects.

Pharmacokinetics.

After oral administration, paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Maximum plasma concentration is reached within 10–60 minutes.

Paracetamol is distributed throughout most body tissues. It crosses the placental barrier and is excreted in breast milk. When administered at usual therapeutic doses, paracetamol is only slightly bound to plasma proteins; however, the degree of binding increases with higher concentrations.

Paracetamol is primarily metabolized in the liver via two pathways: glucuronidation and sulfation. It is excreted in the urine predominantly as glucuronide and sulfate conjugates. The elimination half-life ranges from 1 to 3 hours.

Maximum plasma concentration of pheniramine maleate is achieved within 1–2.5 hours; the elimination half-life is 16–19 hours. 70–83% of the orally administered dose is excreted in the urine unchanged or as metabolites.

Phenylephrine hydrochloride is absorbed in the gastrointestinal tract and undergoes presystemic metabolism by monoamine oxidase in the intestine and liver; thus, following oral administration, phenylephrine has reduced bioavailability. It is excreted in the urine almost entirely as a sulfate conjugate. Maximum plasma concentrations are observed within 45 minutes to 2 hours, and the elimination half-life is 2–3 hours.

Clinical characteristics.

Indications.

Treatment of symptoms of influenza and cold, including fever and chills, headache, runny nose, nasal and sinus congestion, sneezing, and body aches.

Contraindications.

Hypersensitivity to any component of the drug. Severe cardiovascular disorders, severe impairment of liver and/or kidney function, congenital hyperbilirubinemia, arterial hypertension, acute pancreatitis, hyperthyroidism, pheochromocytoma, blood disorders (including severe anemia, leukopenia), thrombosis, thrombophlebitis, closed-angle glaucoma, glucose-6-phosphate dehydrogenase deficiency, severe forms of diabetes mellitus, alcoholism, prostate hypertrophy with urinary retention, bladder neck obstruction, pyloroduodenal obstruction, bronchial asthma, epilepsy, sleep disorders. Concomitant treatment with monoamine oxidase inhibitors (MAOIs) and within 2 weeks after discontinuation of their use, tricyclic antidepressants, beta-blockers, and other sympathomimetics.

Interaction with other medicinal products and other types of interactions.

Drug interactions involving each individual component of TRICITRON EXTRA are well known. There is no reason to assume that the use of these ingredients in combination may affect the drug interaction profile.

Paracetamol

With regular long-term use, paracetamol may enhance the anticoagulant effect of warfarin or other coumarin derivatives and increase the risk of bleeding. This effect is not pronounced with occasional use of paracetamol.

Hepatotoxic drugs may increase the likelihood of paracetamol accumulation and overdose. The risk of hepatotoxic effects of paracetamol may increase in patients receiving drugs that induce hepatic microsomal enzymes, such as barbiturates and antiepileptic agents (phenytoin, phenobarbital, carbamazepine), and antituberculosis agents rifampicin and isoniazid.

Metoclopramide increases the rate of paracetamol absorption and leads to increased plasma peak levels. Domperidone may similarly increase the rate of paracetamol absorption. Paracetamol may prolong the half-life of chloramphenicol.

Paracetamol may reduce lamotrigine bioavailability with a possible reduction in its effect due to possible induction of its hepatic metabolism.

Absorption of paracetamol may be reduced when administered concomitantly with cholestyramine, but the reduction in absorption is insignificant if cholestyramine is administered 1 hour apart.

Regular concomitant use of paracetamol with zidovudine may lead to neutropenia and increased risk of liver damage. Paracetamol reduces the effectiveness of diuretics.

Probenecid affects paracetamol metabolism. For patients taking probenecid concomitantly, the dose of paracetamol should be reduced.

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 pyroglutamic acidosis, especially in patients with risk factors (see section "Special precautions").

Hepatotoxicity of paracetamol may be enhanced by prolonged or excessive alcohol consumption. Paracetamol may affect test results for uric acid levels when measured by the phosphotungstic acid method.

Pheniramine maleate

First-generation antihistamines such as pheniramine maleate may enhance the central nervous system depressant effects of other drugs (e.g., MAO inhibitors, tricyclic antidepressants, hypnotics and sedatives, neuroleptics, alcohol, antiparkinsonian agents, barbiturates, anesthetics, tranquilizers, and narcotic analgesics). Pheniramine enhances the anticholinergic effect of atropine and spasmolytics. Pheniramine maleate may also inhibit the action of anticoagulants.

Phenylephrine hydrochloride

The use of the drug is contraindicated in patients undergoing therapy with MAO inhibitors or in patients who have used MAO inhibitors within the last 2 weeks. Phenylephrine may potentiate the action of MAO inhibitors and provoke a hypertensive crisis.

Concomitant use of phenylephrine with other sympathomimetic agents or tricyclic antidepressants (e.g., amitriptyline) may increase the risk of cardiovascular side effects.

