Darfen® express

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Darfen® Express

Composition:

Active substance: ibuprofen;

10 ml of suspension contains 200 mg of ibuprofen;

Excipients: sodium benzoate (E 211), anhydrous citric acid, sodium citrate, sodium saccharin, sodium chloride, hypromellose 15 cP (substitution degree 2910), xanthan gum, maltitol liquid (E 965), glycerol 99.8 %, strawberry flavoring, purified water.

Pharmaceutical form. Oral suspension.

Main physicochemical properties: viscous suspension, free from extraneous particles, white or almost white in color, with a characteristic strawberry odor.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives. Ibuprofen. ATC code M01AE01.

Pharmacological properties.

Pharmacodynamics.

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID), a propionic acid derivative, which has demonstrated efficacy by inhibiting the synthesis of prostaglandins—mediators of pain and inflammation. Ibuprofen exerts analgesic, antipyretic, and anti-inflammatory effects. The onset of analgesic and antipyretic action of ibuprofen occurs within 30 minutes. In addition, ibuprofen reversibly inhibits platelet aggregation.

Experimental data indicate that ibuprofen may attenuate the effect of low-dose acetylsalicylic acid (aspirin) on platelet aggregation when both medicinal products are used concomitantly. In a study, when a single dose of 400 mg ibuprofen was taken within 8 hours before or within 30 minutes after administration of immediate-release acetylsalicylic acid (aspirin) 81 mg, a reduced effect of acetylsalicylic acid on thromboxane formation or platelet aggregation was observed. However, due to the limited nature of these data and uncertainty regarding extrapolation to the clinical setting, it cannot be excluded that chronic, long-term use of ibuprofen may diminish the cardioprotective effect of low-dose acetylsalicylic acid. Therefore, with occasional use of ibuprofen, such clinically significant effects are considered unlikely.

Pharmacokinetics.

No specific pharmacokinetic studies have been conducted in children. Published data confirm that absorption, metabolism, and elimination of ibuprofen in children occur similarly to those in adults.

After oral administration, ibuprofen is rapidly absorbed and distributed throughout the body. Ibuprofen is partially absorbed in the stomach and then completely absorbed in the small intestine. Maximum plasma concentration is reached within 1–2 hours after administration. Following metabolism in the liver (hydroxylation, carboxylation, conjugation), pharmacologically inactive metabolites are eliminated completely, predominantly via the kidneys (90%), and also through bile. The elimination half-life in healthy volunteers as well as in patients with kidney or liver disease ranges from 1.8 to 3.5 hours. Plasma protein binding is approximately 99%.

Renal impairment.

Since ibuprofen and its metabolites are primarily eliminated via the kidneys, the pharmacokinetics of the drug may be altered in patients with various degrees of renal impairment. In patients with impaired renal function, lower plasma protein binding, increased plasma levels of total ibuprofen and unbound (S)-ibuprofen, higher AUC values for (S)-ibuprofen, and elevated enantiomeric AUC (S/R) ratios have been observed compared to the control group of healthy volunteers. In patients with end-stage renal disease on dialysis, the mean fractional excretion of ibuprofen was approximately 3%, compared to 1% in healthy volunteers. Severe renal dysfunction may lead to accumulation of ibuprofen metabolites. The clinical significance of this effect is unknown. Metabolites may be removed by hemodialysis.

Hepatic impairment.

Alcoholic liver disease with mild to moderate hepatic dysfunction did not result in significant changes in pharmacokinetic parameters. Liver disease may alter the distribution kinetics of ibuprofen. In patients with cirrhosis and moderate hepatic impairment (Child–Pugh class 6–10), an approximately two-fold increase in elimination half-life was observed, and the enantiomeric AUC (S/R) ratio was significantly lower compared to healthy control volunteers, indicating impaired metabolic inversion of (R)-ibuprofen to the active (S)-enantiomer.

Clinical characteristics.

Indications.

