Bifoc® ic

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT BIFOC® IS (BIFOC IS)

Composition:

Active substances: ibuprofen, codeine phosphate hemihydrate;

1 tablet contains ibuprofen 200 mg (0.2 g), codeine phosphate hemihydrate (calculated as codeine base monohydrate) 10 mg (0.01 g);

Excipients: microcrystalline cellulose, potato starch, sodium starch glycolate (type A), hypromellose (hydroxypropylmethylcellulose), crospovidone, colloidal anhydrous silicon dioxide, talc, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white, flat cylindrical tablets with a bevel; the trade mark of the manufacturer is imprinted on one side of the tablet, a line is present on the other side.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives. Ibuprofen combinations. ATC code M01AE51.

Pharmacological Properties.

Pharmacodynamics.

Ibuprofen is a non-steroidal anti-inflammatory drug, a propionic acid derivative, exerting analgesic, antipyretic, and anti-inflammatory effects. Its mechanism of action is based on inhibition of prostaglandin synthesis—mediators of pain, inflammation, and hyperthermic response. Additionally, ibuprofen reversibly inhibits platelet aggregation.

Experimental data indicate that ibuprofen may competitively reduce the effect of low-dose acetylsalicylic acid on platelet aggregation when both drugs are administered concomitantly. Some pharmacodynamic studies have shown that administration of single 400 mg doses of ibuprofen within 8 hours before or within 30 minutes after immediate-release acetylsalicylic acid (81 mg) was associated with reduced effects of aspirin (acetylsalicylic acid) on thromboxane formation or platelet aggregation. Although uncertainty exists regarding extrapolation of these findings to clinical settings, it cannot be excluded that regular long-term use of ibuprofen may diminish the cardioprotective effect of low-dose acetylsalicylic acid. Such a clinically significant effect is considered unlikely with occasional use of ibuprofen.

Codeine is an opioid analgesic with effects similar to morphine, but with significantly weaker analgesic activity and a milder sedative effect. Codeine is a weak centrally-acting analgesic. It exerts its effects through interaction with μ-opioid receptors, although it has low affinity for these receptors; the analgesic effect of codeine is attributed to its conversion into morphine. The combination of a centrally-acting analgesic with a peripherally-acting analgesic having good tolerability provides optimal pain relief with a reduced risk of adverse reactions. Codeine, particularly in combination with other analgesics such as paracetamol, has been shown to be effective in the treatment of acute nociceptive pain. At low doses, it does not cause respiratory center depression.

Pharmacokinetics.

Ibuprofen is rapidly absorbed from the gastrointestinal tract following oral administration. Maximum plasma concentration is reached within 45 minutes after dosing when administered on an empty stomach; when taken with food, peak plasma levels occur within 1–2 hours after administration. Ibuprofen is metabolized in the liver and excreted by the kidneys (90%) both unchanged and as metabolites, as well as in bile. Elimination half-life is approximately 1.8 hours; in patients with hepatic or renal impairment, it ranges from 1.8 to 3.5 hours. Ibuprofen is highly protein-bound (99%) in plasma, slowly penetrates into synovial spaces, where its concentration may remain high even as plasma levels decline. No significant differences in pharmacokinetic profile are observed in elderly patients.

Codeine and its salts are rapidly absorbed from the gastrointestinal tract. Following oral administration, peak plasma codeine concentrations are achieved within 1 hour. Due to its lipophilicity, codeine rapidly crosses the blood-brain barrier and accumulates in fatty tissues and, to a lesser extent, in highly perfused tissues (lungs, liver, kidneys, and spleen). The elimination half-life from plasma is 3–4 hours. The ratio of analgesic potency following oral administration versus intramuscular injection is approximately 1 : 1.5. Codeine is metabolized in the liver via O- and N-demethylation to form morphine and norcodeine, both of which possess intrinsic analgesic activity. Codeine and its metabolites are excreted renally, primarily as glucuronide conjugates. Most excretory products are eliminated in urine within 6 hours, and up to 86% of the dose is eliminated from the body within 24 hours. Approximately 70% of the dose is excreted as free codeine, 10% as free and conjugated morphine, and another 10% as free or conjugated norcodeine. Only trace amounts of excretory products are found in feces.

Clinical characteristics.

Indications.

For short-term treatment of acute, moderate pain not relieved by other analgesics such as paracetamol, ibuprofen, or acetylsalicylic acid (particularly headache, migraine, periodic pain, dental pain, neuralgia, rheumatic and muscular pain, back pain).

Contraindications.

Hypersensitivity to ibuprofen, codeine, or other opioid analgesics, or to any component of the medicinal product.

Hypersensitivity reactions (including bronchospasm, bronchial asthma, rhinitis, angioneurotic edema, or urticaria) previously observed after administration of ibuprofen, acetylsalicylic acid (aspirin), or other nonsteroidal anti-inflammatory drugs (NSAIDs).

Active or history of recurrent peptic ulcer disease or gastrointestinal bleeding (two or more confirmed episodes of peptic ulcer or bleeding).

