Combicitron

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT COMBICITRON (COMBICITRON)

Composition:

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

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

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, soft lumps may be present, with a lemon odor.

Pharmacotherapeutic group.

Analgesics and antipyretics. Paracetamol combinations without psycholeptics. ATC code N02B E51.

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 (CNS). It does not affect platelet function or hemostasis. The absence of peripheral inhibition of prostaglandin synthesis ensures important properties of the drug, such as preservation of protective prostaglandin synthesis in the gastrointestinal tract. Therefore, paracetamol can be administered to 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 administered in therapeutic doses to relieve nasal congestion, it does not exhibit a significant stimulatory effect on cardiac beta-adrenergic receptors or a significant effect on the CNS. It is a well-established nasal decongestant that acts via vasoconstriction, reducing edema and hyperemia of the nasal mucosa.

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

Ascorbic acid may be beneficial in compensating for the increased demand of the body 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 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 extent of binding increases with rising concentrations.

Paracetamol is primarily metabolized in the liver via two pathways: glucuronidation and sulfation. It is excreted in 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. Approximately 70–83% of the orally administered dose is excreted in 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; therefore, oral phenylephrine has reduced bioavailability. It is excreted in urine almost entirely as sulfate conjugate. Maximum plasma concentration is observed 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 into all body cells, with 25% bound to plasma proteins. Excess ascorbic acid not required by the body is excreted in urine as metabolites.

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to any component of the drug. 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, prostate hyperplasia with urinary retention, bladder neck obstruction, pyloroduodenal obstruction, bronchial asthma, epilepsy, sleep disorders.

The use of the drug is contraindicated during concomitant therapy with monoamine oxidase inhibitors (MAOIs) and for 2 weeks after discontinuation of MAOIs, as well as during concomitant therapy with tricyclic antidepressants, beta-blockers, and other sympathomimetics.

Interaction with other medicinal products and other types of interactions.

Drug interactions for each individual component of the drug 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 elimination half-life of chloramphenicol.

Paracetamol may reduce the bioavailability of lamotrigine, decreasing its effect, likely due to 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. 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 levels when determined by the phosphotungstic acid method.

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").

Pheniramine maleate

First-generation antihistamines, such as pheniramine maleate, may enhance the CNS 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 MAO inhibitors. 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 adverse cardiovascular reactions.

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 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 when administered orally enhances the absorption of penicillin and iron, 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 large doses reduce the effectiveness of tricyclic antidepressants. Antidepressants, antiparkinsonian and antipsychotic agents, phenothiazine derivatives increase the risk of urinary retention, dry mouth, and constipation. Ascorbic acid may be taken only 2 hours after deferoxamine injection, as their concomitant use increases iron toxicity, especially in the myocardium. Prolonged intake of large doses during disulfiram therapy inhibits the disulfiram-alcohol reaction.

Special precautions for use

Use the medication with caution in patients with:

• Impaired kidney and/or liver function;
• Acute hepatitis;
• Hemolytic anemia;
• Chronic malnutrition and dehydration;
• Cardiovascular diseases;
• Diabetes mellitus;
• Benign prostatic hyperplasia, as these patients may be prone to urinary retention;
• Pyloric stenosis.

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

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

Alcohol consumption should be avoided during treatment, as ethanol taken simultaneously 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, patients taking medications affecting the liver, and elderly patients. The medication should be avoided in elderly patients with confusion.

There have been reports of possible premature closure of the fetal ductus arteriosus 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 prolonged headache;
• Regarding the possibility of using the medication in case of impaired kidney or liver function.

These manifestations may indicate a more serious underlying condition.

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

The medication contains phenylephrine, which may provoke angina attacks.

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

The medication should be used with caution in patients with recurrent uric acid kidney stones. 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 labored 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 pyroglutamic acidosis have been reported in critically ill patients, such as those with 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 close patient monitoring are recommended. Measurement of 5-oxoproline levels in urine may be helpful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

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

Reporting suspected adverse reactions after the drug has been authorized is important. This enables continued monitoring of the benefit-risk balance of the medication.

Use during pregnancy or breastfeeding

The use of this medication 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 involving pregnant women has not revealed congenital or fetotoxic/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.

To date, there are insufficient data from studies on reproductive function and embryotoxic/fetotoxic effects of pheniramine.

Limited data are available on the use of phenylephrine hydrochloride in pregnant women. Vasoconstriction of the uterus 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 paracetamol therapy.

There is insufficient information regarding the excretion of pheniramine into breast milk and the amount of the drug that may be transferred to the infant.

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

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

Ability to affect reaction speed when driving or operating machinery

The medication 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 equipment requiring concentration.

Method of Administration and Dosage

For oral use. Adults and children aged 12 years and older should take 1 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. It is not recommended to use the medication 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 required to achieve symptom relief should be used.

Patients with Hepatic Impairment

Patients with impaired liver function should reduce the dose or increase the interval between doses.

Elderly Patients

Dose adjustment in elderly patients is not required.

Children

The medication must not be administered to 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, liver necrosis may develop. Paracetamol overdose, including high cumulative doses taken over a prolonged period, may lead to 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 such as chronic excessive ethanol use, glutathione depletion (digestive disorders, cystic fibrosis, HIV infection, cachexia), ingestion of 5 g or more of paracetamol may result in liver injury.

There is a risk of poisoning, especially 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, hepatic failure may progress to encephalopathy, coma, and may be fatal.

With prolonged use of the drug in high doses, hematological disorders may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. Central nervous system (CNS) effects from high doses may include dizziness, psychomotor agitation, and disorientation. Urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, capillary 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 appear within the first 24–48 hours but may occur later, within 4–6 days after drug administration. 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: Paracetamol overdose requires immediate medical attention, even if no symptoms are apparent. Administration of N-acetylcysteine intravenously or orally as an antidote to paracetamol may be indicated in the early stages. 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 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, followed by excitation (especially in children) or CNS 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 have been reported following pheniramine overdose. Atropine-like symptoms may include mydriasis, photophobia, dry skin and mucous membranes, hyperthermia, and intestinal atony.

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

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 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.

Side effects

The side effects 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 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.

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 liver enzyme levels, 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.

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

Description of selected side effects

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 due to low glutathione levels in these patients.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life. 2 years.

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

Keep out of reach of children.

Packaging. 13.6 g per sachet; 10 sachets per pack.

Authorization category. Over-the-counter.

Manufacturer. JSC "Farmak".

Manufacturer's address and location of operations.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.