Symptomatic treatment of fever and pain of various origins in children aged 6 to 11 years with body weight from 20 to 39 kg, as well as in adults and adolescents aged 12 years and older with body weight ≥ 40 kg (including fever following vaccination, acute respiratory viral infections, influenza, teething pain, post-extraction dental pain, toothache, headache, sore throat, ligament sprain pain, and other types of pain, particularly of inflammatory origin).

Contraindications.

• Hypersensitivity to ibuprofen or to any component of the medicinal product.
• History of hypersensitivity reactions (such as bronchospasm, asthma, rhinitis, angioedema, or urticaria) following administration of ibuprofen, acetylsalicylic acid (aspirin), or other NSAIDs.
• Active peptic ulcer disease or gastrointestinal bleeding, or history of recurrence (two or more episodes of confirmed peptic ulcer or bleeding).
• History of gastrointestinal bleeding or perforation associated with previous use of NSAIDs.
• Active inflammatory bowel disease.
• Cerebrovascular or other hemorrhages.
• Hemorrhagic diathesis or other coagulation disorders.
• Severe heart failure (NYHA class IV), severe hepatic insufficiency, or severe renal insufficiency.
• Third trimester of pregnancy.
• Severe dehydration (due to vomiting, diarrhea, or insufficient fluid intake).
• Hereditary fructose intolerance.
• Children under 6 years of age and/or weighing less than 20 kg due to the high amount of active substance in one sachet.

Interaction with other medicinal products and other forms of interaction.

Ibuprofen, like other NSAIDs, should not be used in combination with:

− acetylsalicylic acid, as this may increase the risk of adverse reactions, except when acetylsalicylic acid (dose not exceeding 75 mg per day) is prescribed by a physician. Experimental data indicate that concomitant use of ibuprofen may inhibit the antiplatelet effect of low-dose acetylsalicylic acid. However, limited data and uncertainty regarding extrapolation of ex vivo data to clinical settings preclude definitive conclusions about the systematic use of ibuprofen. Therefore, clinically significant effects are considered unlikely with occasional use of ibuprofen.

− other NSAIDs, including selective cyclooxygenase-2 inhibitors, as this may increase the risk of adverse effects.

Use ibuprofen with caution in combination with the following medicinal products:

− anticoagulants: NSAIDs may enhance the effects of anticoagulants such as heparin or its derivatives, vitamin K antagonists (acenocoumarol or warfarin), and oral anticoagulants (rivaroxaban, apixaban, or dabigatran).

− antihypertensive agents (ACE inhibitors, β-blockers, and angiotensin II antagonists): NSAIDs may reduce the effectiveness of these drugs. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), concomitant use of ACE inhibitors, β-blockers, or angiotensin II antagonists with cyclooxygenase inhibitors may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, such combinations should be used cautiously, especially in elderly patients. Patients should consume adequate fluids, and renal function should be monitored after initiation of concomitant therapy and periodically thereafter.

− corticosteroids: increased risk of gastrointestinal ulcers and bleeding.

− antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding.

− cardiac glycosides, e.g., digoxin: NSAIDs may exacerbate cardiac dysfunction, reduce glomerular filtration rate, and increase plasma levels of glycosides. NSAIDs may elevate digoxin plasma levels, thereby increasing the risk of digoxin toxicity.

− pentoxifylline: increased risk of hemorrhage in patients receiving ibuprofen in combination with pentoxifylline.

− lithium: NSAIDs may increase lithium plasma levels, possibly due to reduced renal clearance. Concomitant use of these medicinal products should be avoided unless lithium levels are monitored. Dose reduction of lithium may be considered. Routine monitoring of serum lithium concentration during administration is generally not required (no more than 3 days).

− methotrexate at doses of 15 mg/week or higher: use of NSAIDs within 24 hours before or after methotrexate administration may increase methotrexate plasma concentration (likely due to reduced renal clearance of methotrexate caused by NSAIDs) and subsequently enhance its toxic effects. Therefore, ibuprofen should be avoided in patients receiving high-dose methotrexate.