Erosive and ulcerative gastrointestinal tract disorders in the phase of exacerbation, including ulcerative colitis, peptic ulcer, Crohn’s disease.

History of gastrointestinal bleeding or perforation associated with previous use of NSAIDs.

Cerebrovascular or other active bleeding conditions.

Coagulation disorders of unknown etiology. Hemorrhagic diathesis or other coagulation disorders.

Severe heart failure [NYHA Class IV (New York Heart Association)] (see section "Special precautions").

Respiratory depression, obstructive respiratory tract diseases, bronchial asthma (opioids should not be used during an asthma attack).

Head injuries or conditions associated with increased intracranial pressure (in addition to the risk of respiratory depression and increased intracranial pressure, codeine may affect pupillary response and other vital signs during neurological assessment).

Conditions where inhibition of peristalsis should be avoided or where abdominal distension occurs.

Risk of paralytic ileus, chronic constipation.

Active inflammatory bowel disease.

Severe hepatic impairment.

Severe renal impairment.

Severe dehydration caused by vomiting, diarrhea, or insufficient fluid intake.

Alcohol intoxication.

Concomitant use with other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, monoamine oxidase inhibitors (MAOIs), or within 2 weeks after discontinuation of MAOIs.

The medicinal product is contraindicated in the following patient groups:

• Children under 12 years of age;
• Children aged 12 to 18 years undergoing tonsillectomy and/or adenoidectomy to prevent the occurrence of obstructive sleep apnea;
• Children aged 12 to 18 years with compromised respiratory function;
• Women during pregnancy or breastfeeding;
• Patients of any age who are ultra-rapid metabolizers via CYP2D6.

Interaction with other medicinal products and other forms of interaction.

Interactions related to ibuprofen

Ibuprofen, like other NSAIDs, should not be used in combination with the following medicinal products:

• Acetylsalicylic acid (aspirin), as this may increase the risk of adverse reactions, except when low-dose aspirin (not exceeding 75 mg daily) has been prescribed by a physician (see sections "Pharmacological properties", "Special precautions");
• Other NSAIDs, including selective COX-2 inhibitors: simultaneous use of two or more NSAIDs should be avoided, as this may increase the risk of adverse effects (see section "Special precautions").

Ibuprofen should be used with caution in combination with the following medicinal products:

• Corticosteroids: increased risk of gastrointestinal ulceration and bleeding (see section "Special precautions");
• Antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists, β-blockers) and diuretics: NSAIDs may reduce the therapeutic efficacy of these drugs.

In some patients with compromised renal function (e.g., dehydrated patients or elderly patients with impaired renal function), concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or β-blockers with cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, such combinations should be prescribed with caution, especially in elderly patients. If prolonged treatment is necessary, adequate hydration should be ensured, and monitoring of renal function should be considered at the start of combination therapy and periodically thereafter. Diuretics may increase the risk of nephrotoxic effects of NSAIDs. Concomitant use of potassium-sparing diuretics with ibuprofen may lead to hyperkalemia (monitoring of plasma potassium levels is recommended).

• Probenecid and sulfinpyrazone: may delay the elimination of ibuprofen;
• Anticoagulants: NSAIDs may potentiate the therapeutic effect of anticoagulants such as warfarin (see section "Special precautions");
• Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding;
• Cardiac glycosides: NSAIDs may exacerbate cardiac dysfunction, reduce glomerular filtration rate, and increase plasma levels of glycosides;
• Lithium, phenytoin: evidence suggests potential elevation of plasma lithium and phenytoin levels when used concomitantly with ibuprofen.

With proper use, routine monitoring of plasma concentrations of lithium or phenytoin is generally not required.

• Methotrexate: possible increase in plasma methotrexate levels;
• Cyclosporine, tacrolimus: increased risk of nephrotoxicity;
• Mifepristone: NSAIDs should not be used earlier than 8–12 days after mifepristone administration, as they may reduce its efficacy;
• Zidovudine: increased risk of hematological toxicity is known when zidovudine is used concomitantly with NSAIDs.

Evidence suggests increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia receiving concomitant zidovudine and ibuprofen.

• Quinolone antibiotics: animal studies indicate that NSAIDs may increase the risk of seizures associated with quinolone antibiotics; therefore, patients receiving NSAIDs in combination with quinolones may have an increased risk of seizures;
• Oral hypoglycemic agents: possible inhibition of sulfonylurea metabolism, prolonged elimination half-life, increased risk of hypoglycemia; blood glucose monitoring is required;
• Cytochrome CYP2C9 inhibitors, such as voriconazole or fluconazole: possible enhancement of ibuprofen's effect.

Interactions related to codeine

Monoamine oxidase inhibitors (MAOIs): central nervous system (CNS) depression or excitation may occur when codeine is used concomitantly with MAOIs or within 2 weeks after discontinuation of MAOIs.

Moclobemide: concomitant use with codeine may lead to hypertensive crisis.

