Pyronef

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

Composition:

Active ingredient: ibuprofen;

1 ml of solution contains 100 mg of ibuprofen;

Excipients: arginine, 20% hydrochloric acid or 20% sodium hydroxide (for pH adjustment), water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless solution.

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

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action.

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that has demonstrated efficacy in standard animal models of inflammation, likely due to inhibition of prostaglandin synthesis. Ibuprofen exerts antipyretic effects and reduces inflammatory pain and swelling. Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when administered concomitantly. Some pharmacodynamic studies have shown that when a single 400 mg dose of ibuprofen is taken within 8 hours before or within 30 minutes after immediate-release acetylsalicylic acid (81 mg), the effect of acetylsalicylic acid on thromboxane formation or platelet aggregation is reduced.

Clinical studies have demonstrated that intravenous infusion of ibuprofen at doses of 100 mg, 200 mg, and 400 mg administered as a single dose reduces glomerular filtration rate in a dose-dependent manner by 15 to 30%.

Pharmacokinetics.

Absorption.

The medicinal product is administered intravenously; therefore, the absorption process does not occur, and the bioavailability of ibuprofen is complete.

Distribution.

The calculated volume of distribution ranges from 0.11 to 2.21 L/kg. Ibuprofen is highly bound to plasma proteins, primarily albumin.

Biological transformation.

Ibuprofen is metabolized in the liver into two inactive metabolites, which, together with unchanged ibuprofen, are excreted by the kidneys.

Elimination.

Renal elimination is rapid and complete. The elimination half-life is approximately 2 hours.

Linearity/Non-linearity.

Ibuprofen exhibits linearity of the area under the plasma concentration-time curve (AUC) following single doses of ibuprofen in the range of 200–800 mg. Pharmacokinetic/Pharmacodynamic relationship.

There is a relationship between plasma levels of ibuprofen, its pharmacodynamic properties, and its overall safety profile. The pharmacokinetics of ibuprofen are stereoselective following either intravenous or oral administration. The mechanism of action and pharmacology of intravenous ibuprofen do not differ from that of oral ibuprofen.

Clinical characteristics.

Indications.

The medicinal product is indicated for adults and children aged from 3 months for:

• treatment of mild and moderate pain, and treatment of moderate and severe pain as an adjunct to opioid analgesics;
• relief of symptoms of fever.

Contraindications.

• Hypersensitivity to ibuprofen or to any component of the medicinal product or to other nonsteroidal anti-inflammatory drugs (NSAIDs).
• Use in patients with a history of asthma, urticaria, or allergic-type reactions after taking acetylsalicylic acid or other NSAIDs (in such patients, anaphylactic reactions to NSAIDs have been reported, which may be fatal).
• Coronary artery bypass graft (CABG) surgery for the treatment of perioperative pain.
• Third trimester of pregnancy.
• Severe heart failure (NYHA class IV).
• Severe hepatic impairment.
• Severe renal impairment.

Interaction with other medicinal products and other forms of interaction.

Other NSAIDs, including COX-2 inhibitors and salicylates. Due to synergistic effects, concomitant use of two or more NSAIDs may increase the risk of gastrointestinal ulceration and bleeding. Therefore, simultaneous use of ibuprofen and other NSAIDs should be avoided. Concomitant use of the medicinal product with other NSAIDs should also be avoided, as it may increase the risk of gastrointestinal ulceration and hemorrhage.

Acetylsalicylic acid. Concomitant use of ibuprofen and acetylsalicylic acid is generally not recommended due to the potential for increased adverse effects. Experimental data indicate that ibuprofen may competitively inhibit the antiplatelet effect of low-dose acetylsalicylic acid when administered concomitantly. Although there is uncertainty regarding extrapolation of these data to clinical settings, it cannot be excluded that regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. A clinically significant effect is not considered likely with occasional use of ibuprofen.

Digoxin. Concomitant use of ibuprofen with digoxin preparations may increase serum digoxin levels. Serum digoxin monitoring is usually not required with appropriate use (maximum for 3 days).

Corticosteroids. Corticosteroids may also increase the risk of adverse reactions, particularly those related to the gastrointestinal tract (GI) (ulceration or gastrointestinal bleeding).

Antiplatelet agents (e.g., clopidogrel and ticlopidine). Increased risk of gastrointestinal bleeding.

