Iburox

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

Composition:

active substance: ibuprofen (ibuprofen);

1 ml contains 100 mg of ibuprofen; 1 ampoule contains 400 mg or 800 mg of ibuprofen;

excipients: L-arginine, L-arginine 10% solution, hydrochloric acid, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

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

The mechanism of action of ibuprofen, as with other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Ibuprofen is a potent inhibitor of prostaglandin synthesis in vitro. Concentrations achieved during therapy produce effects in vivo. Prostaglandins sensitize afferent nerves and potentiate the pain-inducing action of bradykinin in animal models. Prostaglandins are mediators of inflammation. Since ibuprofen inhibits prostaglandin synthesis, its mechanism of action may be attributed to reduced levels of prostaglandins in peripheral tissues.

Pharmacokinetics

Ibuprofen is a racemic mixture of [-] R- and [+] S-isomers. In vivo and in vitro studies indicate that the [+] S-isomer is responsible for the clinical activity. The [-] R-form, although considered pharmacologically inactive, is slowly and incompletely (~60%) converted into the active [+] S-form in adults. The [-] R-isomer serves as a circulating reservoir to maintain levels of the active component. Pharmacokinetic parameters of ibuprofen concentrations determined in a study involving volunteers are presented in Table 1 below.

Table 1

AUC = area under the curve.

Cmax = peak plasma concentration.

CV = coefficient of variation.

KEL = first-order elimination rate constant.

T 1/2 = elimination half-life.

* = infusion duration of 60 minutes.

Pharmacokinetic parameters of ibuprofen concentrate determined in a study in children with fever are presented in Table 2. The median Tmax was found to occur at the end of infusion, and ibuprofen had a shorter elimination half-life in children compared to adults.

Table 2

* Median (minimum-maximum).

^ Open-label study in hospitalized pediatric patients with pain or fever.

** = infusion time of 10 minutes.

Ibuprofen, like most NSAIDs, is highly bound to plasma proteins (> 99% bound at 20 µg/mL). Protein binding is significant, and binding becomes nonlinear at concentrations > 20 µg/mL. Based on data from oral dosing, there is an age- or fever-related change in the volume of distribution of ibuprofen.

Clinical characteristics

Indications

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

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

Contraindications

• Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to ibuprofen or any component of the medicinal product.
• History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs.
• During coronary artery bypass graft (CABG) surgery.

Interaction with other medicinal products and other forms of interaction

Medicinal products affecting hemostasis

Ibuprofen and anticoagulants, such as warfarin, have a synergistic effect on bleeding. Concomitant use of ibuprofen and anticoagulants increases the risk of serious bleeding compared to use of either medicinal product alone. Platelet serotonin release plays an important role in hemostasis. Concomitant use of agents that inhibit serotonin reuptake with NSAIDs may increase the risk of bleeding more than NSAIDs alone.

Patients receiving concomitant ibuprofen with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), or serotonin-norepinephrine reuptake inhibitors (SNRIs) should be monitored for signs of bleeding (see section "Special precautions for use").

Aspirin. Pharmacodynamic studies have demonstrated an effect on the antiplatelet activity of aspirin when ibuprofen 400 mg was administered three times daily with enteric-coated low-dose aspirin. Interaction occurs even after administration of a single daily dose of ibuprofen 400 mg, particularly if ibuprofen is taken before aspirin. The interaction is minimized if immediate-release low-dose aspirin is taken at least 2 hours before the once-daily ibuprofen dosing regimen. Clinical studies have shown that concomitant use of NSAIDs and analgesic doses of aspirin provides no additional therapeutic benefit compared to NSAID use alone. In a clinical study, concomitant use of NSAIDs and aspirin was associated with a significantly higher incidence of gastrointestinal adverse reactions compared to NSAID use alone (see section "Special precautions for use"). Since the cardiovascular risk may be increased due to the interaction of ibuprofen with the antiplatelet effect of aspirin, patients taking low-dose aspirin for cardioprotection and requiring analgesics should consider using an NSAID that does not interfere with the antiplatelet action of aspirin. In general, concomitant use of ibuprofen and analgesic doses of aspirin is not recommended due to increased risk of bleeding (see section "Special precautions for use"). Ibuprofen is not a substitute for low-dose aspirin for cardiovascular protection.