Hydroxyzine: concomitant use of hydroxyzine (an anxiolytic) with codeine may enhance analgesic effects as well as increase sedative, hypotensive, and CNS-depressant effects.

MEDICINAL PRODUCTS THAT DEPRESS THE CNS: the CNS-depressant effect of codeine is enhanced by CNS depressants such as alcohol, anesthetics, hypnotics and sedatives, antihistamines with sedative properties, tricyclic antidepressants, and antipsychotics (including phenothiazines).

Diuretics and antihypertensive agents: the hypotensive effect of diuretics and antihypertensive agents may be enhanced when used concomitantly with opioid analgesics.

Quinidine: quinidine may block the analgesic effect of codeine.

Mexiletine: codeine may slow the absorption of mexiletine, leading to reduced antiarrhythmic effect.

Cardiac glycosides: when codeine is used in high doses, the effect of cardiac glycosides (digoxin and others) may be enhanced.

Antidiarrheal and antiperistaltic agents: concomitant use of codeine with antidiarrheal and antiperistaltic agents such as loperamide and kaolin may increase the risk of severe constipation.

Antimuscarinic medicinal products: concomitant use of codeine with antimuscarinic agents or agents with antimuscarinic activity, including atropine and certain antidepressants, may increase the risk of severe constipation, potentially leading to paralytic ileus and/or urinary retention.

Neuromuscular blockers: possible enhancement of respiratory depression.

Metoclopramide, cisapride, domperidone: codeine may antagonize the effects of cisapride, metoclopramide, and domperidone on gastrointestinal motility.

Cimetidine: inhibits the metabolism of opioid analgesics, leading to increased plasma concentrations.

Opioid antagonists (e.g., buprenorphine, naloxone, naltrexone): use of codeine in combination with opioid antagonists may precipitate withdrawal syndrome.

Naloxone: antagonizes the analgesic effect of opioid analgesics as well as their CNS and respiratory depressant effects.

Naltrexone: blocks the therapeutic effect of opioids.

Non-opioid analgesics: enhanced analgesic effect.

Chloramphenicol: possible increase in plasma codeine concentration due to inhibition of its metabolism.

Ciprofloxacin: opioid premedication should be avoided, as opioids reduce plasma ciprofloxacin concentrations.

Ritonavir: possible increase in plasma levels of opioid analgesics (particularly codeine).

Effect on diagnostic investigations. Opioid analgesics affect laboratory test results, including levels of bilirubin and activities of amylase, lipase, alkaline phosphatase, lactate dehydrogenase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in plasma. Opioid use may interfere with gastric emptying studies, as they delay gastric emptying, and hepatobiliary imaging using Technetium Tc 99m Disofenin, since opioid therapy may cause sphincter of Oddi constriction and increased pressure in the biliary tract.

Special precautions for use.

The potential risk of adverse reactions can be minimized by using the lowest effective dose required for treatment over the shortest possible duration.

Elderly patients have an increased risk of developing adverse reactions when using NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal (see section "Dosage and administration").

Concomitant alcohol consumption may enhance adverse reactions associated with NSAID use, especially those affecting the gastrointestinal tract or the central nervous system.

Respiratory effects

Bronchospasm may occur in patients with bronchial asthma or allergic disorders, or with a history of such conditions.

Cardiovascular and cerebrovascular effects

Patients with a history of hypertension and/or heart failure should start treatment cautiously (medical consultation is required), as fluid retention, development of hypertension, and edema have been reported during therapy with ibuprofen and other NSAIDs.

Clinical trials and epidemiological data indicate that the use of ibuprofen, particularly at high doses (2400 mg per day) and during long-term treatment, may be associated with a slightly increased risk of arterial thrombotic events (such as myocardial infarction or stroke). Overall, epidemiological data do not suggest that low doses of ibuprofen (e.g., ≤1200 mg per day) are associated with an increased risk of myocardial infarction.

Treatment with ibuprofen may be prescribed by a physician only after careful assessment of the clinical picture for patients with uncontrolled hypertension, congestive heart failure (NYHA class II–III), diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. High doses (2400 mg per day) should not be used.

Long-term treatment with NSAIDs, especially at high ibuprofen doses (2400 mg per day), should be prescribed to patients with significant cardiovascular risk factors (such as hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful evaluation of the benefit-risk ratio.

Cases of Kounis syndrome have been reported in patients taking ibuprofen. Kounis syndrome is defined as a constellation of cardiovascular symptoms arising from an allergic/hypersensitivity reaction associated with coronary artery spasm, which may potentially lead to myocardial infarction.

Gastrointestinal effects

NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn’s disease), as these conditions may be exacerbated (see section "Adverse reactions").

Caution should be exercised when treating patients who are concurrently receiving medications that may increase the risk of gastotoxicity, ulcers, or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors (SSRIs), or antiplatelet agents (e.g., acetylsalicylic acid) (see section "Interaction with other medicinal products and other forms of interaction").