Anticoagulants. NSAIDs may potentiate the effects of anticoagulants such as warfarin and heparin. In case of concomitant use, coagulation parameters should be monitored. Phenytoin. Concomitant use of ibuprofen with phenytoin preparations may increase serum phenytoin levels. Serum phenytoin monitoring is usually not required with appropriate use (maximum for 3 days). Selective serotonin reuptake inhibitors (SSRIs). May increase the risk of gastrointestinal bleeding.

Lithium. Concomitant use of ibuprofen with lithium preparations may increase serum lithium levels. Serum lithium monitoring is usually not required with appropriate use (maximum for 3 days).

Probenecid and sulfinpyrazone. Medicinal products containing probenecid or sulfinpyrazone may slow the elimination of ibuprofen.

Diuretics, ACE inhibitors, beta-blockers, and angiotensin II antagonists. Diuretics and ACE inhibitors may enhance the nephrotoxicity of NSAIDs. NSAIDs may reduce the efficacy of diuretics and other antihypertensive agents. In patients with renal impairment (e.g., dehydrated patients or elderly patients with impaired renal function), concomitant therapy with ACE inhibitors, beta-blockers, or angiotensin II antagonists and cyclooxygenase inhibitors may be associated with renal dysfunction, including acute renal failure, which is usually reversible. Therefore, concomitant therapy should be administered with caution, especially in elderly patients. Patients should be adequately hydrated, and monitoring of renal function should be considered after initiation of concomitant therapy and performed periodically. Concomitant use of ACE inhibitors and ibuprofen may lead to hyperkalemia.

Potassium-sparing diuretics. Concomitant use of ibuprofen and potassium-sparing diuretics may be associated with increased potassium levels; therefore, monitoring of plasma potassium levels is recommended.

Methotrexate. NSAIDs inhibit tubular secretion of methotrexate and thus may cause metabolic interactions leading to reduced methotrexate clearance. Administration of ibuprofen 24 hours before or after methotrexate may result in elevated plasma methotrexate levels and subsequent increase in its toxicity. Therefore, concomitant use of NSAIDs and high-dose methotrexate should be avoided. In addition, the potential risk of interaction should be considered when treating with low-dose methotrexate, especially in patients with impaired renal function. Renal function should be monitored during combination therapy. Cyclosporine. The risk of renal dysfunction is increased with concomitant use of certain NSAIDs. This effect cannot be excluded when combining cyclosporine with ibuprofen.

Zidovudine. Increased risk of hematological toxicity when NSAIDs are taken concomitantly with zidovudine. Data indicate an increased risk of hemarthrosis and hematomas in HIV (+) hemophiliacs who concurrently use zidovudine and ibuprofen. Blood analysis is recommended 1–2 weeks after initiation of concomitant use.

Sulfonylureas. Clinical studies have demonstrated interactions between NSAIDs and sulfonylureas. Although information on the interaction between ibuprofen and sulfonylureas is lacking, plasma glucose levels should be monitored as a precautionary measure during concomitant use.

Quinolone antibiotics. Animal data 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.

Mifepristone. NSAIDs should not be administered within 8–12 days after mifepristone administration, as the effect of mifepristone may be reduced.

Baclofen. Ibuprofen may potentiate the toxicity of baclofen through possible accumulation due to ibuprofen-induced renal impairment.

Pentoxifylline. In patients taking ibuprofen in combination with pentoxifylline, an increased risk of bleeding may occur; therefore, bleeding time should be monitored. Tacrolimus. Concomitant use with ibuprofen may increase the risk of nephrotoxicity. Aminoglycosides. NSAIDs may enhance the nephrotoxicity of aminoglycosides, especially if aminoglycosides are administered in high doses over a prolonged period. Alcohol. Use of ibuprofen should be avoided in individuals with chronic alcohol consumption due to increased risk of gastrointestinal adverse effects, including bleeding.

Herbal extracts. Ginkgo biloba may enhance the risk of bleeding when used concomitantly with this medicinal product.

Special precautions for use.

Cardiovascular thrombotic events.