− methotrexate at doses below 15 mg/week: ibuprofen increases methotrexate levels. Careful monitoring of the patient's blood count is required when ibuprofen is used in combination with low-dose methotrexate. Monitoring should be intensified in case of worsening renal function, even minimally, and in elderly patients, and renal function should be monitored to prevent possible reduction in methotrexate clearance.

− cyclosporine and tacrolimus: possible increased risk of nephrotoxicity with concomitant use of NSAIDs due to reduced renal prostaglandin synthesis. Renal function should be closely monitored when these medicinal products are used together with NSAIDs.

− mifepristone: NSAIDs should not be used earlier than 8–12 days after administration of mifepristone, as they may reduce its efficacy.

− sulfonylurea agents: interactions between NSAIDs and hypoglycemic agents (sulfonylureas) have been observed. NSAIDs may enhance the hypoglycemic effect of sulfonylureas by displacing them from plasma protein binding sites; glucose levels in blood should be monitored when sulfonylureas are used concomitantly with ibuprofen.

− probenecid and sulfinpyrazone: possible increase in ibuprofen plasma concentration and delayed elimination of ibuprofen, possibly due to inhibitory mechanisms at the site of renal tubular secretion and glucuronidation; therefore, dose adjustment of ibuprofen may be necessary.

− baclofen: risk of baclofen toxicity after initiation of ibuprofen therapy.

− ritonavir: possible increase in plasma concentrations of NSAIDs.

− aminoglycosides: NSAIDs may reduce the excretion of aminoglycosides.

− captopril: experimental studies have shown that ibuprofen inhibits the natriuretic effect of captopril.

− voriconazole and fluconazole (CYP2C9 inhibitors): concomitant use of ibuprofen with CYP2C9 inhibitors may enhance the effect of ibuprofen (a CYP2C9 substrate). In a study using voriconazole and fluconazole (CYP2C9 inhibitors), the effect of S(+)-ibuprofen was increased by approximately 80–100%. When ibuprofen is used concomitantly with strong CYP2C9 inhibitors, reduction of ibuprofen doses is recommended, especially if high doses of ibuprofen are required together with voriconazole or fluconazole.

− cholestyramine: ibuprofen and cholestyramine should be taken several hours apart due to delayed and reduced (by 25%) absorption of ibuprofen when used concomitantly.

− zidovudine: increased risk of hematological toxicity with concomitant use of zidovudine and NSAIDs. Evidence suggests an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia receiving concomitant treatment with zidovudine and ibuprofen.

− herbal extracts: when used concomitantly with NSAIDs, Ginkgo biloba may potentiate the risk of bleeding.

− quinolone antibiotics: data from animal studies indicate that NSAIDs may increase the risk of seizures associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing seizures.

− hydantoins and sulfonamides: possible increase in the toxic effects of these medicinal products. Plasma levels of phenytoin may increase with concomitant treatment with ibuprofen. Routine monitoring of serum phenytoin levels is generally not required with proper use (maximum for 4 days).

− thiazides, thiazide-like agents, loop diuretics, and potassium-sparing diuretics: NSAIDs may counteract the diuretic effect of these medicinal products. Concomitant use of NSAIDs and diuretics may increase the risk of NSAID-induced nephrotoxicity (e.g., in dehydrated patients or elderly patients with impaired renal function) due to worsening of renal blood flow. Therefore, such combinations should be used cautiously, especially in elderly patients. Patients should consume adequate fluids, and renal function should be monitored after initiation of concomitant therapy and periodically thereafter. As with other NSAIDs, concomitant therapy with potassium-sparing diuretics may be associated with elevated potassium levels; therefore, plasma potassium levels should be monitored.

• alcohol: adverse reactions related to the active substance, particularly those affecting the gastrointestinal tract or central nervous system (CNS), may be intensified when alcohol is consumed concomitantly with NSAIDs.

Administration of ibuprofen with food slows absorption, although it does not affect the extent of absorption (see section "Pharmacokinetics").