ACE inhibitors, angiotensin receptor blockers, and beta-blockers. NSAIDs may attenuate the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).

In elderly patients, patients with hypovolemia (including those receiving diuretic therapy), or those with impaired renal function, concomitant use of NSAIDs with ACE inhibitors or ARBs may lead to deterioration in renal function, including possible acute renal failure. These effects are usually reversible. Blood pressure should be monitored during concomitant use of ibuprofen with ACE inhibitors, ARBs, or beta-blockers.

Renal function should be monitored in elderly patients, patients with hypovolemia, or those with impaired renal function who are receiving concomitant ibuprofen with ACE inhibitors or ARBs (see section "Special precautions for use"). Adequate hydration should be ensured when these medicinal products are used concomitantly. Renal function should be assessed at the start of concomitant therapy and periodically thereafter.

Diuretics. Clinical studies and post-marketing observations have shown that NSAIDs reduce the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect is attributed to inhibition of renal prostaglandin synthesis by NSAIDs.

When ibuprofen is used concomitantly with diuretics, patients should be monitored for signs of worsening renal function, in addition to ensuring the diuretic's effectiveness, including antihypertensive effect (see section "Special precautions for use").

Digoxin. Concomitant use of ibuprofen with digoxin has been reported to increase serum digoxin concentration and prolong digoxin half-life. Serum digoxin levels should be monitored when ibuprofen is used concomitantly with digoxin.

Lithium. NSAIDs may increase plasma lithium levels and reduce renal lithium clearance. The average minimum lithium concentration increased by 15%, and renal clearance decreased by approximately 20%. This effect is attributed to inhibition of renal prostaglandin synthesis by NSAIDs. Patients receiving concomitant ibuprofen and lithium should be monitored for signs of lithium toxicity.

Methotrexate. Concomitant use of NSAIDs and methotrexate may increase the risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Patients receiving concomitant ibuprofen and methotrexate should be monitored for signs of methotrexate toxicity.

Cyclosporine. Concomitant use of ibuprofen and cyclosporine may enhance cyclosporine nephrotoxicity. Patients receiving concomitant ibuprofen and cyclosporine should be monitored for signs of worsening renal function.

NSAIDs and salicylates. Concomitant use of ibuprofen with other nonsteroidal anti-inflammatory drugs or salicylates (e.g., diflunisal, salsalate) increases the risk of gastrointestinal toxicity with little or no increase in efficacy (see section "Special precautions for use"). Concomitant use of ibuprofen with other NSAIDs or salicylates is not recommended.

Pemetrexed. Concomitant use of ibuprofen and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and gastrointestinal toxicity (see pemetrexed product information). In patients with renal impairment (creatinine clearance between 45 and 79 mL/min) receiving concomitant ibuprofen and pemetrexed, myelosuppression, renal, and gastrointestinal toxicity should be monitored. NSAIDs with short half-lives (e.g., diclofenac, indomethacin) should be avoided for 2 days before, on the day of, and for 2 days after pemetrexed administration. In the absence of data on potential interactions between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should discontinue them at least 5 days before, on the day of, and for 2 days after pemetrexed administration.

Special precautions for use

Adverse reactions following the use of ibuprofen and NSAIDs in general can be minimized by using the lowest effective dose required to relieve symptoms, for the shortest duration necessary.

Elderly patients are more likely to experience adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal. Cardiovascular and cerebrovascular effects

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

Patients with a history of arterial hypertension and/or mild to moderate congestive heart failure should begin long-term treatment with caution (medical consultation is required), as fluid retention, arterial hypertension, and edema have been reported during therapy with ibuprofen and other NSAIDs.

