This information is intended for use by health professionals

1. Name of the medicinal product

Ibuprofen 400 mg Solution For Infusion

2. Qualitative and quantitative composition

Each ml of the solution contains 4 mg ibuprofen.

Each 100 ml bag contains 400 mg ibuprofen.

Excipient(s) with known effect: each 100 ml contains 13 mmol (303 mg) sodium.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for infusion.

Clear and colourless solution.

pH: 7.8-8.4

Osmolality: 270-330 mOsm/l.

4. Clinical particulars
4.1 Therapeutic indications

Ibuprofen is indicated in adults for the short-term symptomatic treatment of acute moderate pain, and for the short-term symptomatic treatment of fever, when administration by intravenous route is clinically justified when other routes of administration are not possible.

4.2 Posology and method of administration

Posology

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).

Adequate hydration of the patient should be maintained to minimize the risk of possible adverse reactions at renal level.

Adults

The recommended dose is 400 mg of ibuprofen every 6 to 8 hours as necessary, without exceeding the maximum daily recommended dose of 1200 mg.

This medicinal product is indicated for short-term treatment (a maximum treatment duration of 3 days) and limiting the duration of treatment to the acute symptomatic phase when the oral administration is inappropriate. Patients must switch to oral treatment as soon as this is possible.

Elderly:

No dose reduction is required. However, precautions should be taken when treating elderly patients as they are generally more prone to adverse effects (see section 4.4 and 4.8), and are more likely to have renal, hepatic and cardiovascular dysfunction and to be using concomitant medications. Due to the possibility to suffer from adverse reactions (see section 4.4) it is recommended to monitor these patients. Treatment should be reviewed at regular intervals and discontinued if no benefit is seen or intolerance occurs. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.

Renal impairment:

Precautions should be taken when NSAIDs are used in patients with renal insufficiency.

In patients with mild or moderate renal impairment the initial dose should be reduced and be kept as low as possible for the shortest duration necessary to control symptoms and renal function monitored.

This medicinal product is contraindicated in patients with severe renal insufficiency (see section 4.3).

Hepatic impairment:

Precautions should be taken when NSAIDs are used in this population although differences in the pharmacokinetic profile have not been observed.

Patients with mild or moderate hepatic insufficiency should start the treatment with reduced doses, the dose should be kept as low as possible for the shortest duration necessary and they should be carefully monitored.

This medicinal product is contraindicated in patients with severe hepatic insufficiency (see section 4.3).

Paediatric population

This medicinal product should not be used in children and adolescents. The use of Ibuprofen has not been studied in children and adolescents. Therefore, the safety and efficacy have not been established.

Method of administration

Intravenous use.

This medicinal product should be administered as an intravenous infusion for 30 minutes, see section 6.6.

The remaining solution should be discarded, see section 6.6.

Restricted to hospital use only.

4.3 Contraindications

• Hypersensitivity to the active substance, to other NSAIDs or to any of the excipients listed in section 6.1.

• Patients who have previously had bronchospasm, asthma, rhinitis, angioedema or urticaria associated with acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs).

• Patients with a history of gastrointestinal bleeding or perforation related to previous NSAIDs therapy.

• Active or history of recurrent peptic ulcer/gastrointestinal haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

• Severe hepatic impairment

• Severe renal impairment

• Severe heart failure (NYHA Class IV)

• Cerebrovascular bleeding or other active bleeding.

Conditions involving an increased tendency or active bleeding such as thrombocytopenia.

Unclarified blood-formation disturbances.

• Severe dehydratation (caused by vomiting, diarrhoea or inadequate liquid intake).

• During the third trimester of pregnancy(see section 4.6)

4.4 Special warnings and precautions for use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see gastrointestinal and cardiovascular risks).

The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal (see section 4.2).

Respiratory:

Caution is required if this medicinal product is administered to patients suffering from, or with a previous history of, bronchial asthma, chronic rhinitis or allergic diseases since NSAIDs have been reported to cause bronchospasm, urticaria or angioedema in such patients.

Anaphylactoid Reactions:

As standard practice during intravenous infusion, close patient monitoring is recommended, especially at the beginning of the infusion to detect any anaphylactic reaction caused by the active substance or the excipients.

