Paraitron

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PARACITRON (PARACITRON)

Composition:

Active substances: paracetamol, phenylephrine hydrochloride, pheniramine maleate, ascorbic acid;

One sachet contains 325 mg of paracetamol, 10 mg of phenylephrine hydrochloride, 20 mg of pheniramine maleate, 50 mg of ascorbic acid;

Excipients: sodium citrate, malic acid, anhydrous citric acid, calcium phosphate, sucrose, curcumin (E 100), titanium dioxide (E 171), lemon flavor.

Pharmaceutical form. Oral powder for solution.

Main physicochemical properties: free-flowing granular powder with white and yellowish granules, in which soft lumps may be present, with a lemon odor.

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 inhibition of prostaglandin synthesis provides important properties of the drug, such as preservation of protective prostaglandin synthesis in the gastrointestinal tract. Therefore, paracetamol can be used in patients for whom peripheral inhibition of prostaglandin synthesis is undesirable (e.g., patients with a history of gastrointestinal bleeding or elderly patients).

Phenylephrine hydrochloride is a sympathomimetic amine that primarily acts directly on alpha-adrenergic receptors. When used in therapeutic doses to relieve nasal congestion, the drug does not exhibit significant stimulatory effects on cardiac beta-adrenergic receptors or significant effects 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 that exerts antiallergic effects, reducing the severity of local exudative manifestations, tearing, rhinorrhea, and itching in the eyes and nose. It reduces the expression of general allergic symptoms associated with respiratory tract diseases. It also exhibits a moderate sedative effect. Additionally, it has antimuscarinic activity.

Ascorbic acid may be beneficial in compensating for the increased body demand for vitamin C during fever and influenza.

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 to most body tissues. It crosses the placental barrier and is excreted into breast milk. When administered at usual therapeutic doses, paracetamol is only minimally bound to plasma proteins; however, the degree of binding increases with rising concentrations.

Paracetamol is primarily metabolized 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 reached 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 unevenly absorbed in the gastrointestinal tract and undergoes presystemic metabolism by monoamine oxidase in the intestine and liver, resulting in reduced bioavailability after oral administration. It is excreted in the urine almost entirely as a sulfate conjugate. Maximum plasma concentration occurs within 45 minutes to 2 hours, and the plasma elimination half-life is 2–3 hours.

Ascorbic acid is rapidly and completely absorbed in the gastrointestinal tract and distributed to all cells of the body; 25% is bound to plasma proteins. Excess ascorbic acid not required for body needs is excreted in the urine as metabolites.

Clinical Characteristics

Indications. Treatment of symptoms of influenza and common 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 hepatic and/or renal impairment, 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, prostatic hyperplasia with urinary retention, bladder neck obstruction, pyloroduodenal obstruction, bronchial asthma, epilepsy, sleep disorders.

Use of the medicinal product is contraindicated during concomitant treatment with monoamine oxidase inhibitors (MAOIs) and for 2 weeks after discontinuation of MAOI therapy, as well as during concomitant treatment with tricyclic antidepressants, beta-blockers, and other sympathomimetics.

Interaction with other medicinal products and other forms of interaction

Drug interactions of each individual component of the medicinal product are well known. There is no reason to assume that the use of these substances 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, and the risk of bleeding may increase. 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, and 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 half-life of chloramphenicol.

Paracetamol may reduce the bioavailability of lamotrigine, decreasing its effect due to probable 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 the development of neutropenia and increased risk of liver damage. Paracetamol reduces the effectiveness of diuretics.

Probenecid affects paracetamol metabolism. The dose of paracetamol should be reduced in patients receiving probenecid concomitantly.

Paracetamol hepatotoxicity may be enhanced by prolonged or excessive alcohol consumption.

Paracetamol may affect test results for serum uric acid when measured by the phosphotungstic acid method.

Caution should be exercised when using paracetamol concomitantly with flucloxacillin, as this combination has been associated with metabolic acidosis with a high anion gap, particularly in patients with risk factors (see section "Special precautions").

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 effects of atropine, spasmolytics, other antihistamines, antiparkinsonian agents, and phenothiazine neuroleptics. Pheniramine maleate may also inhibit the action of anticoagulants.

Phenylephrine hydrochloride

The use of the drug is contraindicated during therapy with MAO inhibitors and for 2 weeks after discontinuation of MAOI treatment. 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 reactions.

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

Ascorbic acid enhances the absorption of penicillin and iron when administered orally, reduces the effectiveness of heparin and indirect anticoagulants, increases the risk of crystalluria during salicylate therapy and the risk of glaucoma during glucocorticoid therapy, and high doses reduce the effectiveness of tricyclic antidepressants. Antidepressants, antiparkinsonian and antipsychotic agents, and phenothiazine derivatives may increase the risk of urinary retention, dry mouth, and constipation. Ascorbic acid should be taken only 2 hours after deferoxamine injection, as their concomitant use increases iron toxicity, especially in the myocardium. Prolonged use of high doses during disulfiram treatment inhibits the disulfiram–alcohol reaction.

Special precautions for use

The medicinal product should be used with caution in patients:

• with impaired kidney and/or liver function;
• with acute hepatitis;
• with hemolytic anemia;
• in cases of chronic malnutrition and dehydration;
• with cardiovascular diseases;
• with diabetes mellitus;
• with prostate hyperplasia — due to possible development of urinary retention;
• with stenosing peptic ulcer.

Concomitant use of other medicinal products containing paracetamol should be avoided due to the risk of severe liver damage in case of overdose. Paracetamol overdose may cause liver failure, which may require liver transplantation or may be fatal.