Data indicate that the use of ibuprofen, especially at high doses (2400 mg per day) or for prolonged periods, slightly increases the risk of arterial thrombotic complications (e.g., myocardial infarction or stroke). In general, low-dose ibuprofen (e.g., ≤ 1200 mg per day) is not expected to increase the risk of myocardial infarction. Long-term treatment in patients with uncontrolled hypertension, congestive heart failure, diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease may be prescribed by a physician only after careful consideration. Long-term NSAID therapy in patients with significant cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) should be prescribed only after careful evaluation.

Status after coronary artery bypass grafting (CABG)

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

Patients after myocardial infarction

Observational studies conducted in the Danish National Registry demonstrated that patients receiving NSAIDs after myocardial infarction had an increased risk of recurrent myocardial infarction, cardiovascular death, and all-cause mortality, starting from the first week of treatment. In this cohort, the rate of fatal outcomes in the first year after myocardial infarction was 20 per 100 person-years in patients receiving NSAIDs, compared to 12 per 100 person-years in those not receiving NSAIDs. Although the absolute mortality rate decreased somewhat after the first year following myocardial infarction, the elevated relative risk of fatal outcomes in NSAID users persisted for at least the next four years of observation.

The use of ibuprofen should be avoided in patients with recent myocardial infarction unless the expected benefit outweighs the risk of recurrent cardiovascular thrombotic complications. If ibuprofen is used in patients with recent myocardial infarction, patients should be monitored for signs of cardiac ischemia.

Gastrointestinal tract

NSAIDs should be used with caution in patients with chronic inflammatory bowel diseases (ulcerative colitis, Crohn's disease), as these conditions may be exacerbated. Cases of gastrointestinal bleeding, perforation, and ulcers, sometimes fatal, have been reported during NSAID therapy at any stage of treatment, regardless of the presence of prior warning symptoms or history of severe gastrointestinal disorders.

The risk of gastrointestinal bleeding, perforation, and ulcers increases with higher NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, and in elderly patients. These patients should initiate treatment with the lowest doses. Caution should be exercised when treating patients receiving concomitant medications that may increase the risk of gastotoxicity or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), or antiplatelet agents (e.g., acetylsalicylic acid). For long-term treatment in these patients, as well as in patients requiring concomitant low-dose acetylsalicylic acid (aspirin) or other gastrointestinal-risk-increasing drugs, the physician should consider the appropriateness of prescribing combination therapy with misoprostol or proton pump inhibitors. Patients with a history of gastrointestinal disorders, particularly elderly patients, should be informed about any unusual gastrointestinal symptoms (especially bleeding), particularly gastrointestinal bleeding at the beginning of treatment. If gastrointestinal bleeding or ulcers are detected in patients receiving ibuprofen, treatment should be discontinued immediately.

Renal and hepatic function impairment

Ibuprofen should be used cautiously in patients with a history of kidney or liver disease, especially when concurrently treated with diuretics, as prostaglandin inhibition may cause fluid retention and renal function impairment. When administering the drug to these patients, the lowest possible dose of ibuprofen should be used, and renal function should be monitored regularly. In cases of dehydration, appropriate fluid intake should be ensured, as dehydration may trigger the development of renal failure. Chronic use of analgesics, particularly combinations of different analgesics, may lead to chronic kidney injury with a risk of renal failure (analgesic nephropathy). Patients at highest risk for such reactions include elderly patients and those with impaired renal function, hepatic dysfunction, diuretic therapy, or ACE inhibitors. Cases of hyperkalemia have been reported in patients with renal insufficiency and dehydration after high-dose tromethamine administration. As with other NSAIDs, ibuprofen may cause a slight, temporary increase in certain liver function parameters, as well as significant elevations in transaminase levels. If substantial increases in these parameters occur, treatment should be discontinued.

Heart failure and edema

A meta-analysis of randomized controlled trials by the Coxib and traditional NSAID Trialists demonstrated approximately twice as many hospitalizations for heart failure in patients receiving selective COX-2 inhibitors and nonselective NSAIDs compared to those receiving placebo. In the Danish National Registry study, NSAID use in patients with heart failure increased the risk of MI, hospitalization for heart failure, and fatal outcomes.