There have been reports of potentially fatal gastrointestinal bleeding, ulcers, or perforations occurring at any stage of NSAID treatment, regardless of the presence of warning symptoms or a history of severe gastrointestinal disorders (including ulcerative colitis, Crohn’s disease).

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, a history of peptic ulcer disease (especially if complicated by bleeding or perforation) (see section "Contraindications"), and in elderly patients. These patients should start treatment with the lowest dose. Consideration should be given to combining therapy with gastroprotective agents (e.g., misoprostol or proton pump inhibitors) for such patients, as well as for patients requiring long-term use of low-dose acetylsalicylic acid or other medications that may increase the risk of gastrointestinal adverse reactions.

Patients with a history of gastrointestinal toxicity, particularly elderly patients, should be informed about any unusual gastrointestinal symptoms (especially gastrointestinal bleeding), particularly at the beginning of treatment.

In cases of gastrointestinal bleeding or ulceration in patients receiving ibuprofen, treatment should be discontinued immediately.

Hepatic effects

Liver function impairment. Caution is required when treating patients with impaired liver function (see sections "Contraindications", "Adverse reactions").

Renal effects

Worsening of kidney function and development of renal failure are possible (see sections "Contraindications", "Adverse reactions").

Prolonged use of NSAIDs may lead to dose-dependent reduction in prostaglandin synthesis and may provoke renal failure. Patients at high risk of renal failure include those with impaired kidney or heart function, impaired liver function, those taking diuretics, and elderly patients. Renal function should be monitored in such patients.

Children with dehydration are at risk of developing impaired kidney function (see sections "Contraindications", "Adverse reactions").

Cases of severe hypokalemia and renal tubular acidosis associated with prolonged use of ibuprofen at doses exceeding the recommended levels have been reported. This risk is increased when using a medicinal product containing a combination of codeine and ibuprofen, as patients may develop dependence on the drug due to the presence of codeine (see sections "Overdose", "Adverse reactions"). Symptoms include decreased level of consciousness and general weakness. If a patient presents with hypokalemia and unexplained metabolic acidosis, ibuprofen-induced renal tubular acidosis should be considered.

Skin and subcutaneous tissue effects

Severe skin adverse reactions

Severe skin adverse reactions (SSARs) associated with ibuprofen use have been reported. SSARs include exfoliative dermatitis, erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP), and may be life-threatening or fatal (see section "Adverse reactions"). These reactions usually occur within the first month of treatment.

If signs or symptoms suggestive of SSARs occur, use of the medicinal product Bifok® IS should be discontinued immediately and alternative treatment considered (if necessary).

In rare cases, varicella may cause severe infectious complications involving the skin and soft tissues. At present, the potential influence of NSAIDs on worsening the course of these infections cannot be excluded; therefore, the use of ibuprofen in cases of varicella is not recommended.

Masking symptoms of underlying infections

Ibuprofen may mask symptoms of infectious diseases, potentially delaying appropriate treatment and thereby complicating disease progression. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When ibuprofen is used for elevated body temperature or pain relief in infectious diseases, monitoring of the course of the infection is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Systemic lupus erythematosus and mixed connective tissue diseases

Ibuprofen should be used with caution in systemic lupus erythematosus and mixed connective tissue diseases due to an increased risk of aseptic meningitis (see section "Adverse reactions").

Effects on female fertility

Limited data suggest that medicinal products inhibiting cyclooxygenase/prostaglandin synthesis may impair female fertility by affecting ovulation. This effect may be reversible upon discontinuation of ibuprofen.

Long-term use of ibuprofen (at a daily dose of 2400 mg for more than 10 days) is not recommended in women attempting to conceive due to potential impairment of female fertility. This medicinal product should not be used in women experiencing difficulties in becoming pregnant or undergoing infertility investigations.

Porphyria metabolism disorders

Caution is required in patients with inherited porphyrin metabolism disorders (e.g., acute intermittent porphyria).

Allergic reactions

Caution is required in patients with allergic reactions to other substances, as such patients have an increased risk of hypersensitivity reactions when using ibuprofen.

Surgical procedures

Caution is required when using ibuprofen immediately after major surgical procedures.

Other NSAIDs

Concomitant use of ibuprofen with other NSAIDs, including selective COX-2 inhibitors, should be avoided due to increased risk of adverse reactions (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction").

The use of Bifok® IS in combination with other medicinal products containing codeine is contraindicated.

Codeine use requires regular benefit-risk assessment by a physician.