Phenylephrine may reduce the effectiveness of beta-blockers and other antihypertensive drugs (e.g., debrisoquin, guanethidine, reserpine, methyldopa). The risk of developing arterial hypertension and other cardiovascular side effects may increase.

Concomitant use of phenylephrine with digoxin and cardiac glycosides may increase the risk of arrhythmia or cardiac attack.

Concomitant use of phenylephrine with ergot alkaloids (ergotamine and methysergide) may increase the risk of ergotism.

Prolonged intake of large doses during disulfiram treatment inhibits the disulfiram-alcohol reaction.

Special precautions for use.

Avoid concomitant use of other medicinal products containing paracetamol due to the risk of severe liver damage in case of overdose. The simultaneous use of this product with vasoconstrictive agents is not recommended. Do not exceed the specified doses.

Alcoholic beverages should be avoided during treatment, as ethanol taken concomitantly with paracetamol may cause liver function impairment.

Use this product with caution in patients with mild to moderate renal and/or hepatic impairment, acute hepatitis, severe haemolytic anaemia, chronic malnutrition, dehydration, mild to moderate cardiovascular disorders, mild to moderate diabetes mellitus, prostatic hypertrophy without urinary retention (as such patients may be prone to urinary retention), stenosing peptic ulcer, Raynaud's disease, thyroid disorders (except hyperthyroidism), chronic pulmonary diseases, patients receiving hepatotoxic medicinal products, and elderly patients.

Patients should consult a physician:

• if they have breathing problems such as asthma, emphysema, or chronic bronchitis;
• if symptoms do not improve within 5 days or are accompanied by high fever lasting more than 3 days, skin rash, or persistent headache;
• regarding the possibility of using the product in case of renal or hepatic impairment.

These symptoms may indicate a more serious underlying condition.

The product contains phenylephrine, which may provoke angina attacks.

In patients with severe infections such as sepsis, associated with reduced glutathione levels, paracetamol administration 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 is required 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 underlying 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 over a prolonged period or in combination with flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol and careful monitoring are recommended. Measurement of urinary 5-oxoproline levels may be helpful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

One sachet contains 19.4 g of sucrose, which should be taken into account in patients with diabetes mellitus. This product should not be used by patients with rare hereditary conditions such as fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

One sachet contains 7.4 mg of sodium. Patients on a sodium-restricted diet should take into account the sodium content.

The product contains the colouring agent E 102, which may cause allergic reactions.

Reporting suspected adverse reactions is important. It allows continued monitoring of the benefit-risk balance of the medicinal product.

Use during pregnancy or breastfeeding.

The use of this product is not recommended during pregnancy or breastfeeding, as its safety in these conditions has not been studied.

Pregnancy.

Currently, there are no traditional studies using accepted standards for assessing reproductive toxicity and developmental toxicity.

Extensive data from pregnant women do not indicate congenital or fetal/neonatal toxicity. Epidemiological studies on neurodevelopmental outcomes in children exposed in utero to paracetamol show insufficiently conclusive results. If clinically necessary, paracetamol may be used during pregnancy at the lowest effective dose, for the shortest duration, and with the lowest frequency possible.

There are currently no adequate data on reproductive toxicity or embryo-/fetotoxicity from studies with pheniramine.

Only limited data are available on the use of phenylephrine hydrochloride in pregnant women. Vasoconstriction of the uterine vessels and reduced uterine blood flow associated with phenylephrine use may lead to fetal hypoxia. The use of phenylephrine hydrochloride during pregnancy should be avoided.

Breastfeeding.

Paracetamol is excreted in breast milk, but in amounts that are not clinically significant. Available published data do not justify recommending discontinuation of breastfeeding during paracetamol use.

There is insufficient information on the excretion of pheniramine into breast milk and the amount that may potentially reach the infant.

There are no available data on whether phenylephrine passes into breast milk. The use of phenylephrine should be avoided in women who are breastfeeding.

Fertility.

The effect of the product on fertility has not been specifically studied. Preclinical data on paracetamol do not indicate any particular risk to fertility at therapeutic doses. Adequate reproductive toxicity studies in animals have not been conducted with phenylephrine or pheniramine.

Ability to affect reaction speed when driving or operating machinery.

The product may cause drowsiness. Caution should be exercised when driving or operating machinery requiring concentration.

Dosage and Administration.

For adults and children aged 12 years and older, administer 1 sachet every 4–6 hours (as needed for symptomatic relief), but not more than 3–4 sachets per day. The single dose must not exceed 1 sachet. It is not recommended to use the drug for longer than 5 days. The contents of 1 sachet should be dissolved in a glass of boiled hot water (not boiling water) and taken while hot.

Patients with hepatic impairment.

For patients with impaired liver function or Gilbert's syndrome, the dose should be reduced or the interval between doses increased.

Elderly patients. Dose adjustment in elderly patients is not required.

Children.

The drug must not be administered to children under 12 years of age.

Overdose.

In case of overdose, symptoms caused by paracetamol overdose will be most prominent.