The product is not recommended to be used concomitantly with vasoconstrictive agents. Do not exceed the recommended doses.

During treatment with this medicinal product, consumption of alcoholic beverages should be avoided, as ethanol taken concomitantly with paracetamol may cause liver function impairment. Paracetamol should be used with caution in patients with alcohol dependence, Raynaud's disease, heart diseases (including arrhythmia, bradycardia), thyroid disorders, glaucoma, chronic lung diseases, as well as in patients taking medicinal products affecting the liver, and in elderly patients. The product should be avoided in elderly patients with confusion.

There have been reports of possible premature closure of the fetal arterial duct following paracetamol use during pregnancy.

Patients should consult a physician:

• if they have breathing problems such as asthma, emphysema, or chronic bronchitis;
• if symptoms persist for more than 5 days or if symptoms are accompanied by high fever lasting more than 3 days, rash, or persistent headache;
• regarding the possibility of using the product in cases of impaired kidney or liver function.

These manifestations may be symptoms of a more serious condition.

The medicinal product may affect laboratory test results for blood glucose levels.

The medicinal product contains phenylephrine, which may provoke angina attacks.

Cases of hepatic dysfunction/failure have been reported in patients with reduced glutathione levels, for example, in patients suffering severely from malnutrition, anorexia, those with low body mass index, or chronic alcohol dependence.

The product should be used with caution in patients with recurrent urate kidney stones. In patients with severe infections such as sepsis, associated with reduced glutathione levels, paracetamol use 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 should be sought if these symptoms occur.

Caution is recommended when paracetamol is used concomitantly with flucloxacillin due to an increased risk of high anion gap metabolic acidosis, especially in patients with severe renal impairment, sepsis, malnutrition, or other causes of glutathione deficiency (e.g., chronic alcoholism), as well as when maximum daily doses of paracetamol are administered. Careful monitoring, including measurement of urinary 5-oxoproline levels, is recommended.

One sachet of the medicinal product contains 12.085 g of sucrose per dose. Use with caution in patients with diabetes mellitus.

Pregnancy and breastfeeding

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

Pregnancy

Analysis of a large amount of data on pregnant women has not revealed teratogenic or fetal/neonatal toxicity. Epidemiological studies on neurodevelopmental outcomes in children exposed to paracetamol in utero are inconclusive. 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 function and embryotoxic/fetotoxic effects of pheniramine use.

There are also only limited data on the use of phenylephrine hydrochloride during pregnancy. Vasoconstriction of the uterus and impaired uterine blood flow associated with phenylephrine use may lead to fetal hypoxia. The use of phenylephrine hydrochloride should be avoided during pregnancy.

Breastfeeding period

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

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

It is unknown whether phenylephrine passes into breast milk. The use of phenylephrine should be avoided in women who are breastfeeding.

Ascorbic acid is excreted in breast milk but reaches saturation levels. The use of ascorbic acid is compatible with breastfeeding.

Ability to influence reaction speed when driving or operating machinery. The medicinal product may cause drowsiness in some patients (especially due to pheniramine), which may significantly affect the ability to drive or operate machinery. Caution should be exercised when driving vehicles or operating machinery requiring concentration of attention.

Method of Administration and Dosage

The medicinal product is taken orally. Adults and children aged 12 years and older should take 1 sachet every 4–6 hours (if symptom relief is required), but not more than 4 sachets per day. The single dose must not exceed 1 sachet. It is not recommended to use the drug for longer than 7 days without consulting a physician. The minimum interval between doses is 4 hours. The contents of 1 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

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

Elderly Patients

Dose adjustment in elderly patients is not required.

Children. The medicinal product is not recommended for 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 effect, in severe cases leading to liver necrosis. Paracetamol overdose, including high total doses taken over a prolonged period, may cause nephropathy with irreversible impairment of liver function.

Liver 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 such as 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, chronically undernourished patients, 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 may be fatal.

With prolonged use of the drug in high doses, hematological disorders such as aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia may develop. With large doses, central nervous system effects such as dizziness, psychomotor agitation, and disorientation may occur; urinary system effects include nephrotoxicity (renal colic, interstitial nephritis, cortical necrosis).

Symptoms of paracetamol overdose appearing within the first 24 hours include 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 and may appear later, within 4–6 days after drug administration. Liver damage typically occurs within 72–96 hours after drug intake. 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, presenting 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. Administration of intravenous or oral N-acetylcysteine as an antidote for paracetamol may be indicated early. Gastric lavage and/or oral administration of methionine may be beneficial within 48 hours after overdose.

Administration of activated charcoal and monitoring of respiration and circulation may be helpful. Diazepam may be used in case of seizures.

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, 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, disturbances of 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 care should be provided, including administration of activated charcoal, saline cathartic, and standard supportive measures for cardiovascular and respiratory systems. Stimulants must not be used; vasoconstrictors may be used to treat arterial hypotension.

Alpha-receptor blockers (phentolamine) may be administered intravenously to counteract hypertensive effects, and diazepam may be used in case of seizures.

Symptoms of ascorbic acid overdose will be attributed to severe hepatic failure caused by paracetamol overdose.

Side effects

The frequency of adverse reactions is defined according to the following categories: 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 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, tremor.

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

Cardiac and vascular 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.

Respiratory system disorders: very rare — bronchospasm in patients sensitive to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs.

Hepatobiliary disorders: rare — liver function abnormalities, increased levels of 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 prostate 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 QTc interval prolongation or cardiac arrhythmias.

Reporting of suspected adverse reactions

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

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 13.6 g in sachets; 10 sachets in a carton.

Prescription status. Over-the-counter (without prescription).

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.