The medicinal product should be used with caution in patients with hypotension, hypothyroidism, adrenal insufficiency (e.g., Addison’s disease), acute abdominal syndrome (see section "Contraindications"), myasthenia gravis, impaired liver function (due to the possible development of coma) or kidney function (see section "Contraindications"), seizures, or a history of peptic ulcer disease (see section "Contraindications"), patients in shock, patients who have recently undergone gastrointestinal surgery (due to possible reduction in gastrointestinal motility) or surgery on the urinary tract (such patients are more prone to urinary retention caused directly by urethral sphincter spasm and constipation due to codeine use), and patients with a history of drug abuse. Codeine should be used with caution in patients with pheochromocytoma (opioids may stimulate catecholamine release by inducing endogenous histamine release), elderly and debilitated patients, as they may be more sensitive to the respiratory depressant effects of codeine. In elderly patients, metabolism and elimination of opioid analgesics may be slower than in younger adults, so dose reduction of codeine may be appropriate. The dose of the medicinal product should be reduced in patients with prostate hypertrophy, inflammatory bowel diseases (codeine reduces peristalsis, increases intestinal tone and segmentation, and may increase pressure in the colon) (see section "Contraindications"), urethral stricture, and elderly patients with impaired liver and/or kidney function (see section "Dosage and administration").

Patients with biliary tract disorders (particularly cholelithiasis) should avoid opioid analgesics or use them in combination with spasmolytics.

The use of meperidine and possibly other opioid analgesics in patients taking MAO inhibitors may be associated with very severe reactions, sometimes fatal. If the use of codeine in patients taking MAO inhibitors is essential, MAO inhibitors should be discontinued 2 weeks before starting codeine treatment (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction").

Alcohol consumption should be avoided during treatment with this medicinal product.

Opioid use disorder (abuse and dependence)

Repeated use of opioids such as codeine may lead to tolerance, physical and psychological dependence, and opioid use disorder (OUD).

Abuse or intentional misuse of Bifok® IS may lead to overdose and/or fatal outcome.

Serious clinical consequences, including fatalities, associated with drug abuse and dependence have been reported with the use of a medicinal product containing a combination of codeine and ibuprofen, especially with prolonged use at doses exceeding the recommended levels. Specifically, cases of gastrointestinal tract perforations, gastrointestinal bleeding, severe anemia, renal failure, renal tubular acidosis, and severe hypokalemia associated with ibuprofen use as part of a combined medicinal product have been reported.

Before initiating treatment with Bifok® IS, patients should be informed about the risks and signs of OUD and serious clinical consequences. Patients should be advised to consult a physician if such signs appear.

Withdrawal symptoms such as restlessness and irritability may occur after discontinuation of the medicinal product. Treatment should be discontinued gradually in patients who may have physical dependence to avoid precipitating withdrawal symptoms.

Metabolism involving CYP2D6

Codeine is converted to its active metabolite—morphine—in the liver by the CYP2D6 enzyme. If a patient has a deficiency or complete absence of this enzyme, adequate analgesic effect will not be achieved. It is estimated that up to 7% of the Caucasian population may have CYP2D6 deficiency. However, in extensive or ultra-rapid metabolizers via CYP2D6, there is an increased risk of adverse effects—symptoms of opioid toxicity—even with standard doses. In such patients, rapid conversion of codeine to morphine leads to higher serum morphine levels than expected.

General symptoms of opioid toxicity: confusion, drowsiness, shallow breathing, pinpoint pupils, nausea, vomiting, constipation, loss of appetite. In severe cases, circulatory and respiratory depression may occur, which can be life-threatening and, very rarely, fatal.

Data on the prevalence of CYP2D6 ultra-rapid metabolizers in various populations are provided below:

Postoperative use in children

Published literature contains reports indicating that the use of codeine in children after tonsillectomy and/or adenoidectomy for the prevention of obstructive sleep apnea has rarely led to life-threatening adverse reactions, including fatal outcomes (see section "Contraindications"). All children received codeine doses within the recommended range; however, evidence suggests that these children were either ultra-rapid or extensive metabolizers of codeine.

Children with compromised respiratory function

Codeine is contraindicated in children whose respiratory function may be compromised by neuromuscular disorders, severe cardiac or respiratory diseases, upper respiratory tract infections or lung infections, multiple trauma, or extensive surgical interventions. These factors may exacerbate symptoms of morphine toxicity.

Opioid analgesics reduce salivary secretion, which may contribute to the development of dental caries and oral mucosal candidiasis.

NSAIDs may mask the symptoms of meningitis.

The medicinal product should not be used for more than 3 days without consulting a physician.

Prolonged use of analgesics at high doses may lead to headache that cannot be treated by increasing the dose of the medicinal product.

Prolonged use of the medicinal product for headache treatment may result in worsening of headache.

Long-term and uncontrolled use of analgesics, especially combinations of different analgesic active substances, may lead to chronic kidney damage with a risk of renal failure (analgesic nephropathy).

With prolonged use of the medicinal product, liver and kidney function tests, as well as blood morphology, should be monitored regularly.

Do not exceed the recommended doses.

Use during pregnancy or breastfeeding.