Special precautions for use.

Adverse effects of ibuprofen therapy can be minimized by using the lowest effective dose required to control symptoms, for the shortest possible duration.

Elderly patients have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal. Elderly patients are at higher risk of experiencing serious adverse reactions. Prolonged use of NSAIDs is not recommended in elderly patients. In cases of long-term therapy, regular monitoring of the patient is required.

Caution is advised in patients with the following conditions:

− systemic lupus erythematosus and mixed connective tissue disease – due to increased risk of aseptic meningitis;

− inherited disorders of porphyrin metabolism, e.g. acute intermittent porphyria;

− gastrointestinal disorders and chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease);

− history of arterial hypertension and/or heart failure, as there are reports of fluid retention and edema associated with NSAID therapy;

− renal impairment – due to possible worsening of kidney function;

− hepatic dysfunction;

− immediately after major surgical procedures;

− hay fever, nasal polyps, or chronic obstructive respiratory diseases – due to increased risk of allergic reactions, including asthma attacks (so-called analgesic asthma), Quincke’s edema, or urticaria;

− history of allergic reactions to other substances – due to increased risk of hypersensitivity reactions to ibuprofen.

Respiratory effects.

Bronchospasm may occur in patients with bronchial asthma or allergic diseases, or with such conditions in their history.

Other NSAIDs.

Concomitant use of ibuprofen with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided, as this increases the risk of adverse reactions.

Like other NSAIDs, ibuprofen may cause allergic reactions, including anaphylactic/anaphylactoid reactions, even upon first use.

Systemic lupus erythematosus and mixed connective tissue disease.

Ibuprofen should be used with caution in patients with systemic lupus erythematosus or mixed connective tissue disease due to increased risk of aseptic meningitis.

Effects on the cardiovascular and cerebrovascular systems.

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

Clinical studies and epidemiological data indicate that the use of ibuprofen, particularly at high doses (2400 mg per day) and during prolonged treatment, may be associated with a small increase in the risk of arterial thrombotic complications (such as myocardial infarction or stroke). Overall, epidemiological studies do not show that low-dose ibuprofen (e.g. ≤1200 mg per day) is associated with an increased risk of myocardial infarction.

Cases of Kounis syndrome have been reported in patients receiving treatment with Darfen® Express. Kounis syndrome is defined as cardiovascular symptoms caused by an allergic or hypersensitivity reaction associated with coronary artery spasm, which may potentially lead to myocardial infarction.

Patients with uncontrolled arterial hypertension, congestive heart failure (NYHA class II–III), diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should take ibuprofen only after careful clinical assessment. High doses (2400 mg per day) should be avoided.

Careful clinical evaluation is also required before initiating long-term treatment in patients with risk factors for cardiovascular complications (such as arterial hypertension, hyperlipidemia, diabetes, smoking), especially if high doses of ibuprofen (2400 mg per day) are required.

Effects on kidneys and liver.

Caution is advised in patients with renal impairment due to possible worsening of kidney function. Ibuprofen should be used with caution in patients with kidney or liver disease, particularly when concomitantly treated with diuretics, as prostaglandin inhibition may lead to fluid retention and further deterioration of renal function. Such patients should receive the lowest possible dose of ibuprofen, and renal function should be monitored regularly. Adequate fluid intake should be ensured in cases of dehydration. There is a risk of renal failure in dehydrated children and adolescents.

Generally, habitual use of analgesics, especially combinations of different painkillers, may lead to chronic kidney damage with risk of renal failure (analgesic nephropathy). The highest risk of this reaction occurs in elderly patients, patients with renal, cardiac, or hepatic insufficiency, and those receiving diuretics or ACE inhibitors. After discontinuation of NSAID therapy, renal function usually returns to the pre-treatment state.

Liver function may be impaired. Like other NSAIDs, ibuprofen may cause transient increases in certain liver function parameters, as well as significant elevations in AST and ALT levels. If substantial increases in these parameters occur, treatment should be discontinued.