Severe acute hypersensitivity reactions (e.g. anaphylactic shock) are very rarely observed. At the first signs of a hypersensitivity reaction following the administration of ibuprofen, therapy must be stopped and symptomatic treatment must be established. Medically required measures, in line with the symptoms, must be initiated by specialist personnel.

Other NSAIDs:

The use of Ibuprofen with concomitant NSAIDs, including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

SLE and Mixed Connective Tissue Disease (MCTD):

Some cases of aseptic meningitis have been reported with the use of ibuprofen in patients with systemic lupus erythematosus (SLE). Aseptic meningitis is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases (see section 4.8).

Renal and hepatic impairment:

Ibuprofen should be used with caution in patients with history of renal or hepatic disease and specially during concomitant treatment with diuretics as inhibition of prostaglandins may produce fluid retention and renal function deterioration (see sections 4.3 and 4.8). In case of administration to these patients, the dose of ibuprofen should be keep the lowest as possible and regular monitoring of the renal function should be performed.

In case of dehydratation, suitable liquid intake should be guaranteed, as dehydratation can be a trigger for developing renal failure.

In general regular use of analgesics, especially combination of differents analgesics agents, may lead to long-lasting renal damage with risk of develop renal failure (analgesic nephropathy). Patients at greatest risk of this reaction are elderly patients and those with impaired renal function, heart failure, hepatic dysfunction, those who are being treated with diuretics or ACE inhibitors.

Discontinuation of NSAID therapy is usually followed by recovery to the pre-treatment state (see sections 4.3 and 4.8).

As with other NSAIDs, ibuprofen may produce mild transitory increases of some parameters of the hepatic function, as well as significative increases of transaminases. In case an important increase of these parameters occur, the treatment should be discontinued (see sections 4.2 and 4.3).

Cardiovascular and cerebrovascular effects:

Clinical studies suggest that use of ibuprofen, particularly at a high dose (2400 mg daily), may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g. ≤ 1200 mg daily) is associated with an increased risk of arterial thrombotic events.

Patients with uncontrolled hypertension, congestive heart failure (NYHA II-III), established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen if the doctor considers the benefit/risk balance is favourable and high doses (2400 mg/day) should be avoided. Careful consideration should also be exercised before initiating long-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking), particularly if high doses of ibuprofen (2400 mg/day) are required.

Female fertility impairment:

The use of ibuprofen may impair female fertility affecting ovulation (see section 4.6).

Gastrointestinal:

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8).

Gastrointestinal bleeding, ulceration or perforations which can be fatal have been reported at anytime during the treatment with NSAIDs, with or without warning symptoms or a previous history of serious gastrointestinal events.

The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).

Patients with a history of gastrointestinal toxicity, particularly when elderly, should report inmediately any unusual abdominal symptoms (especially gastrointestinal bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or gastrointestinal bleeding, such as oral corticoids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors (SSRI) or anti-platelet agents such as acetylsalicylic acid (see section 4.5).

When gastrointestinal bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn immediately.

Severe skin reactions:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring within the first month of treatment in the majority of cases. Acute generalised exanthematous pustulosis (AGEP) has been reported in relation to ibuprofen-containing products. Ibuprofen should be discontinued immediately at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Exceptionally, chicken pox can be the origin of severe skin infections and soft tissue complications. So far, the role of NSAIDs in the worsening of these infections can not be discarded. So that, in case of chicken pox administration of ibuprofen should be avoided.

Hematological Effects:

Ibuprofen may temporarily inhibit the blood-platelet function (thrombocyte aggregation), increasing the bleeding time and the risk of haemorrhage.

Patients with coagulation disorders or those undergoing surgery should therefore be monitored. Special medical vigilance is required for use in patients immediately after undergoing major surgery.

Ibuprofen should only be used with particular caution in patients receiving acetylsalicylic acid to inhibit platelet aggregation (see sections 4.5 and 5.1).

Ophthalmological Effects:

Blurred or diminished vision, scotomata, and changes in colour vision have been reported with oral ibuprofen. Discontinue ibuprofen if the patient develops such complaints, and refer the patient for an ophthalmologic examination that includes central visual fields and colour vision testing.

Other special warnings and precautions for use:

NSAIDs may mask the signs of infection.