Additionally, fluid retention and edema have been observed in some patients receiving NSAIDs. The use of ibuprofen may blunt the cardiovascular effects of several therapeutic agents used to treat these conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs)). It is recommended to avoid ibuprofen in patients with severe heart failure, except when the expected benefit outweighs the risk of worsening heart failure. If ibuprofen is used in patients with severe heart failure, patients 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 kidney damage.

Renal toxicity has also been observed in patients in whom renal prostaglandins play a compensatory role in maintaining renal perfusion. In these patients, NSAID use may cause dose-dependent reduction in prostaglandin formation and, consequently, renal blood flow, potentially leading to overt renal decompensation. Patients at highest risk for this reaction include those with impaired renal function, dehydration, hypovolemia, heart failure, hepatic dysfunction, those taking diuretics, 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 ibuprofen in patients with progressive kidney disease. The effect of ibuprofen on the kidneys may accelerate the progression of renal dysfunction in patients with pre-existing kidney disease.

It is recommended to correct fluid volume in patients with dehydration or hypovolemia before initiating ibuprofen. Renal function should be monitored in patients with impaired renal or hepatic function, heart failure, dehydration, or hypovolemia during ibuprofen use. Ibuprofen should be avoided in patients with progressive renal insufficiency, except when the expected benefit outweighs the risk of worsening renal function. If ibuprofen is used in patients with progressive renal insufficiency, patients should be monitored for signs of worsening renal function.

Hyperkalemia. Increased serum potassium concentration, including hyperkalemia, has been reported with NSAID use, even in some patients without impaired renal function. In patients with normal renal function, these effects are associated with hyporeninemic hypoaldosteronism.

Anaphylactoid reactions: During intravenous infusion, close monitoring of the patient is recommended, especially at the beginning of the infusion, to detect any anaphylactic reaction caused by the active substance or excipients. Severe acute hypersensitivity reactions (e.g., anaphylactic shock) are very rare. At the first signs of a hypersensitivity reaction after taking ibuprofen, therapy should be discontinued and symptomatic treatment initiated.

Aspirin-sensitive asthma

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

Serious skin adverse reactions (SSARs)

Serious 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), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal, have been reported with ibuprofen use (see section "Adverse reactions"). Most of these reactions occurred within the first month of treatment.

If signs or symptoms suggesting these reactions appear, ibuprofen should be discontinued immediately, and alternative treatment considered (if necessary). In rare cases, varicella may cause severe skin infections and soft tissue complications. The role of NSAIDs in exacerbating these infections cannot currently be ruled out. Therefore, ibuprofen should be avoided during varicella.

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, but 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 often present. Since this disorder may present variably, other organ systems not listed here may be involved. It is important to note that early signs of hypersensitivity, such as fever or lymphadenopathy, may be present even if rash is not apparent. If such signs or symptoms are present, ibuprofen should be discontinued and the patient evaluated immediately.

Impairment of fertility in women

Limited data suggest that drugs inhibiting cyclooxygenase/prostaglandin synthesis may affect ovulation. This effect is reversible upon discontinuation of treatment. Long-term use (referring to doses of 2400 mg per day and treatment duration exceeding 10 days) of ibuprofen may impair female fertility and is therefore not recommended for women trying to conceive. This medication should be discontinued in women experiencing difficulty conceiving or undergoing infertility evaluation.

Hematological effects. Ibuprofen may temporarily inhibit platelet function (platelet aggregation), prolonging bleeding time and increasing the risk of bleeding. Therefore, patients with coagulation disorders should be monitored. Ibuprofen should be used with particular caution in patients receiving acetylsalicylic acid for platelet aggregation inhibition.