Effects on the gastrointestinal tract.

NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn’s disease), as their condition may worsen. Such patients should consult a physician.

Cases of gastrointestinal bleeding, perforation, and ulcers, potentially fatal, have been reported during NSAID therapy at any stage, regardless of prior warning symptoms or history of severe gastrointestinal disorders.

The risk of gastrointestinal bleeding, perforation, or ulcers increases with higher NSAID doses, history of peptic ulcer disease (especially complicated by bleeding or perforation), and in elderly patients. Such patients should start treatment with the lowest doses. For these patients, as well as those requiring concomitant use of low-dose acetylsalicylic acid or other drugs that may increase gastrointestinal risk, combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) is recommended.

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

Caution is advised when treating patients who are concurrently using medications that may increase the risk of ulceration or bleeding, including oral corticosteroids, anticoagulants (e.g. heparin or its derivatives, vitamin K antagonists (acenocoumarol or warfarin), oral anticoagulants (rivaroxaban, apixaban, or dabigatran), SSRIs, or antiplatelet agents (e.g. acetylsalicylic acid).

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

Severe skin adverse reactions (SSARs).

Severe skin adverse reactions (SSARs), including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal, have been reported with ibuprofen use (see section "Adverse reactions"). Most such reactions occurred within the first month.

If signs or symptoms suggestive of these reactions appear, ibuprofen should be discontinued immediately and alternative treatment considered (if necessary).

In rare cases, chickenpox may lead to severe skin and soft tissue infections. At present, a negative influence of NSAIDs on the course of these infections cannot be excluded; therefore, use of ibuprofen in chickenpox is not recommended.

Very rarely, severe acute hypersensitivity reactions (e.g. anaphylactic shock) occur. If early signs of hypersensitivity occur after ibuprofen administration, treatment should be discontinued and immediate medical attention sought.

Ibuprofen may temporarily inhibit platelet aggregation. Therefore, careful monitoring is recommended in patients with coagulation disorders.

With prolonged use of ibuprofen, liver function tests, renal function, and hematological parameters/blood counts should be monitored regularly.

Prolonged use of any analgesic for headache treatment may worsen the condition. In such cases, patients should consult a physician and discontinue treatment. Medication-overuse headache should be considered in patients with frequent or daily headaches despite regular use of headache medications.

Masking symptoms of underlying infections.

NSAIDs may mask symptoms of infection and fever.

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

Patients should consult a physician before taking this medication: pregnant women, women attempting to conceive, elderly individuals, and smokers.

Effects on laboratory test results:

− bleeding time may be prolonged up to one day after discontinuation of treatment;

− blood glucose concentration may decrease;

− creatinine clearance may decrease;

− hematocrit or hemoglobin may decrease;

− blood urea nitrogen concentration and serum creatinine and potassium concentrations may increase;

− liver function tests: increased transaminase levels.

Important information on excipients.

This medicinal product contains liquid maltitol. It should not be administered to patients with rare hereditary fructose intolerance. Due to the presence of liquid maltitol, this medicinal product may have a mild laxative effect.

This medicinal product contains sodium, which should be taken into account in patients on a low-sodium diet.

Use during pregnancy or breastfeeding.

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage, congenital heart defects, and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The risk is considered to increase with higher doses and longer duration of treatment. The absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%. The risk increases with increasing dose and duration of treatment.

From the 20th week of pregnancy, use of Darfen® Express may cause oligohydramnios due to fetal renal dysfunction. This condition may occur early in treatment and is usually reversible upon discontinuation. Additionally, there are reports of arterial duct constriction after treatment in the second trimester, most of which resolved after discontinuation of the drug. Therefore, Darfen® Express should not be prescribed during the first and second trimesters unless clearly necessary.

If ibuprofen is used by a woman attempting to conceive or during the first and second trimesters of pregnancy, the lowest possible dose for the shortest duration should be used.