Masking of symptoms of underlying infections:

Ibuprofen can mask symptoms of infection, which may lead to delayed initiation of appropriate treatment and thereby worsening the outcome of the infection. This has been observed in bacterial community acquired pneumonia and bacterial complications to varicella. When Ibuprofen is administered for fever or pain relief in relation to infection, monitoring of infection is advised. In non-hospital settings, the patient should consult a doctor if symptoms persist or worsen.

In patients in long-term treatment with ibuprofen the renal, hepatic and hematologic function as well as hematic count should be controlled as preventive measure.

Transitory hypoglycaemia has been reported with the use of Trometamol. It is recommended to determinate glucose plasma levels during the treatment.

Prolonged use of painkillers may cause, headache that must not be treated with increased doses of the medicinal product.

Patient should be carefully observed at the beginning of the infusion for anaphylactoid/hypersensitivity reactions to any component of the product. Infusion should be stopped and symptomatic treatment established.

Exceptionally, varicella can cause serious cutaneous and soft tissues infectious complications. To date, the contributing role of NSAIDs in the worsening of these infections cannot be ruled out. Thus, it is advisable to avoid use of Ibuprofen in case of varicella.

Interferences with analytical tests:

• Bleeding time (can be prolongued during 1 day after withdrawn the treatment).

• Blood glucose concentration (may decrease).

• Creatinine clearance (may decrease)

• Hematocrit or hemoglobin (may decrease)

• Blood concentrations of ureic nitrogen and seric concentrations of creatinin and potassium (may increase).

• In hepatic function tests: increase in transaminases values.

Ibuprofen should only be used after strict assessment of the benefit / risk in patients with congenital disorder of porphyrin metabolism (e.g. acute intermittent porphyria).

Through concomitant consumption of alcohol, active substance-related undesirable effects, particularly those that concern the gastrointestinal tract or the central nervous system, may be increased on use of NSAIDs.

Caution is required in patients with certain conditions, which may be made worse:

• In patients who react allergically to other substances, as an increased risk of hypersensitivity reactions occurring also exists for them on use of this medicinal product.

• In patients who suffer from hay fever, nasal polyps or chronic obstructive respiratory disorders as an increased risk exists for them of allergic reaction occurring. These may present as asthma attacks (so-called analgesic asthma), Quincke´s oedema or urticaria.

This medicinal product contains 303 mg sodium per 100 ml, equivalent to 15% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5 Interaction with other medicinal products and other forms of interaction

Other NSAIDs, including COX-2 inhibitors and salicylates:

As a result of synergist effects, the concurrent administration use of two or more NSAIDs may increase the risk of gastrointestinal ulcers and bleeding. Co-administration of ibuprofen with other NSAIDs should therefore be avoided (see section 4.4).

Concomitant use with other NSAIDs should be avoided as it may increase the risk of gastrointestinal ulceration and haemorrhages (see section 4.4).

Acetylsalicylic acid:

Concomitant administration of ibuprofen and acetylsalicylic acid is not generally recommended because of the potential of increased adverse effects.

Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly. Although there are uncertainties regarding extrapolation of these data to the clinical situation, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

Cardiac glycosides (Digoxin):

NSAIDs may exacerbate cardiac failure, reduce glomerular filtration rate and increase plasma levels of cardiac glycosides. Monitoring of serum digoxin is recommended.

Corticosteroids:

Corticoids can also increase the risk of suffer adverse reactions, specially those related with gastrointestinal tract (ulceration or gastrointestinal bleeding (see section 4.4).

Anti-platelet agents (e.g. clopidogrel and tioclopidine):

Increase the risk of gastrointestinal bleeding (see section 4.4). NSAIDs should not be combined with ticlopidine due to the risk of an additive effect in the inhibition of platelet function.

CYP2C9 Inhibitors:

Concomitant administration of ibuprofen with CYP2C9 inhibitors may increase the exposure to ibuprofen (CYP2C9 substrate). In a study with voriconazole and fluconazole (CYP2C9 inhibitors), an increased S(+)- ibuprofen exposure by approximately 80 to 100% has been shown. Reduction of the ibuprofen dose should be considered when potent CYP2C9 inhibitors are administered concomitantly, particularly when high-dose ibuprofen is administered with either voriconazole or fluconazole.