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years' duration have shown an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which may be fatal. Based on available data, it is unclear whether the risk of thrombotic events is similar for all NSAIDs or not. The relative increase in the number of serious cardiovascular thrombotic events compared to baseline levels caused by NSAID use is similar in patients with and without known cardiovascular disease or cardiovascular risk factors. However, patients with known cardiovascular disease or cardiovascular risk factors had a higher absolute frequency of serious cardiovascular thrombotic events. Some studies have found that the increased risk of serious thrombotic events began as early as the first weeks of treatment. The increase in cardiovascular thrombotic risk was most consistently observed with higher doses. To minimize the potential risk of adverse cardiovascular events in patients receiving NSAIDs, the lowest effective dose should be used for the shortest duration necessary. Physicians and patients should remain vigilant for the development of such events throughout the entire course of treatment, even in the absence of prior cardiovascular symptoms. Patients should be informed about symptoms of serious cardiovascular events and the steps to take if they occur. There is no convincing evidence that concomitant use of aspirin reduces the increased risk of serious cardiovascular thrombotic events associated with NSAID use. Concurrent use of aspirin and NSAIDs, such as ibuprofen, increases the risk of serious gastrointestinal (GI) adverse events. Cases of Kounis syndrome have been reported in patients receiving ibuprofen treatment. 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.

Status after coronary artery bypass graft (CABG) surgery.

Two large controlled clinical trials of a selective COX-2 NSAID for pain treatment in the first 10–14 days following CABG surgery revealed an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG.

Patients after myocardial infarction (MI).

Observational studies have demonstrated that patients who received NSAIDs in the post-MI period had an increased risk of recurrent MI, cardiovascular death, and overall mortality, starting from the first week of treatment. In this cohort, the mortality rate in the first year after MI was 20 per 100 patient-years among patients receiving NSAIDs, compared to 12 per 100 patient-years in those not exposed to NSAIDs. Although the absolute mortality rate slightly decreased after the first year following MI, the elevated relative risk of death in NSAID users persisted for at least the next 4 years of observation. The use of the medicinal product should be avoided in patients with recent MI, except when the expected benefit outweighs the risk of recurrent cardiovascular thrombotic events. When using the medicinal product in patients with recent MI, they should be monitored for signs of cardiac ischemia.

Gastrointestinal bleeding, ulcers, and perforation.

NSAIDs, including ibuprofen, can cause serious gastrointestinal (GI) adverse events, including inflammation, bleeding, ulcers, and perforation of the esophagus, stomach, small or large intestine, which may be fatal. These serious adverse events may occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event during NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3–6 months and in about 2–4% of patients treated for 1 year. However, even short-term therapy is not without risk. Risk factors for gastrointestinal bleeding, ulcers, and perforation:

In patients with a history of peptic ulcer disease and/or GI bleeding who use NSAIDs, the risk of GI bleeding is increased more than 10-fold compared to patients without risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; alcohol consumption; advanced age; and poor general health. Most post-marketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with progressive liver disease and/or coagulopathy have an increased risk of GI bleeding.

Strategies to minimize gastrointestinal risk in patients receiving NSAIDs:

It is recommended to use the lowest effective dose for the shortest possible time and to avoid administering more than one NSAID simultaneously. NSAID use should be avoided in patients at increased risk, unless the expected benefit outweighs the increased risk of bleeding. For such patients, as well as those with active GI bleeding, alternative treatment methods other than NSAIDs should be considered. Patients should be monitored for signs and symptoms of GI ulceration and bleeding during NSAID therapy. If a serious GI adverse event is suspected, immediate evaluation and treatment should be initiated, and the medicinal product should be discontinued. Particular caution should be exercised when monitoring patients for signs of GI bleeding during concomitant use of low-dose aspirin for cardioprophylaxis (see section "Interaction with other medicinal products and other forms of interaction").

Hepatotoxicity.

Elevations in ALT or AST levels (≥3 times the upper limit of normal [ULN]) have been reported in approximately 1% of patients receiving NSAIDs in clinical trials. Additionally, rare, sometimes fatal, cases of severe liver injury, including fulminant hepatitis, liver necrosis, and hepatic failure, have been reported. Elevations in ALT or AST (less than 3 times ULN) may occur in up to 15% of patients treated with NSAIDs, including ibuprofen.

Patients should be informed about the signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, malaise, diarrhea, pruritus, jaundice, right upper quadrant pain, and flu-like symptoms). If clinical signs and symptoms suggestive of liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), the medicinal product should be discontinued immediately, and the patient should be evaluated.

Hypertensive disease.

NSAIDs, including ibuprofen, may lead to new-onset hypertension or worsening of pre-existing hypertension, potentially increasing the frequency of cardiovascular events. Patients taking angiotensin-converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired responses to these agents when taking NSAIDs. Blood pressure should be monitored at the initiation of NSAID therapy and throughout the treatment course.

Heart failure and edema.