Pregnancy

Use of the medicinal product during pregnancy is contraindicated.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. In animals, administration of prostaglandin synthesis inhibitors resulted in increased pre- and post-implantation losses and embryonic/fetal mortality. Furthermore, increased incidence of various developmental abnormalities, including cardiovascular malformations, has been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis. Epidemiological data indicate an increased risk of miscarriage, congenital heart defects, and gastroschisis following the use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of therapy. Use of medicinal products that inhibit prostaglandin synthesis from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This pathological condition may develop soon after initiation of treatment, is usually reversible, and resolves upon discontinuation of the medicinal product. Additionally, there have been reports of fetal ductus arteriosus constriction following intrauterine exposure to prostaglandin synthesis inhibitors in the second trimester of pregnancy, which in most cases resolved after discontinuation of treatment.

Use of any prostaglandin synthesis inhibitor in the third trimester of pregnancy may cause

in the fetus:

‒ cardiovascular and pulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);

‒ renal dysfunction (see above);

in the mother and newborn, as well as at the end of pregnancy:

‒ prolonged bleeding time, anti-aggregatory effect, which may occur even with low-dose use of the medicinal product;

‒ inhibition of uterine contractility, leading to delayed onset of labor or prolonged labor.

There have been reports of a possible association between congenital respiratory and cardiac malformations in infants and codeine use during the first trimester of pregnancy. Regular use of codeine during pregnancy may lead to physical dependence in the fetus, resulting in withdrawal symptoms in the newborn. Use of codeine during labor may depress respiration in the newborn. Use of opioid analgesics may cause gastric stasis during labor, increasing the risk of aspiration pneumonia in the mother.

Breastfeeding

Use of the medicinal product during breastfeeding is contraindicated.

Ibuprofen has been detected in breast milk at very low concentrations in some studies, making it unlikely to have a negative effect on the breastfed infant.

At usual therapeutic doses, codeine and its active metabolite may be present in breast milk at very low concentrations, which are unlikely to adversely affect the infant. However, if the patient is an ultra-rapid metabolizer via CYP2D6, higher levels of morphine may accumulate in breast milk, and in very rare cases this may cause potentially fatal opioid toxicity symptoms in the breastfed infant.

Ability to affect reaction speed when driving vehicles or operating machinery.

During treatment with this medicinal product, patients should refrain from driving vehicles or operating machinery due to possible effects such as dizziness, drowsiness, sedation, disorientation, confusion; rarely, hallucinations, blurred vision or diplopia, orthostatic hypotension, or seizures may occur. The effects of alcohol are enhanced by opioid analgesics.

Method of Administration and Dosage

For oral use. Tablets should be taken with water.

Adults and children aged 12 years and older

The recommended dose is 1–2 tablets every 4–6 hours.

Children under 12 years of age

Use is contraindicated (see sections "Contraindications", "Special precautions", "Children").

Elderly patients

Dosage adjustment is not required in elderly patients, except for those with impaired renal or hepatic function; in such cases, an individual dose adjustment is necessary.

Do not exceed 6 tablets within 24 hours. The minimum interval between doses is 4 hours. The maximum daily dose of ibuprofen is 1200 mg (equivalent to 6 tablets of the medicinal product).

For short-term use only. The medicinal product should be used at the lowest effective dose for the shortest duration necessary to relieve symptoms (see section "Special precautions"), but treatment duration should not exceed 3 days. If longer use than 3 days is required, or if symptoms do not resolve or worsen, medical advice should be sought.

Children.

The use of this medicinal product in children under 12 years of age is contraindicated due to the risk of developing serious and life-threatening adverse reactions resulting from the variable and unpredictable metabolism of codeine to morphine in this age group (see section "Contraindications").

Codeine must not be used in children aged 12 to 18 years undergoing tonsillectomy and/or adenoidectomy to prevent the occurrence of obstructive sleep apnea, due to the risk of serious and life-threatening adverse reactions (see sections "Contraindications", "Special precautions").

Codeine must not be used in children aged 12 to 18 years with compromised respiratory function due to the risk of serious and life-threatening adverse reactions (see sections "Contraindications", "Special precautions").

Codeine must not be used in children aged 12 to 18 years who are ultra-rapid metabolizers via CYP2D6 (see sections "Contraindications", "Special precautions").

Overdose.

Overdose effects are potentiated by concomitant use of alcohol and psychotropic agents. Administration of doses exceeding the recommended dose or prolonged use of the medicinal product may lead to physical or psychological dependence and cause restlessness and irritability upon discontinuation of treatment.

Symptoms of ibuprofen overdose. Administration of ibuprofen in children at doses exceeding 400 mg/kg may cause symptoms of overdose. In adults, the dose–response relationship is less pronounced. The elimination half-life in overdose is 1.5–3 hours.

In most patients, ingestion of clinically significant amounts of NSAIDs causes only nausea, vomiting, epigastric pain, or less frequently, diarrhea. Other possible symptoms include tinnitus, headache, dizziness, and gastrointestinal bleeding. In more severe poisoning, CNS toxicity may occur, manifesting as drowsiness, nystagmus, visual disturbances, and occasionally as psychomotor agitation, disorientation, or coma. Seizures may occasionally occur. In severe poisoning, hyperkalemia with cardiac arrhythmias, metabolic acidosis, and prolonged prothrombin time / increased international normalized ratio (INR) may develop, possibly due to effects on circulating blood coagulation factors. Acute renal failure, hepatic injury, arterial hypotension, elevated body temperature, respiratory failure, and cyanosis may occur. Prolonged use of ibuprofen at doses exceeding the recommended levels may lead to severe hypokalemia and renal tubular acidosis. Symptoms may include impaired consciousness and general weakness (see sections "Special precautions", "Adverse reactions"). In patients with bronchial asthma, asthma exacerbation may occur. Hemolytic anemia, granulocytopenia, and thrombocytopenia have been observed sporadically after prolonged treatment.