Anticoagulants:

NSAIDs may enhance the effects of anticoagulants, such as warfarin and heparin (see section 4.4). In case of concomitant use, it is recommended to monitor the coagulation levels.

Phenytoin:

Plasmatic levels of phenytoin may be increased in the concomitant treatment with ibuprofen and therefore the risk of toxicity may increase.

Captopril:

Experimental studies indicate that ibuprofen counteracts the effect of captopril of increased sodium excretion.

Selective serotonin reuptake inhibitors (SSRIs):

Can increase the risk of gastrointestinal bleeding (see section 4.4).

Lithium:

Co-administration of ibuprofen with lithium preparations can increase the serum level of these medicinal products. Cheking the serum lithium level is necessary.

Probenecid and sulfinpyrazone:

Medicines which contains probenecid or sulfinpyrazone may retard the excretion of ibuprofen.

Diuretics, ACE inhibitors, beta-blockers and angiotensin II antagonists:

Diuretics and ACE-inhibitors may increase the nephrotoxicity of NSAIDs. NSAIDs may reduce the effect of diuretics and other anti-hypertensives. In patients with renal impairment (e.g. dehydrated patients or elderly patients with renal funtion impaired) concomitant treatment with ACE inhibitors, beta-blockers or angiotensin II antagonists and cyclooxigenase inhibitors may be associated to a deterioration of the renal function, including an acute renal failure which is normally reversible. So that concomitant administration should be done with caution, specially in elderly. Patients should be hydrated and a renal monitorization after starting the concomitant treatment should be considered as well as a periodic monitorization right after.

The concomitant administration of ibuprofen ACE-inhibitors may lead to hyperkalaemia.

Potassium-sparing diuretics:

Concomitant use of ibuprofen and potassium-sparing diuretics may be associated with an increase in the potassium levels, so that it is recommended to control plasmatic levels of this ion.

Methotrexate:

NSAIDs inhibit the tubular secretion of methotrexate and certain metabolic interactions may occur resulting in decreased clearance of methotrexate. Administration of ibuprofen 24 hours before or after administration of methotrexate, it may occur an increase of the methotrexate plasmatic level with the consequent increase in its toxic effect. Therefore, concomitant use of NSAIDs and high doses of methotrexate should be avoided. Also, the potential risk of interactions in low dose treatment with methotrexate should be considered, especially in patients with impaired renal funcion. In combined treatment, renal function should be monitored.

Ciclosporin:

The risk of renal impairment is increased due to concomitant administration with certain NSAIDs. This effect also cannot be ruled out for a combination of ciclosporin with ibuprofen.

Zidovudine:

Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen. Blood counts 1-2 weeks after starting use together are recommended.

Sulfonylureas:

Clinical investigations have demonstrated interactions between NSAIDs and sulfonylureas.

NSAIDs can increase the hypoglycemic effect of sulfonylureas. In the case of simultaneous treatment, monitoring of blood glucosa levels is recommended.

Quinolone antibiotics:

Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

Mifepristone:

NSAIDs should not be administered within 8-12 days after the administration of mifepristone as the effecs of this drug can be reduced.

Baclofen:

Ibuprofen may enhance baclofen toxicity by means of a possible accumulation due to the renal failure caused by ibuprofen.

Pentoxifylline:

In patients receiving treatment with ibuprofen in combination with pentoxifylline it may increase the risk of bleeding, so it is recommended to monitor bleeding time.

Tacrolimus:

Concomitant administration with ibuprofen may increase the risk of nephrotoxicity-

Aminoglycosides:

NSAIDs may enhance nephrotoxicity of aminoglycosides, even more if aminoglycosides have been administered at high doses for long period of time.

Alcohol

The use of ibuprofen in individuals with chronic alcohol consumption (14-20 drinks/week or more) should be avoided due to increased risk of significant GI adverse effects, including bleeding.

Herbal extracts:

Ginkgo biloba may potentiate the risk of bleeding with NSAIDs.

4.6 Fertility, pregnancy and lactation

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after the use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk of cardiac malformations was increased from less than 1% to 1.5% approximately. It seems that the risk increases with the dose and duration of the treatment.

In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period (Section 5.3).