A meta-analysis of randomized controlled trials by the Coxib and traditional NSAID Trialists’ Collaboration demonstrated approximately a twofold increase in hospitalizations due to heart failure in patients treated with COX-2 inhibitors compared to those not receiving NSAIDs. Available data from studies in patients with heart failure indicate that NSAID use increases the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients receiving NSAIDs. Ibuprofen may reduce the effectiveness of cardiovascular medications (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) (see section "Interaction with other medicinal products and other forms of interaction"). Ibuprofen should be avoided in patients with severe heart failure, unless the expected benefit outweighs the risk of worsening heart failure. If ibuprofen is used in patients with severe heart failure, they should be monitored for signs of worsening heart failure.

Renal toxicity and hyperkalemia.

Renal toxicity.

Long-term use of NSAIDs has led to renal papillary necrosis and other renal damage. Renal toxicity has also been observed in patients in whom renal prostaglandins play a compensatory role in maintaining renal perfusion. In these patients, administration of NSAIDs may cause dose-dependent reduction in prostaglandin formation and, consequently, renal blood flow, potentially triggering renal decompensation. Patients at greatest risk of this reaction include those with impaired renal function, dehydration, hypovolemia, heart failure, hepatic dysfunction, those taking diuretics and ACE inhibitors or ARBs, and elderly individuals. Discontinuation of NSAID therapy is usually followed by recovery to the pre-treatment state. There is no information from controlled clinical trials regarding the use of the medicinal product in patients with progressive renal insufficiency. Progression of renal dysfunction in patients with pre-existing renal insufficiency may be accelerated. Dehydration or hypovolemia should be corrected before initiating treatment. Renal function should be monitored in patients with impaired renal or hepatic function, heart failure, dehydration, or hypovolemia during treatment. Ibuprofen should be avoided in patients with progressive renal insufficiency, unless the expected benefit outweighs the risk of worsening renal function. If ibuprofen is used in patients with progressive renal insufficiency, they should be monitored for signs of worsening renal function.

Hyperkalemia.

Elevated serum potassium concentrations, including hyperkalemia, have been reported with NSAID use, even in some patients without impaired renal function. In patients with normal renal function, these effects were associated with hyporeninemic-hypoaldosteronism.

Anaphylactic reactions.

Ibuprofen has been associated with anaphylactic reactions in patients with known hypersensitivity to ibuprofen and in those without, as well as in patients with aspirin-sensitive asthma. Immediate emergency treatment should be provided if an anaphylactic reaction occurs.

Exacerbation of bronchial asthma associated with aspirin sensitivity.

A subgroup of patients with asthma may have aspirin-sensitive asthma, which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Due to reported cross-reactivity between aspirin and other NSAIDs in such aspirin-sensitive patients, ibuprofen is contraindicated in patients with this form of aspirin sensitivity. When using ibuprofen in patients with pre-existing asthma (without known aspirin sensitivity), patients should be monitored for changes in asthma signs and symptoms.

Serious skin reactions.

NSAIDs, including ibuprofen, may cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, which may be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin reactions, and ibuprofen should be discontinued at the first appearance of skin rash or any other signs of hypersensitivity. Ibuprofen is contraindicated in patients with previous serious skin reactions to NSAIDs.

Drug reaction with eosinophilia and systemic symptoms (DRESS).

Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in patients taking NSAIDs such as ibuprofen. Some of these events were fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes, DRESS symptoms may resemble acute viral infection. Eosinophilia is frequently observed. Because this disorder is variable in its presentation, other organ systems may be involved. Early signs of hypersensitivity, such as fever or lymphadenopathy, may be present even if rash is not evident. If such signs or symptoms occur, ibuprofen should be discontinued and the patient should be evaluated immediately.

Fetal toxicity.

Premature closure of the fetal ductus arteriosus.

NSAIDs, including ibuprofen, should be avoided in pregnant women at approximately 30 weeks of gestation and later. NSAIDs increase the risk of premature closure of the fetal ductus arteriosus at this gestational age.

Oligohydramnios/neonatal renal dysfunction.

The use of NSAIDs, including ibuprofen, at approximately 20 weeks of gestation or later may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are observed, on average, within several days or weeks of treatment, although oligohydramnios has rarely been reported as early as 48 hours after initiating NSAID therapy. Oligohydramnios is often, but not always, reversible upon discontinuation of treatment. Complications of prolonged oligohydramnios may include limb contractures and delayed lung maturation. In some post-marketing cases, neonatal renal impairment required exchange transfusion or dialysis. If NSAID treatment is necessary between approximately 20 and 30 weeks of gestation, ibuprofen use should be limited to the lowest effective dose and shortest possible duration. Ultrasound monitoring of amniotic fluid should be performed if treatment with ibuprofen exceeds 48 hours. If oligohydramnios occurs, ibuprofen should be discontinued and the patient monitored.