Masking symptoms of underlying infections

Ibuprofen may mask symptoms of infection, potentially leading to delayed initiation of appropriate treatment and thus worsening the outcome of infectious disease. This has been observed in bacterial pneumonias and bacterial complications of varicella. If ibuprofen is required to reduce fever and relieve pain during infection, patient monitoring is recommended. In outpatient settings, patients should seek immediate medical attention if symptoms persist or the patient's condition worsens.

In rare cases, varicella may cause serious skin and soft tissue infections. The role of NSAIDs in exacerbating these infections cannot currently be excluded. Therefore, it is advisable to avoid ibuprofen use in varicella.

Effects on laboratory tests

• Bleeding time (may be prolonged for up to 1 day after discontinuation of treatment).
• Blood glucose concentration (may decrease).
• Creatinine clearance (may decrease).
• Hematocrit or hemoglobin (may decrease).
• Blood urea nitrogen concentration and blood creatinine and potassium concentrations (may increase).
• Liver function: increased transaminase levels.

Ibuprofen should be used only after careful benefit-risk assessment in patients with inherited porphyrin metabolism disorders (e.g., acute intermittent porphyria).

Ophthalmological effects

There have been reports of blurred vision or visual impairment, scotomas, and color vision disturbances with oral ibuprofen use.

Aseptic meningitis

Aseptic meningitis with fever and coma has been observed in patients taking oral ibuprofen. Although this is likely more common in patients with systemic lupus erythematosus and related connective tissue diseases, it has also been reported in patients without underlying chronic conditions. If signs or symptoms of meningitis develop in a patient taking ibuprofen, it should be considered whether these signs or symptoms are related to ibuprofen therapy.

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 the use of prostaglandin synthesis inhibitors in early pregnancy. The risk is believed to increase with higher doses and longer duration of therapy. From the 20th week of pregnancy, the use of ibuprofen may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation of therapy. Additionally, there have been reports of ductus arteriosus constriction after 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 trying to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible.

Prenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to ibuprofen for several days starting from the 20th gestational week. The drug should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

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

Risks to the fetus:

• Cardio-pulmonary toxicity (premature constriction/closure of the fetal ductus arteriosus with pulmonary hypertension);
• Impaired renal function (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 delay or prolong labor and increase the tendency for bleeding in both mother and child, even with low-dose administration.

Period of breastfeeding

Studies on the use of ibuprofen during lactation have not been conducted. A small amount of ibuprofen has been detected in breast milk. Harmful effects on infants are currently unknown; therefore, interruption of breastfeeding is usually not required for short-term treatment. There are no reports of negative effects on the breastfed infant or on lactation. The benefits of breastfeeding should be weighed against the mother's clinical need for the drug and any potential adverse effects of ibuprofen on the breastfed infant.

Fertility

Drugs that inhibit cyclooxygenase/prostaglandin synthesis may cause impairment of fertility in women by affecting ovulation. Published animal studies have shown that prostaglandin synthesis inhibitors may potentially disrupt prostaglandin-mediated follicular rupture necessary for ovulation. Small studies in women receiving NSAIDs have also shown reversible ovulation delay. This effect is reversible upon discontinuation of treatment.

Ability to affect reaction speed when driving or operating machinery

The drug may cause dizziness, drowsiness, disorientation, or visual disturbances. Patients experiencing these symptoms should refrain from driving or operating machinery.

Administration and Dosage

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

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

Adults

For pain treatment

The dose is 400 mg to 800 mg intravenously every 6 hours as needed. The infusion time should be at least 30 minutes. The maximum daily dose is 3200 mg.

For relief of fever symptoms

The dose is 400 mg intravenously, followed by 400 mg every 4–6 hours or 100–200 mg every 4 hours as needed. The infusion time should be at least 30 minutes. The maximum daily dose is 3200 mg.

Pediatric Patients

For treatment of pain and relief of fever symptoms

Children aged 12 to 17 years

The dose is 400 mg intravenously every 4–6 hours as needed. The infusion time should be at least 10 minutes. The maximum daily dose is 40 mg/kg or 2400 mg, whichever is lower.