Symptoms caused by paracetamol overdose: hepatotoxic effect; in severe cases, liver necrosis may develop. Paracetamol overdose, including high total doses received over a prolonged period, may cause analgesic-induced nephropathy with irreversible impairment of liver function.

Liver damage is possible 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 excessive alcohol consumption, glutathione depletion (digestive disorders, cystic fibrosis, HIV infection, cachexia)—the ingestion of 5 g or more of paracetamol may lead to liver damage.

There is a risk of poisoning, particularly in elderly patients, young children, patients with liver disease, patients with chronic malnutrition, and patients receiving hepatic enzyme inducers (long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort). In severe poisoning, liver failure may progress to encephalopathy, coma, and fatal outcome.

With prolonged use of the drug in high doses, aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia may develop from the hematopoietic system. From the central nervous system—dizziness, psychomotor agitation, and disorientation; from the urinary system—nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis).

Symptoms of paracetamol overdose appearing within the first 24 hours: pallor, nausea, vomiting, and loss of appetite. The first sign of liver damage may be abdominal pain, which does not always manifest within the first 24–48 hours but may occur later, within 4–6 days after drug intake. Liver damage usually occurs within 72–96 hours after drug administration. Abnormalities in glucose metabolism (hypoglycemia) and metabolic acidosis, as well as bleeding, may occur. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage and may present as severe back pain, hematuria, and proteinuria. Cases of cardiac arrhythmias and pancreatitis have been reported.

Treatment. In case of paracetamol overdose, immediate medical assistance is required. Administration of intravenous or oral N-acetylcysteine as an antidote to paracetamol at an early stage, and possibly gastric lavage and/or oral administration of methionine, may have a beneficial effect for at least 48 hours after overdose.

Administration of activated charcoal and monitoring of respiration and circulation may be helpful. In case of seizures, diazepam may be administered.

Symptoms caused by overdose of pheniramine maleate and phenylephrine hydrochloride. Symptoms resulting from the mutual potentiation of the anticholinergic effect of the antihistamine and the sympathomimetic effect of phenylephrine hydrochloride include drowsiness, which may be followed by excitation (especially in children) or central nervous system depression, visual disturbances, rash, nausea, vomiting, persistent headache, hyperhidrosis, nervousness, dizziness, tremor, insomnia, hyperreflexia, irritability, restlessness, circulatory disturbances, arterial hypertension, and bradycardia.

In severe cases of phenylephrine overdose, impaired consciousness, arrhythmias, coma, and seizures may occur.

Cases of atropine-like "psychosis" have been reported following pheniramine overdose. Atropine-like symptoms may include: mydriasis, photophobia, dryness of skin and mucous membranes, hyperthermia, and intestinal atony.

Treatment. There is no specific antidote for antihistamine overdose. Standard emergency measures should be provided, including administration of activated charcoal, a saline laxative, and standard supportive measures for the cardiovascular and respiratory systems. Stimulants must not be used; vasopressors may be used to treat arterial hypotension.

To counteract hypertensive effects, an intravenous alpha-receptor blocker may be used.

Adverse Reactions

The adverse reactions listed below may occur with the following frequencies: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders: very rare – thrombocytopenia; agranulocytosis; leukopenia; anemia, including hemolytic; pancytopenia; sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain); bruising or bleeding.

Immune system disorders: rare – hypersensitivity, Quincke's edema; frequency not known – anaphylactic reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Psychiatric disorders: rare – nervousness, insomnia, confusion, psychomotor agitation and disorientation, anxiety, fear, irritability, sleep disturbances, hallucinations, depressive states.

Nervous system disorders: common – drowsiness; rare – dizziness, headache, paresthesia, tinnitus.

Cardiac disorders: rare – tachycardia, palpitations, arterial hypertension.

Endocrine disorders: rare – hypoglycemia, up to hypoglycemic coma.

Gastrointestinal disorders: common – nausea, vomiting; rare – dry mouth, constipation, abdominal pain and discomfort, diarrhea, heartburn, decreased appetite, hypersalivation.

Metabolism and nutrition disorders: frequency not known – metabolic acidosis with high anion gap.

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

Hepatobiliary disorders: rare – liver function abnormalities, increased liver enzymes, usually without development of jaundice.

Renal and urinary disorders: rare – dysuria, nephrotoxicity, renal colic.

Skin and subcutaneous tissue disorders: rare – rash, pruritus, erythema multiforme, urticaria.

General disorders: rare – general weakness, malaise.

Unlike second-generation antihistamines, pheniramine use is not associated with QT interval prolongation or cardiac arrhythmias.

Description of selected 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 as a result of low glutathione levels in these patients.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in a place inaccessible to children.

Packaging.

10 or 30 sachets in a cardboard box.

Prescription status. Over-the-counter.

Manufacturer.

Pharmaceutical Company "FARCO" LLC, Ukraine.

Manufacturer's address and place of business.

360, Sviato-Pokrovska St., village Hostomel, Irpin, Kyiv region, 08290, Ukraine.