Hematological toxicity.

Anemia has occurred in patients receiving NSAIDs. This may be related to occult or gross GI blood loss, fluid retention, or effects on erythropoiesis. If a patient taking ibuprofen shows any signs or symptoms of anemia, hemoglobin and hematocrit should be monitored. NSAIDs, including ibuprofen, may increase the risk of bleeding. Concomitant conditions such as coagulation disorders, and concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors, may increase this risk. These patients should be monitored for signs of bleeding. Ibuprofen must be diluted before administration. Infusion of the undiluted medicinal product may cause hemolysis.

Masking of inflammation and fever.

The pharmacological activity of ibuprofen in reducing inflammation and possibly fever may reduce the usefulness of diagnostic signs for detecting infections.

Laboratory monitoring.

Because serious gastrointestinal bleeding, hepatotoxicity, and renal injury may occur without warning symptoms or signs, patients receiving long-term NSAID therapy should be periodically monitored with CBC.

Visual disturbances.

Blurred vision or visual loss, scotomata, and color vision changes have been reported with oral ibuprofen use. Discontinue ibuprofen and perform an ophthalmological examination if a patient reports visual disturbances.

Aseptic meningitis.

Aseptic meningitis with fever and confusion has been observed in patients receiving oral ibuprofen therapy. Although it is more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients without underlying chronic disease. If a patient taking ibuprofen develops signs or symptoms of meningitis, consideration should be given to whether these signs or symptoms are related to ibuprofen therapy.

Important information on excipients.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Study data indicate an increased risk of miscarriage and congenital malformations following use of prostaglandin synthesis inhibitors in early pregnancy. The risk is considered to increase with increasing dose and duration of therapy. From the 20th week of gestation, ibuprofen use may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation of therapy. Additionally, there are reports of ductus arteriosus constriction following treatment in the second trimester of pregnancy, most of which resolved after discontinuation of treatment. Therefore, NSAIDs should not be taken during the first two trimesters of pregnancy or during labor unless the expected benefit to the patient outweighs the potential risk to the fetus.

If ibuprofen is used by a woman attempting to conceive or during the first or second trimester of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Fetal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to ibuprofen for several days starting from the 20th gestational week. The medicinal product should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

During the third trimester of pregnancy, use of any prostaglandin synthesis inhibitor may affect the fetus by causing cardiopulmonary toxicity (premature constriction/closure of the fetal ductus arteriosus with pulmonary hypertension) and renal dysfunction (see above), which may progress to renal failure manifesting as oligohydramnios. Ibuprofen is contraindicated during the third trimester of pregnancy (see section "Contraindications") due to the potential for inhibition of uterine contractility, which may lead to prolonged labor with a tendency toward increased bleeding in both mother and child, even with low-dose use.

Period of breastfeeding.

A small amount of ibuprofen has been detected in breast milk. To date, no harmful effects on infants have been reported; therefore, interruption of breastfeeding is usually not required for short-term treatment with lower doses. However, interruption of breastfeeding is recommended when doses exceeding 1200 mg per day are used or during prolonged treatment periods due to the potential ability to inhibit prostaglandin synthesis in newborns.

Fertility.

Medicinal products that inhibit cyclooxygenase/prostaglandin synthesis may impair fertility in women by affecting ovulation. This effect is reversible upon discontinuation of treatment.

Ability to influence reaction speed when driving or operating machinery.

When used at recommended doses, the medicinal product does not affect reaction speed when driving or operating machinery. Patients who experience dizziness, drowsiness, disorientation, or visual disturbances while taking NSAIDs should refrain from driving and operating machinery.

Method of Administration and Dosage

To minimize adverse effects, the medicinal product should be administered at the lowest effective doses for the shortest duration possible.

Adequate hydration of the patient should be maintained to minimize the risk of potential renal adverse reactions.

For analgesia (pain treatment):

The dose is 400 mg to 800 mg intravenously every 6 hours as needed. The infusion time should be no less than 30 minutes.

The maximum daily dose is 3200 mg.

Treatment of fever symptoms:

The dose is 400 mg intravenously, followed by 400 mg every 4–6 hours or 100–200 mg every 4 hours, if necessary. The infusion time should be no less than 30 minutes.