Treatment. There is no specific antidote or specific treatment for ibuprofen overdose. Management should be symptomatic and supportive, including ensuring airway patency and monitoring vital functions, measuring blood pressure, performing ECG, and assessing symptoms indicating possible gastrointestinal bleeding, metabolic acidosis, or CNS disturbances. Oral administration of activated charcoal or gastric lavage is recommended within 1 hour after ingestion of a potentially toxic dose of ibuprofen. If ibuprofen has already been absorbed in the gastrointestinal tract, alkalizing agents may be administered to enhance urinary excretion of the acidic ibuprofen. Intravenous diazepam or lorazepam should be administered for frequent or prolonged seizures. Bronchodilators should be used in cases of bronchial asthma.

Symptoms of codeine overdose. Severe CNS depression, including respiratory depression, may develop, particularly with concomitant use of other sedative agents (including alcohol) or significant overdose. The classic triad of opioid overdose includes coma, pinpoint pupils, and respiratory depression (which may lead to cyanosis), followed by pupil dilation as hypoxia develops. Other symptoms of opioid overdose include dry mouth, nausea, vomiting, facial flushing, nervousness or restlessness, sedation or psychomotor agitation, hallucinations, confusion, loss of consciousness, seizures (especially in children), severe dizziness, marked drowsiness, arterial hypotension and tachycardia (possible but unlikely), bradycardia, circulatory failure, slow or labored breathing, marked weakness, hypothermia, and increased sweating. Dyspnea, apnea, collapse, and urinary retention may occur; pulmonary edema is rare; signs of histamine release may be observed. Cases of rhabdomyolysis progressing to renal failure have been reported with opioid overdose.

Treatment: General symptomatic and supportive measures, including interventions to support the respiratory center and monitoring of vital signs until stabilization. Gastric lavage is recommended. Activated charcoal should be administered if less than 1 hour has passed since ingestion of a codeine dose exceeding 350 mg in adults or 5 mg/kg body weight in children. In cases of severe CNS depression, artificial respiratory support and oxygen should be provided, and naloxone should be administered parenterally. Naloxone is a competitive antagonist with a short elimination half-life; therefore, repeated administration of high doses may be necessary in patients with severe poisoning. Patients should be observed for at least 4 hours after naloxone administration, or for 8 hours if a prolonged-release naloxone preparation has been used. Electrolyte levels should be monitored.

Side effects

Prolonged use of the medicinal product for headache treatment may lead to worsening of headache.

Side effects associated with ibuprofen listed below were observed during short-term treatment with ibuprofen at doses not exceeding 1200 mg per day. Additional side effects may occur during long-term use of ibuprofen for treatment of chronic conditions.

Gastrointestinal adverse reactions were the most commonly observed with ibuprofen use. Adverse reactions are dose-dependent; in particular, the risk of gastrointestinal bleeding depends on the administered doses and duration of treatment.

Side effects associated with the use of ibuprofen and codeine are classified by organ systems and frequency. Frequency is defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Immune system disorders: hypersensitivity reactions¹, including: uncommon – urticaria, pruritus; very rare – severe hypersensitivity reactions, symptoms of which may include facial, tongue, and laryngeal swelling, dyspnea, tachycardia, hypotension (anaphylaxis, angioedema, or severe shock); maculopapular rash considered as a symptom of hypersensitivity syndrome associated with oral administration of codeine; urticaria, splenomegaly, lymphadenopathy.

Psychiatric disorders: frequency not known – depression, hallucinations, confusion, dependence, emotional lability, restlessness, nightmares; anxiety, nervousness, irritability, euphoria, dysphoria, development of tolerance.

Nervous system disorders: uncommon – headache; very rare – aseptic meningitis²; frequency not known – dizziness, somnolence, convulsions, increased intracranial pressure, dyskinesia; insomnia, psychomotor agitation, paresthesia.

Eye disorders: frequency not known – blurred vision, diplopia; visual disturbances, optic neuritis, toxic optic neuropathy, scotoma, dry eyes and eye irritation, allergic conjunctival and eyelid edema, miosis, photophobia.

Ear and labyrinth disorders: frequency not known – vertigo; hearing loss, tinnitus.

Cardiovascular system disorders: frequency not known – heart failure, edema, bradycardia, palpitations³, arterial hypertension, orthostatic hypotension³, Kounis syndrome; arterial thrombosis (myocardial infarction or stroke), arterial hypotension (with high-dose use), tachycardia, vasculitis, facial skin hyperemia.