Fetal monitoring for oligohydramnios and arterial duct constriction should be considered after exposure to Darfen® Express for several days, starting from the 20th gestational week. Use of Darfen® Express should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may pose the following risks:

Risks to the fetus:

• cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
• renal dysfunction (see above).

Risks to the mother and newborn, near the end of pregnancy:

• possible prolongation of bleeding time, antiplatelet effect, which may occur even at very low doses;
• inhibition of uterine contractions, leading to delayed or prolonged labor;
• possible increased risk of edema in the mother.

Therefore, ibuprofen is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Breastfeeding.

Ibuprofen and its metabolites pass into breast milk in low concentrations. No adverse effects on the infant are currently known; therefore, breastfeeding usually does not need to be discontinued during short-term treatment of pain and fever at recommended doses.

Fertility.

Limited data suggest that cyclooxygenase/prostaglandin synthesis inhibitors may impair female fertility by affecting ovulation. This effect is reversible upon discontinuation of therapy. Use of ibuprofen is not recommended in women attempting to conceive. For women experiencing infertility or undergoing fertility investigations, discontinuation of this medicinal product should be considered.

Ability to influence reaction speed when driving or operating machinery.

Patients who experience dizziness, vertigo, visual disturbances, or other central nervous system disorders during ibuprofen use should avoid driving or operating machinery while on this medication.

No special precautions are required when a single dose of ibuprofen is used or when the drug is used for a short period.

Dosage and Administration.

Adverse effects can be minimized by using the lowest effective dose necessary to control symptoms for the shortest duration of time.

The dose of ibuprofen depends on the child's body weight and age. For children, the recommended daily dose of ibuprofen is 20–30 mg per kg of body weight, divided into 3–4 doses.

Children under 6 years of age and/or with body weight less than 20 kg

The use of this medicinal product in children under 6 years of age and/or with body weight below 20 kg is contraindicated due to the high amount of active substance in a single sachet.

Children aged 6 to 11 years with body weight from 20 to 39 kg, adults and adolescents aged 12 years and older with body weight ≥ 40 kg

Body weight (age)	Single dose	Maximum daily dose
From 20 to 29 kg (children aged 6 to 9 years)	200 mg (1 sachet)	600 mg ibuprofen (3 sachets)
From 30 to 39 kg (children aged 10 to 11 years)	200 mg (1 sachet)	800 mg ibuprofen (4 sachets)
≥ 40 kg (adults and adolescents from 12 years)	200−400 mg (1 or 2 sachets)	1 200 mg ibuprofen (6 sachets)

The intervals between doses are 6–8 hours.

If symptoms persist for more than 3 days from the start of treatment or worsen in children, medical advice should be sought.

If fever persists for more than 3 days in adults, or if symptoms persist for more than 4 days during pain treatment or worsen, medical advice should be sought.

Special patient categories

Renal impairment

NSAIDs should be used with caution in patients with impaired renal function, as ibuprofen is primarily excreted by the kidneys. Dose adjustment is not required in patients with mild or moderate renal impairment. Ibuprofen is contraindicated in patients with severe renal insufficiency (see section "Contraindications").

Hepatic impairment

Although no differences in the pharmacokinetic profile of ibuprofen have been observed in patients with hepatic insufficiency, NSAIDs should be used with caution in such patients. Dose adjustment is not required in patients with mild or moderate hepatic impairment. Ibuprofen is contraindicated in patients with severe hepatic insufficiency (see section "Contraindications").

Method of administration

The medicinal product is for oral use. The contents of the sachet should be poured into a tablespoon or directly into the mouth, followed by water. Before administration, the suspension should be made homogeneous by kneading the sachet—pressing with fingers on both sides of the packet for at least 30 seconds. Patients with a sensitive stomach are advised to take the product during meals.

Children

The medicinal product is indicated for children aged 6 to 11 years with body weight from 20 to 39 kg, and for adolescents aged 12 years and older with body weight ≥ 40 kg. The use of this medicinal product is contraindicated in children with body weight less than 20 kg.

Overdose.