The maximum daily dose is 3200 mg.

Paediatric patients.

For analgesia (pain treatment) and fever:

Age from 12 to 17 years.

The dose is 400 mg intravenously every 4–6 hours as needed. The infusion time should be no less than 10 minutes.

The maximum daily dose is 40 mg/kg or 2400 mg, whichever is lower.

Age from 6 months to 12 years.

The dose is 10 mg/kg intravenously up to a maximum single dose of 400 mg every 4–6 hours as needed. The infusion time should be no less than 10 minutes. The maximum daily dose is 40 mg/kg or 2400 mg, whichever is lower.

Dosing for paediatric patients required for the treatment of fever and pain.

Age group	Dosage	Administration interval	Minimum infusion time	Maximum daily dose
From 6 months to less than 12 years	10 mg/kg up to a maximum of 400 mg.	As needed, every 4–6 hours	10 minutes	*40 mg/kg or 2400 mg
12–17 years	400 mg	As needed, every 4–6 hours	10 minutes	*40 mg/kg or 2400 mg

• The maximum daily dose is 40 mg/kg or 2400 mg, whichever is lower.

Age from 3 months to less than 6 months.

The dosage is a single intravenous dose of 10 mg/kg, up to a maximum single dose of 100 mg. The infusion time should be no less than 10 minutes.

Administration method.

The medicinal product Pyronef, solution for infusion, 100 mg/mL, 4 mL (400 mg) or 8 mL (800 mg) in a vial, MUST BE DILUTED before administration.

Dilute to a final concentration of 4 mg/mL or less.

Suitable diluents include 0.9% sodium chloride injection solution, 5% dextrose injection solution, or Ringer's lactate solution.

Dose of 400 mg: dilute 4 mL of Pyronef in at least 100 mL of diluent.

Dose of 800 mg: dilute 8 mL of Pyronef in at least 200 mL of diluent.

For weight-based dosing at 10 mg/kg, ensure that the concentration of Pyronef is 4 mg/mL or less.

Before administration, the parenteral solution should be inspected visually for particulate matter and discoloration. If visible particles, discoloration, or other foreign matter are observed, the solution must not be used. Diluted solutions are stable for 24 hours at room temperature (20 to 25 °C) and under normal room light.

Children.

The medicinal product is indicated for use in children aged from 3 months.

Overdose.

The elimination half-life in overdose is 1.5–3 hours.

Symptoms. In most patients, ingestion of large amounts of NSAIDs causes only nausea, vomiting, epigastric pain, and very rarely diarrhea. Tinnitus, headache, dizziness, and gastrointestinal bleeding may also occur. In more severe poisoning, toxic effects on the central nervous system may develop, manifesting as drowsiness, nystagmus, visual disturbances, and occasionally agitation, disorientation, or coma. Seizures may occasionally occur in patients. Severe poisoning may lead to hyperkalemia and metabolic acidosis, acute renal failure, liver damage, arterial hypotension, respiratory failure, and cyanosis. In patients with bronchial asthma, exacerbation of asthma may occur.

Treatment. There is no specific antidote; symptomatic treatment should be initiated. Therapeutic management of intoxication should be based on the severity, plasma levels, and clinical symptoms, in accordance with standard intensive care practices.

Adverse reactions

All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data). The most frequently occurring adverse reactions are gastrointestinal (GI) events, which are mostly dose-dependent. Peptic ulcers, gastrointestinal perforation or gastrointestinal bleeding, sometimes fatal, may occur, particularly in elderly patients. Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported. Gastritis has been observed less frequently. Very rare cases of severe hypersensitivity reactions (including infusion site reactions, anaphylactic shock) and serious skin reactions such as bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme and alopecia have been reported.

Exacerbation of infectious inflammation (e.g. development of necrotizing fasciitis) has been described in temporal association with NSAID use. This may be related to the mechanism of action of NSAIDs. During varicella infection, photosensitivity, allergic vasculitis may occur, and in exceptional cases, severe skin infections and soft tissue complications. Edema, hypertension and heart failure have been reported in association with NSAID treatment. Clinical studies suggest that the use of ibuprofen, particularly at high doses (2400 mg/day), may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke).

