Tricitron

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRICYTRON

Composition:

Active substances: paracetamol, pheniramine maleate, phenylephrine hydrochloride;

1 sachet contains 325 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. Powder for oral solution.

Main physicochemical properties: white or light-yellow powder with a typical lemon aroma; soft granules of more intense color may be present. Solution: clear light-yellow solution with lemon taste.

Pharmacotherapeutic group.

Analgesics and antipyretics. Paracetamol combinations without psycholeptics.

ATC code N02BE51.

Pharmacological Properties

Pharmacodynamics

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

Paracetamol exerts 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. The absence of peripheral prostaglandin inhibition confers important properties to the drug, such as preservation of protective prostaglandins in the gastrointestinal tract. Therefore, paracetamol can be administered to patients for whom peripheral prostaglandin inhibition is undesirable (e.g., patients with a history of gastrointestinal bleeding or elderly patients).

Pheniramine maleate, an H1-receptor blocker, exerts antihistaminic effects, reducing the intensity of local exudative manifestations, tearing, rhinorrhea, and itching in the eyes and nose. Reduction of general allergic symptoms is associated with respiratory tract disorders, and it produces a moderate sedative effect. Pheniramine maleate also exhibits antimuscarinic activity.

Phenylephrine hydrochloride is a sympathomimetic amine that acts primarily directly on alpha-adrenergic receptors. When used in therapeutic doses to relieve nasal congestion, it has no significant stimulatory effect on cardiac beta-adrenergic receptors or on the central nervous system. It is a well-established nasal decongestant that acts via vasoconstriction, reducing swelling and hyperemia of the nasal mucosa.

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 protein binding increases with rising concentration.

Paracetamol is metabolized primarily in the liver via two pathways: glucuronidation and sulfation. It is excreted in the urine mainly as glucuronide and sulfate conjugates. Less than 5% of the dose is excreted unchanged. 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. Approximately 70–83% of the orally administered dose is excreted in the urine unchanged or as metabolites.

Phenylephrine hydrochloride is unevenly absorbed in the gastrointestinal tract and undergoes presystemic metabolism by monoamine oxidase in the intestine and liver; thus, after oral administration, phenylephrine has reduced bioavailability. It is excreted in the urine almost entirely in the form of sulfate conjugates. Maximum plasma concentrations are observed within 45 minutes to 2 hours, and the plasma 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 medicinal product. 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. Not to be used during treatment with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuation of such treatment. Concomitant use with tricyclic antidepressants, beta-blockers, and other sympathomimetics is contraindicated.

Interaction with medicinal products and other types of interactions.

Drug interactions involving each individual component of TriCitron 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 of paracetamol, the anticoagulant effect of warfarin or other coumarin derivatives may be enhanced, increasing 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 an increase in its maximum plasma concentration. Domperidone may similarly increase the rate of paracetamol absorption. Paracetamol may prolong the elimination half-life of chloramphenicol.

Paracetamol may reduce the bioavailability of lamotrigine, potentially reducing its effect due to possible induction of its hepatic metabolism.

Absorption of paracetamol may be reduced when used 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 concurrently receiving probenecid, 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, particularly 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 certain 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 effects of atropine, spasmolytics, other antihistamines, antiparkinsonian agents, and phenothiazine neuroleptics. Pheniramine maleate may also inhibit the action of anticoagulants.

Phenylephrine hydrochloride

Use of the drug is contraindicated in patients undergoing therapy with MAO inhibitors or in patients who have taken MAO inhibitors within the previous 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 adverse effects.

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

Concomitant use of phenylephrine with digoxin and cardiac glycosides may increase the risk of cardiac arrhythmias or cardiac events.

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.

Use the medicine with caution in patients with:

• impaired kidney and/or liver function;
• acute hepatitis;
• haemolytic anaemia;
• chronic malnutrition and dehydration;
• cardiovascular diseases;
• diabetes mellitus;
• benign prostatic hyperplasia, as they may be prone to urinary retention;
• stenosing peptic ulcer.

Contains paracetamol. Avoid concomitant use of other medicinal products containing paracetamol due to the risk of severe liver damage in case of overdose. Paracetamol overdose may cause liver failure, which may require liver transplantation or lead to death.

The medicine is not recommended to be used concomitantly with vasoconstrictors. Do not exceed the recommended doses.

Alcohol consumption should be avoided during treatment with this medicine, as ethanol taken concomitantly with paracetamol may cause liver function impairment. Paracetamol should be used with caution in patients with Raynaud's disease, heart diseases (including arrhythmia, bradycardia), thyroid disorders, glaucoma, chronic lung diseases, patients taking medicinal products affecting the liver, and elderly patients. The medicine should be avoided in elderly patients with confusion. There have been reports of possible premature closure of the fetal ductus arteriosus with paracetamol use during pregnancy.

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 medicine in case of impaired kidney or liver function.

These conditions may be symptoms of a more serious illness.

The medicine may affect laboratory test results for blood glucose levels.

The medicine contains phenylephrine, which may provoke angina attacks.

Cases of hepatic dysfunction/failure have been reported in patients with reduced glutathione levels, such as those severely affected by malnutrition, anorexia, low body mass index, or chronic alcohol dependence.