During the first and second trimester of pregnancy, this medicine should not be given unless clearly necessary. If Ibuprofen is used by a woman attempting to conceive, or during the first or second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

• Cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension)

• Renal dysfunction, which may progress to renal failure with oligohydramniosis.

the mother and the neonate, at the end of pregnancy to:

• Possible prolongation of bleeding time due to an anti-aggregating effect, which may occur even at very low doses.

• Inhibition of uterine contractions, resulting in delayed or prolonged labour.

Consequently, ibuprofen is contraindicated during the third trimester of pregnancy.

Breastfeeding

Ibuprofen and its metabolites can pass in low concentrations into the breast milk. No harmful effects to infants are known to date, so for short-term treatment with lower doses interruption of breastfeeding would generally not be necessary. However, it is recommended to interrupt breastfeeding when using higher doses than 1200 mg daily or longer treatment periods due to the potential to inhibit prostaglandin synthesis in the neonate.

Fertility

There is some evidence that drugs which inhibit cyclo-oxygenase / prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment.

4.7 Effects on ability to drive and use machines

The influence of Ibuprofene on the ability to drive and use machines is minor.

Some isolated patients may experience dizziness and fatigue, so that the ability to drive a vehicle and/or use machines can be affected. This applies to a greater extent in combination with alcohol.

4.8 Undesirable effects

Tabulated list of adverse reactions

The undesirable effects possibly related to ibuprofen are listed by organ system classes and frequencies according to the following categories: 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), Not known (frequency cannot be estimated from the available data).

The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, GI perforation or bleeding, sometimes fatal, may occur particularly in the elderly (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (see section 4.4) have been reported following administration. Less frequently, gastritis has been observed. Particularly the risk of gastrointestinal bleeding occurring is dependent on the dose range and the duration of use.

Very rarely have been reported severe hypersensitivity reactions (including infusion site reactions, anaphylactic shock) and serious cutaneous adverse reactions such as bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme and alopecia.

Exacerbation of infection-related inflammations (e.g. development necrotising fasciitis) coinciding with the use of nonsteroidal anti-inflammatory drugs has been described. This is possibly associated with the mechanism of action of the non-steroidal anti-inflammatory drugs.

Photosensitivity, allergic vasculitis and in exceptional cases, severe skin infections and soft-tissue complications may occur during a varicella infection (see section 4.4).

Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.

Clinical studies suggest that use of ibuprofen, particularly at a high dose (2400 mg/day) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

Infections and infestations

Very rare

Exacerbations of infection related inflammations (e.g. development necrotising fasciitis) coinciding with the use of non-steroidal anti-inflammatory drugs has been described. This is possibly associated with the mechanism of action of the non-steroidal anti-inflammatory drugs.

Blood and lymphatic system disorders

Very rare

Disturbances to blood formation (anaemia, agranulocytosis, leucopoenia, thrombocytopenia, and pancytopenia,). First symptoms are: fever, sore throat, superficial mouth wounds, influenza-like complaints, severe lassitude, nosebleeds and skin bleeding.

Immune system disorders

Uncommon

Hypersensitivity reactions with skin rashes and itching, as well as asthma attacks (possibly with drop in blood pressure)

Very rare

Systemic lupus erythematosus, severe hypersensitivity reactions, face oedema, swelling of the tongue, swelling of the internal larynx with constriction of the airways, difficulty breathing, palpitations, hypotension and life threatening shock).

Psychiatric disorders

Uncommon

Anxiety, restlessness

Rare

Psychotic reactions, nervousness, irritability, confusion or disorientation and depression

Nervous system disorders

Very common

Fatigue or sleeplessness, headache, dizziness

Uncommon

Insomnia, agitation, irritability or tiredness

Very rare

Aseptic meningitis (stiff neck, headache, nausea, vomiting, fever or confusion).

Patients with autoimmune disorders (SLE, mixed connective-tissue disease) appear to be predisposed.