MedDRA, Organs and Systems	Frequency	Adverse Reactions
Laboratory findings, infections	Very rare	Exacerbation of infectious inflammation (e.g., development of necrotizing fasciitis) has been reported in association with NSAID use. This may be related to the mechanism of action of NSAIDs.
Blood and lymphatic system disorders	Very rare	Blood dyscrasias (anemia, agranulocytosis, leukopenia, thrombocytopenia, and pancytopenia). Initial symptoms include fever, sore throat, oral ulcers, flu-like symptoms, epistaxis, and skin bleeding.
Immune system disorders	Uncommon	Hypersensitivity reactions. Skin rash, pruritus, asthma attacks.
	Very rare	Systemic lupus erythematosus (SLE), severe hypersensitivity reactions, facial swelling, tongue swelling, laryngeal edema with airway narrowing, dyspnea, palpitations, hypotension, and shock.
Psychiatric disorders	Uncommon	Anxiety, restlessness.
	Rare	Psychotic reactions, nervousness, irritability, confusion or disorientation, depression.
Nervous system disorders	Very common	Fatigue, headache, dizziness.
	Uncommon	Insomnia, excitation, irritability.
	Very rare	Aseptic meningitis (neck stiffness, headache, nausea, vomiting, fever, or confusion).
Eye disorders	Uncommon	Visual disturbances.
	Rare	Reversible toxic amblyopia.
Ear and labyrinth disorders	Common	Vertigo.
	Uncommon	Tinnitus.
	Rare	Hearing disturbances.
Cardiac disorders	Very rare	Palpitations, heart failure, myocardial infarction. Arterial hypertension.
	Frequency unknown	Kounis syndrome.
Respiratory, thoracic and mediastinal disorders	Very rare	Asthma, bronchospasm, dyspnea, wheezing.
Gastrointestinal disorders	Very common	Heartburn, abdominal pain, nausea, vomiting, flatulence, diarrhea, constipation, and minor gastrointestinal bleeding, which may lead to anemia in rare cases.
	Common	Gastrointestinal ulcers, potentially with bleeding and perforation. Ulcerative stomatitis, exacerbation of colitis and Crohn's disease.
	Uncommon	Gastritis.
	Rare	Esophageal stricture, exacerbation of diverticulosis, unspecified hemorrhagic colitis. Gastrointestinal bleeding may lead to anemia and hematemesis.
	Very rare	Esophagitis, pancreatitis, formation of intestinal and diaphragm-like strictures.
Hepatobiliary disorders	Rare	Jaundice, hepatic dysfunction, liver injury, particularly during prolonged therapy of acute hepatitis.
	Frequency unknown	Hepatic failure.
Skin and subcutaneous tissue disorders	Common	Skin rashes.
	Uncommon	Urticaria, pruritus, purpura (including allergic purpura).
	Very rare	Bullous or vesicular reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme, exfoliative dermatitis. Photosensitivity reactions and allergic vasculitis. In rare cases, severe skin reactions during varicella.
	Frequency unknown	Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS syndrome), Generalized Exfoliative Pustular Eruption (GEP), photosensitivity reactions.
Musculoskeletal and connective tissue disorders	Rare	Neck muscle rigidity.
Renal and urinary disorders	Uncommon	Reduced urine excretion, edema, particularly in patients with arterial hypertension or renal insufficiency, nephrotic syndrome, interstitial nephritis, which may be associated with acute renal failure.
	Rare	Papillary necrosis, especially during prolonged therapy, increased serum uric acid concentration.
General disorders and administration site conditions	Common	Pain and burning sensation at the injection site.
	Frequency unknown	Edema, hematoma, or bleeding at the injection site.

Clinical trial experience with ibuprofen.

Adult patients – 560 patients were exposed to ibuprofen, 438 for pain and 122 for fever. In pain studies, ibuprofen was initiated intraoperatively and administered at doses of 400 mg or 800 mg every 6 hours for 3 days. In fever studies, ibuprofen was administered at doses of 100 mg, 200 mg, or 400 mg every 4 or 6 hours for 3 days. The most common type of adverse reaction associated with oral administration of ibuprofen is gastrointestinal.

Pain studies – The frequency of adverse reactions listed in the following table was obtained from multicenter, controlled clinical trials involving postoperative patients, in which ibuprofen was compared with placebo in patients who also received morphine as needed for management of postoperative pain.