In pediatric patients, symptoms of overdose may occur after ingestion of ibuprofen doses exceeding 400 mg/kg. In adults, reactions to overdose are generally less pronounced. The elimination half-life in overdose is 1.5–3 hours.

Symptoms. 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, and gastrointestinal bleeding. In more severe poisoning, toxic effects on the CNS may occur, such as vertigo, dizziness, drowsiness, sometimes excitement, disorientation, or coma. Seizures may occasionally develop. In severe poisoning, hyperkalemia, metabolic acidosis, and prolonged prothrombin time/INR (likely due to interaction with circulating blood coagulation factors) may occur. Acute renal failure, hepatic injury, hypotension, respiratory depression, and cyanosis may also develop. In patients with bronchial asthma, an exacerbation of asthma may occur. Nystagmus, visual disturbances, and loss of consciousness are also possible.

Treatment. There is no specific antidote. Treatment is symptomatic and supportive, including maintaining airway patency, monitoring cardiac function and vital signs until the patient's condition normalizes. Consider administering activated charcoal orally or gastric lavage if less than 1 hour has passed since ingestion of a potentially toxic dose. If ibuprofen has already been absorbed, alkalizing agents may be used to enhance urinary excretion of acidic ibuprofen. For frequent or prolonged seizures, intravenous administration of anticonvulsant agents (e.g., diazepam or lorazepam) should be considered. In cases of bronchial asthma, bronchodilators should be administered. Immediate medical attention is required.

Side effects.

The list of adverse reactions includes all undesirable reactions reported during treatment with ibuprofen, including those observed with high doses used in long-term therapy of patients with rheumatism. The frequencies stated beyond very rare reports refer to short-term use (maximum 1200 mg ibuprofen per day) of oral dosage forms.

Adverse reactions reported during ibuprofen use are listed below by organ systems and frequency of occurrence. Frequency of adverse reactions 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), and not known frequency (cannot be estimated based on available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Gastrointestinal adverse reactions were most commonly observed. Adverse reactions are generally dose-dependent; in particular, the risk of gastrointestinal bleeding depends on dose and duration of treatment. Gastric and intestinal ulcers, perforation, or gastrointestinal hemorrhage, sometimes fatal, may occur, especially in elderly patients. Nausea, vomiting, diarrhea, abdominal distension, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbation of colitis and Crohn’s disease have been reported after ibuprofen use. Gastritis has been observed less frequently.

Edema, arterial hypertension, and heart failure have been reported and associated with NSAID therapy.

Clinical trial data indicate that the use of ibuprofen, particularly at high doses of 2400 mg per day and during long-term treatment, may be associated with an increased risk of arterial thrombotic complications (e.g., myocardial infarction or stroke).

Cases of exacerbation of infection-related inflammation, such as development of necrotizing fasciitis, temporally associated with NSAID use, have been described. This may be related to the mechanism of action of NSAIDs.

If signs of infection develop or worsen during ibuprofen use, patients are advised to seek immediate medical attention. The need for antimicrobial/antibiotic therapy should be evaluated.

Regular blood tests are necessary during long-term therapy.

Patients should seek immediate medical advice and discontinue ibuprofen if any symptoms of hypersensitivity reactions occur, which may develop even after the first use of the drug. Immediate medical assistance is required in such cases.

If severe epigastric pain, melena, or hematemesis occurs, the drug should be discontinued and immediate medical attention sought.

Eye disorders: frequency not known – visual disturbances, optic neuritis may occur during prolonged treatment.

Ear and labyrinth disorders: frequency not known – dizziness may occur during prolonged treatment; rare – tinnitus.

Respiratory, thoracic and mediastinal disorders: frequency not known – respiratory tract reactivity, including asthma, bronchospasm, or dyspnea¹.