Children aged 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 at least 10 minutes. The maximum daily dose is 40 mg/kg or 2400 mg, whichever is lower.

Dosing for pediatric patients required for treatment of fever and pain

Table 3

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

Children aged 3 to 6 months

The dose is 10 mg/kg administered intravenously, but not exceeding the maximum single dose of 100 mg. The infusion must be administered over a period of not less than 10 minutes.

Administration method

Ibuprofen concentrate for solution for infusion 100 mg/mL in a vial for injection 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 lactated Ringer's solution.

Before administration, the parenteral solution should be inspected visually for particulate matter and discoloration. If visible opaque particles, discoloration, or other foreign particles are observed, the solution must not be used. The shelf life of the reconstituted solution is up to 48 hours at a temperature not exceeding 25 °C.

Children

The medicinal product should be administered to children aged 3 months and older.

Overdose

Symptoms. Symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible. Tinnitus, headache, dizziness, and gastrointestinal bleeding may also occur. Arterial hypertension, acute renal failure, respiratory depression, and coma have been observed rarely (see section "Adverse Reactions").

Treatment. There is no specific antidote; symptomatic treatment should be initiated. Therapeutic management of intoxication is determined by the degree, level, and clinical symptoms, in accordance with standard intensive care practices.

Adverse Reactions

All adverse reactions are listed by system organ class and frequency as follows: 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 available data). The following serious adverse reactions are described in more detail above:

• Cardiovascular thrombotic events – frequency not known: Kounis syndrome;
• Gastrointestinal bleeding, ulceration, and perforation;
• Hepatotoxicity;
• Hypertension;
• Heart failure and edema;
• Renal toxicity and hyperkalemia;
• Anaphylactic reactions;
• Serious skin reactions – very rare: severe cutaneous adverse reactions (SCARs) (including erythema multiforme, exfoliative dermatitis, Stevens–Johnson syndrome, and toxic epidermal necrolysis);

Frequency not known: drug-induced eosinophilia with systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP). Photosensitivity reactions;

• Hematological toxicity.

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, the frequency of adverse reactions observed in the clinical trials of a drug cannot be directly compared with the frequency in the clinical trials of another drug and may not reflect the frequency observed in practice.

Adult Patients

During clinical development, 560 patients received ibuprofen concentrate, 438 patients for pain, and 122 for fever. In pain treatment studies, ibuprofen concentrate for infusion solution was administered intraoperatively and given at doses of 400 mg or 800 mg every 6 hours for 3 days. In fever treatment 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 ibuprofen is gastrointestinal adverse reactions.

Pain Treatment Studies

The adverse reaction frequencies shown in Table 4 were derived from multicenter, controlled clinical trials in postoperative patients comparing ibuprofen concentrate for infusion solution with placebo, in patients who also received morphine on an as-needed basis in the postoperative period.

Table 4

• During these studies, all patients received morphine concomitantly.

Fever studies

Fever studies were conducted in hospitalized patients with fever due to malaria and in hospitalized patients with fever of various causes. Adverse reactions were observed in at least 2 patients receiving ibuprofen concentrate, including abdominal pain and nasal congestion.

In hospitalized patients with fever, the observed adverse reactions are presented in Table 5.

Table 5

Pediatric patients

In controlled clinical studies, 143 patients aged from 6 months received ibuprofen concentrate for solution for infusion 100 mg/mL. The most common adverse reactions (incidence ≥2%) were infusion site pain, vomiting, nausea, anemia, and headache.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System of Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions

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

Incompatibilities

The medicinal product must not be mixed with other medicinal products, except those specified in the section “Method of administration and dosage”.

Packaging

4 mL of concentrate in an ampoule. 3 or 5 ampoules per blister pack in a cardboard box.

8 mL of concentrate in an ampoule. 3 or 5 ampoules per blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer

Abhil Laboratories Private Limited.

Manufacturer's address and place of business

Village Bhagwanpur, Tehsil Dera Bassi, District Sahibzada Ajit Singh Nagar, Punjab – 140507, India