Table 1: Postoperative patients with adverse reactions observed in ≥ 3 % of patients in any treatment group ibuprofen in pain studies*
* All patients received concomitant morphine during these studies.
Adverse reaction	Ibuprofen		Placebo (N=287)
	400 mg (N=134)	800 mg (N=304)
Any reaction	118 (88 %)	260 (86 %)	258 (90 %)
Nausea	77 (57 %)	161 (53 %)	179 (62 %)
Vomiting	30 (22 %)	46 (15 %)	50 (17 %)
Flatulence	10 (7 %)	49 (16 %)	44 (15 %)
Headache	12 (9 %)	35 (12 %)	31 (11 %)
Ecchymosis	13 (10 %)	13 (4 %)	16 (6 %)
Dizziness	8 (6 %)	13 (4 %)	5 (2 %)
Peripheral edema	1 (< 1 %)	9 (3 %)	4 (1 %)
Urinary retention	7 (5 %)	10 (3 %)	10 (3 %)
Anemia	5 (4 %)	7 (2 %)	6 (2 %)
Decreased hemoglobin	4 (3 %)	6 (2 %)	3 (1 %)
Dyspepsia	6 (4 %)	4 (1 %)	2 (< 1 %)
Wound hemorrhage	4 (3 %)	4 (1 %)	4 (1 %)
Abdominal discomfort	4 (3 %)	2 (< 1 %)	0
Cough	4 (3 %)	2 (< 1 %)	1 (< 1 %)
Hypokalemia	5 (4 %)	3 (< 1 %)	8 (3 %)

Fever studies.

Fever studies were conducted in febrile hospitalized patients with malaria and febrile hospitalized patients with various causes of fever. In hospitalized patients with fever due to malaria, adverse reactions observed in at least 2 patients receiving ibuprofen included abdominal pain and nasal congestion. In hospitalized patients with fever (from all causes), adverse reactions observed in more than 2 patients in any treatment group are presented in the table below.

Table 2: Patients with adverse reactions observed in ≥ 3 % of patients in any ibuprofen treatment group in the fever of any cause study
Adverse reaction	IBUPROFEN			Placebo N=28
	100 mg N=30	200 mg N=30	400 mg N=31
Any reaction	27 (87 %)	25 (83 %)	23 (74 %)	25 (89 %)
Anemia	5 (17 %)	6 (20 %)	11 (36 %)	4 (14 %)
Eosinophilia	7 (23 %)	7 (23 %)	8 (26 %)	7 (25 %)
Hypokalemia	4 (13 %)	4 (13 %)	6 (19 %)	5 (18 %)
Hypoproteinemia	3 (10 %)	0	4 (13 %)	2 (7 %)
Neutropenia	2 (7 %)	2 (7 %)	4 (13 %)	2 (7 %)
Blood urea increased	0	0	3 (10 %)	0
Hypernatremia	2 (7 %)	0	3 (10 %)	0
Hypertension	0	0	3 (10 %)	0
Hypoalbuminemia	3 (10 %)	1 (3 %)	3 (10 %)	1 (4 %)
Arterial hypotension	0	2 (7 %)	3 (10 %)	1 (4 %)
Diarrhea	3 (10 %)	3 (10 %)	2 (7 %)	2 (7 %)
Bacterial pneumonia	3 (10 %)	1 (3 %)	2 (7 %)	0
Increased blood LDH level	3 (10 %)	2 (7 %)	1 (3 %)	1 (4 %)
Thrombocytopenia	3 (10 %)	2 (7 %)	1 (3 %)	0
Bacteremia	4 (13 %)	0	0	0

Pediatric population.

A total of 143 patients aged 6 months and older received ibuprofen in controlled clinical trials. The most common adverse reactions (incidence ≥2%) in pediatric patients receiving ibuprofen were infusion site pain, vomiting, nausea, anemia, and headache. Twenty-one hospitalized patients aged from 3 to 6 months received ibuprofen for the treatment of pain or fever in an open, uncontrolled clinical study; 18 out of 21 patients received treatment with a single dose.

Post-marketing experience.

The following adverse reactions have been identified during post-marketing use of ibuprofen (and a causal relationship to ibuprofen use is not always established): skin and subcutaneous tissue disorders: exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and fixed drug eruption. Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and patients, as well as legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 ºC. Keep out of reach and sight of children.

Incompatibilities.

The medicinal product must not be mixed with other medicinal products except those specified in the section “Instructions for use and dosage”.

Packaging. 4 ml (400 mg) or 8 ml (800 mg) in a vial, 1 vial in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

VEM Ilac San. ve Tic. A.S., Turkey.

Manufacturer's address and place of business.

Cerkezkoy Organize Sanayi Bolgesi, Karaagac Mahallesi, Fatih Bulvari No: 38, Kapakli / Tekirdag / Turkey.