Blood and lymphatic system disorders: very rare – hematopoietic disorders⁴ (including anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis).

Respiratory, thoracic and mediastinal disorders: frequency not known – airway reactivity (including bronchial asthma, bronchospasm or dyspnea), respiratory depression, cough suppression; allergic rhinitis.

Gastrointestinal disorders: uncommon – abdominal pain, nausea, dyspepsia; rare – diarrhea, flatulence, constipation, vomiting; very rare – peptic ulcer of the stomach and duodenum, gastrointestinal perforation or gastrointestinal bleeding, melena, hematemesis, which in some cases may lead to fatal outcomes (especially in elderly patients), ulcerative stomatitis, gastritis, exacerbation of colitis and Crohn’s disease (see section "Contraindications"); frequency not known – dryness of oral mucosa; esophagitis, gastric spasms, heartburn, pancreatitis, duodenitis, formation of intestinal diaphragm-like strictures.

Hepatobiliary disorders: very rare – liver function abnormalities; frequency not known – hepatic colic; hepatitis, jaundice, especially with prolonged use; spasm of biliary ducts, which may be associated with changes in liver enzyme levels.

Metabolism and nutrition disorders: frequency not known – decreased appetite, hypokalemia⁵.

Endocrine disorders: hyperglycemia.

Renal and urinary disorders: very rare – acute renal failure, including papillary necrosis⁶; frequency not known – ureteric colic, dysuria, renal tubular acidosis⁵; nephrotoxicity (including interstitial nephritis and nephrotic syndrome), allergic nephritis, glomerulonephritis, cystitis, oliguria, polyuria, hematuria, hypernatremia, difficulty in urination, urinary retention.

Reproductive system disorders: decreased libido and potency, sexual dysfunction, erectile dysfunction.

Skin and subcutaneous tissue disorders: uncommon – various skin rashes; very rare – severe skin reactions, including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis; frequency not known – facial flushing, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP); alopecia, photosensitivity.

Musculoskeletal and connective tissue disorders: frequency not known – muscle rigidity; uncontrolled muscle movements.

General disorders: frequency not known – hypothermia, increased sweating, irritability, increased fatigue, malaise.

Investigations: very rare – decreased hemoglobin levels.

Description of selected side effects

1 Hypersensitivity reactions may include: (a) non-specific allergic reactions and anaphylaxis; (b) airway reactivity, including bronchial asthma, asthma exacerbation, bronchospasm, and dyspnea; or (c) various forms of skin reactions, including pruritus, urticaria, purpura, angioedema, and less frequently, exfoliative and bullous dermatoses (including toxic epidermal necrolysis, erythema multiforme).

2 Very rare isolated cases have been reported. The pathogenic mechanism of NSAID-induced aseptic meningitis is not fully understood. However, available data on NSAID-associated aseptic meningitis suggest a hypersensitivity reaction (based on temporal association with drug use and symptom resolution after drug discontinuation). Cases of aseptic meningitis symptoms (such as nuchal rigidity, headache, nausea, vomiting, malaise, or disorientation) have been reported during ibuprofen treatment in patients with autoimmune diseases (such as systemic lupus erythematosus, mixed connective tissue disease) (see section "Special precautions").

3 These adverse events are associated with NSAID use. Clinical trials and epidemiological data indicate that ibuprofen use, particularly at high doses (2400 mg daily) and during long-term treatment, may be associated with a small increased risk of arterial thrombotic events (such as myocardial infarction or stroke) (see section "Special precautions").

4 Initial signs of hematopoietic disorders include malaise, sore throat, superficial ulcers in the oral cavity, flu-like symptoms, severe exhaustion, bleeding, and unexplained bruising.

5 Renal tubular acidosis and hypokalemia have been reported in the post-marketing period, mostly after prolonged use of ibuprofen in combination products at doses exceeding the recommended, due to dependence on the codeine component.

6 Especially with prolonged use; associated with increased serum urea levels and development of edema.

Regular long-term use of codeine leads to dependence and tolerance, and may result in restlessness and irritability after treatment discontinuation.

With prolonged codeine use, tolerance typically develops along with some of the most common side effects – somnolence, nausea, vomiting, confusion. It should be remembered that tolerance diminishes rapidly after codeine discontinuation; therefore, re-administration of a previously tolerated dose may be fatal.

Withdrawal syndrome

Sudden discontinuation of codeine therapy may cause withdrawal syndrome. Possible symptoms include: tremor, insomnia, restlessness, irritability, anxiety, depression, loss of appetite, nausea, vomiting, diarrhea, excessive sweating, lacrimation, rhinorrhea, sneezing, yawning, piloerection, mydriasis, weakness, fever, muscle spasms, dehydration, increased heart rate, respiratory rate, and blood pressure.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in a blister; 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Additional liability company "INTERKHIM".

Manufacturer's address and place of business.

40-A, 21st km, Starokyivska Road, Odesa, Ukraine, 65025.