Gastrointestinal disorders: common – abdominal pain, nausea, dyspepsia, diarrhea, flatulence, constipation, heartburn, vomiting, and minor gastrointestinal blood loss, which in exceptional cases may lead to anemia; uncommon – gastric and duodenal ulcer, perforations or gastrointestinal hemorrhage, melena, hematem游戏副本, sometimes fatal (especially in elderly patients), ulcerative stomatitis, gastritis, exacerbation of colitis and Crohn’s disease; very rare – esophagitis, formation of diaphragm-like intestinal strictures, pancreatitis.

Hepatobiliary disorders: very rare – liver function abnormalities, liver damage, particularly during long-term therapy, liver failure, acute hepatitis.

Renal and urinary disorders: rare – acute renal function impairment, especially with long-term use of NSAIDs, associated with increased serum urea levels and edema; papillary necrosis; very rare – edema formation, particularly in patients with arterial hypertension or renal insufficiency, nephrotic syndrome, interstitial nephritis, which may be accompanied by acute renal failure.

Nervous system disorders: uncommon – headache, dizziness, insomnia, restlessness, irritability, or fatigue; very rare – aseptic meningitis².

Psychiatric disorders: very rare – psychotic reactions, depression; hallucinations, confusion only during prolonged use.

Cardiovascular disorders: very rare – heart failure, tachycardia, edema, myocardial infarction, arterial hypertension, vasculitis; frequency not known – Couinaud’s syndrome.

Blood and lymphatic system disorders: very rare – blood dyscrasias (anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis). Initial symptoms include sore throat, oral ulcerations, influenza-like symptoms, severe exhaustion, epistaxis, skin bleeding, and bruising.

Immune system disorders: uncommon – hypersensitivity reactions¹, urticaria, and pruritus; very rare – severe hypersensitivity reactions, symptoms of which may include facial, tongue, and laryngeal edema, dyspnea, tachycardia, hypotension (anaphylactic reaction, angioneurotic edema, or severe shock)¹, asthma exacerbation.

Skin and subcutaneous tissue disorders: uncommon – various skin rashes¹; very rare – severe skin adverse reactions (SSARs) (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis), bullous reactions, alopecia; frequency not known – drug-induced eosinophilia with systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP), photosensitivity reactions.

General disorders: frequency not known – malaise and fatigue.

Laboratory investigations: rare – decreased hemoglobin levels.

Infections and infestations: very rare – exacerbation of infection-related inflammation (e.g., development of necrotizing fasciitis); in rare cases, varicella may lead to severe skin and soft tissue infections.

¹ Reports of hypersensitivity reactions following ibuprofen treatment include:

− non-specific allergic reactions and anaphylaxis;

− respiratory tract reactions, including bronchial asthma, asthma exacerbation, bronchospasm, or dyspnea;

− various skin disorders, including rashes of different types, pruritus, urticaria, purpura, angioedema, and less frequently exfoliative and bullous dermatoses (including epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme).

² The pathogenic mechanism of drug-induced aseptic meningitis is not fully understood. However, available data on aseptic meningitis associated with NSAID use suggest a hypersensitivity reaction (based on temporal association with drug intake and symptom resolution after drug discontinuation). In particular, during ibuprofen treatment, isolated symptoms of aseptic meningitis (such as nuchal rigidity, headache, nausea, vomiting, fever, or disorientation) have been observed in patients with pre-existing autoimmune disorders (such as systemic lupus erythematosus, mixed connective tissue disease).

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging.

Oral suspension, 200 mg/10 ml; 10 ml in sachet; 10 sachets in a pack.

Prescription status. Over-the-counter.

Manufacturer.

1. EDEFARM, S.L./EDEFARM, S.L.
2. Farmalider S.A./Farmalider S.A.

Manufacturer's address.

1. Polígono Industrial Enchilagar del Rullo, 117, C.P. 46191 Villamarchante, Valencia, Spain.
2. Calle De Los Aragoneses 2, Polígono Industrial Calabozos, Alcobendas, 28108, Spain.

Marketing authorization holder. JSC "Pharmaceutical company "Darnitsya".

Address of the marketing authorization holder.

13, Boryspilska Street, Kyiv, 02093, Ukraine.