In patients with severe infections such as sepsis, which are associated with reduced glutathione levels, the use of paracetamol increases the risk of metabolic acidosis. Symptoms of metabolic acidosis include deep, rapid, or laboured breathing, nausea, vomiting, and loss of appetite. Immediate medical attention should be sought 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 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 for prolonged periods or in combination with flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol and close 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 of the medicine contains 14.4 g of sucrose, which should be taken into account by patients with diabetes mellitus. Patients with rare hereditary conditions such as fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medicine.

The medicine contains a colouring agent (E 102) that may cause allergic reactions.

One sachet of the medicine contains 14.7 mg of sodium. Patients on a sodium-restricted diet should take into account the sodium content.

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine.

Use during pregnancy or breastfeeding

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

Pregnancy

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

Large amounts of data involving pregnant women do not indicate congenital or foetal/neonatal toxicity. Epidemiological studies on the development of the nervous system in children exposed in utero to paracetamol show insufficiently conclusive results. Paracetamol may be used during pregnancy when clinically necessary, at the lowest effective dose, for the shortest duration, and with the lowest frequency possible.

To date, there are no adequate data on reproductive toxicity or embryotoxicity/foetotoxicity with the use of pheniramine.

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

Breastfeeding period

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 treatment with this medicine.

There is insufficient information on the excretion of pheniramine in breast milk and the amount of the medicine that could 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.

Ability to affect reaction speed when driving or operating machinery.

The medicine may cause drowsiness in some patients (especially due to pheniramine), which may significantly impair the ability to drive or operate machinery. Caution should be exercised when driving vehicles or operating machinery requiring concentration.

Method of Administration and Dosage

For oral use. Administer to adults and children aged 12 years and older one sachet every 4–6 hours (as needed for symptom relief), but not more than 4 sachets per day. The single dose must not exceed 1 sachet. The drug should not be used for longer than 7 days without consulting a physician. The minimum interval between doses is 4 hours. The contents of one sachet should be dissolved in a glass of boiled hot water (but not boiling water) and taken while hot. The lowest effective dose for the shortest duration necessary should be used.

Patients with Hepatic Impairment

In patients with impaired liver function, the dose should be reduced or the interval between administrations increased.

Elderly Patients

Dose adjustment in elderly patients is not required.

Children

The drug is contraindicated in children under 12 years of age.

Overdose

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

Symptoms caused by paracetamol

Hepatotoxic effects occur, and in severe cases, liver necrosis may develop. Paracetamol overdose, including high cumulative doses taken over a prolonged period, may cause analgesic-induced nephropathy with irreversible liver function impairment.

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 ethanol consumption, glutathione depletion (digestive disorders, cystic fibrosis, HIV infection, cachexia)—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, hematological disorders may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. Central nervous system effects may include dizziness, psychomotor agitation, and disorientation. Urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, cortical necrosis).

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

Treatment
In case of paracetamol overdose, immediate medical attention is required, even if no symptoms of overdose are apparent. Early administration of intravenous or oral N-acetylcysteine as an antidote to paracetamol, and possibly gastric lavage and/or oral methionine, may be beneficial within at least 48 hours after overdose.

Administration of activated charcoal and monitoring of respiration and circulation may be helpful. Diazepam may be used if seizures occur.

Symptoms caused by pheniramine maleate and phenylephrine hydrochloride

Symptoms due to 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, arrhythmia, coma, and seizures may occur.

Cases of atropine-like "psychosis" due to pheniramine overdose have been reported. 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 care should be provided, including administration of activated charcoal, a saline laxative, and standard supportive measures for the cardiovascular and respiratory systems. Central nervous system stimulants must not be used; vasoconstrictors may be used to treat arterial hypotension.

Alpha-receptor blockers (phentolamine) for intravenous administration may be used to counteract hypertensive effects.

Side effects

The adverse reactions listed below may occur with the following frequency: very common (≥ 1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), or frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders: very rare – thrombocytopenia, agranulocytosis, leukopenia, anemia including hemolytic anemia, 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, tremor.

Eye disorders: mydriasis, acute angle-closure glaucoma (more frequently in patients with glaucoma), accommodation disorders.

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, elevated liver enzymes, usually without development of jaundice.

Renal and urinary disorders: rare – dysuria, nephrotoxicity, renal colic; very rare – urinary retention (more likely in patients with prostatic hyperplasia).

Skin and subcutaneous tissue disorders: rare – rash, pruritus, erythema multiforme, urticaria, eczema, purpura, allergic dermatitis.

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 consequence of low glutathione levels in these patients.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

10 or 30 sachets per cardboard box.

Dispensing category. Over-the-counter.

Manufacturer.

TOV Pharmaceutical Company "FARCO S".

Manufacturer's address and place of business.

360 Svyato-Pokrovska Street, Hostomel settlement, Irpin, Kyiv region, 08290, Ukraine

Marketing authorization holder.

TOV Pharmaceutical Company "FARCO S".

Address of the marketing authorization holder.

50-A Zodchykh Street, Kyiv, 03162, Ukraine