Eye disorders

Uncommon

Visual disturbances

Rare

Reversible toxic amblyopia

Ear and labyrinth disorders

Common

Vertigo

Uncommon

Tinnitus

Rare

Hearing disorders

Cardiac disorders

Very rare

Palpitations, heart failure, myocardial infarction

Vascular disorders

Very rare

Arterial hypertension

Respiratory, thoracic and mediastinal disorders

Very rare

Asthma, bronchospasm, dyspnoea and wheezing

Gastrointestinal disorders

Very common

Pyrosis, abdominal pain, nausea, vomiting, flatulence, diarrhoea, constipation and slight gastro-intestinal blood losses that may cause anaemia in exceptional cases

Common

Gastrointestinal ulcers, potentially with bleeding and perforation. Ulcerative stomatitis, exacerbation of colitis and Crohn's disease.

Uncommon

Gastritis

Rare

Esophageal stenosis, exacerbation of diverticular disease, unspecified haemorrhagic colitis.

If gastrointestinal bleeding occurs could cause anaemia and haematemesis

Very rare

Oesophagitis, pancreatitis, formation of intestinal, diaphragm-like strictures

Hepatobiliary disorders

Rare

Jaundice, hepatic dysfunction, hepatic damage, particularly in long-term therapy, acute hepatitis

Not known

Hepatic insufficiency

Skin and subcutaneous tissue disorders

Common

Skin eruption

Uncommon

Urticaria, pruritus, purpura (including allergic purpura), skin rash

Very rare

Bullous or vesicular reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell´s syndrome), erythema multiforme, alopecia.

Photosensitivity reactions and allergic vasculitis.

In exceptional cases, severe skin infections and soft tissues complications in varicella infection (see also 'Infections and infestations')

Not known

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)

Acute generalised exanthematous pustulosis (AGEP),photosensitivity reactions

Musculoskeletal and connective tissue disorders

Rare

Stiff neck

Renal and urinary disorders

Uncommon

Reduced urinary excretion and formation of oedemas, particularly in patients with arterial hypertension or renal insufficiency, nephrotic syndrome, interstitial nephritis that may be accompanied by acute renal insufficiency.

Rare

Renal tissue damage (papillary necrosis), particularly in long-term therapy, increased serum uric acid concentration in the blood

General disorders and administration site conditions

Common

Pain and burning sensation in the administration site

Not known

Site of injection reactions such as swelling, haematoma or bleeding.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Plasmatic half-life in an overdose is 1.5-3 hours.

Symptoms

Most patients who have ingested important quantities of NSAIDs will develop nausea, vomiting, epigastric pain or rarely diarrhoea. Other possible effects are: tinnitus, headache, dizziness, hypotension and gastrointestinal bleeding. In more severe intoxications, toxicity is observed in the central nervous system, exhibit as drowsiness, agitation (occasionally) and disorientation and coma. Sometimes patients develop convulsions. In a severe intoxication it can be developed metabolic acidosis and an increase in the prothrombin time/INR probably due to an interference with the action of circulating coagulation factors. Acute renal and hepatic impairment can be produced. In asthmatic patients exacerbation of asthma is possible.

In serious poisoning metabolic acidosis may occur.

Therapeutic measures

There is no specific antidote available and patients should be initiate symptomatic treatment. The therapeutic possibilities for treatment of intoxication are dictated by the extent, level and clinical symptoms according to the common intensive care practices.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiinflammatory and antirheumatic products, non-steroids; Propionic acid derivatives, ATC code: M01AE01.

Mechanism of action

Ibuprofen is a non-steroidal anti-inflammatory drug that, in conventional animal-experiment inflammation models, has proven to be effective, probably through prostaglandin synthesis inhibition. In humans, ibuprofen has an antipyretic effect, reduces inflammatory-related pain and swelling. Furthermore, ibuprofen reversibly inhibits ADP- and collagen-induced platelet aggregation.

Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly. Some pharmacodynamic studies showed that when a single dose of 400 mg ibuprofen were taken within 8 hours before or within 30 minutes after immediate release acetylsalycilic acid dosing (81 mg), the effect of the acetylsalicylic acid on the thromboxane formation or in the platelet aggregation was reduced.

Although there are uncertainties regarding extrapolation of these data to the clinical situation, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 4.5).

5.2 Pharmacokinetic properties

Absorption

Ibuprofen is administered by intravenous route, so that, no absorption process occurs and the bioavailability of ibuprofen is total.

Distribution

The estimated distribution volume is 0.11 to 0.21 L/kg.

Ibuprofen is extensively bound to plasmatic proteins, mainly albumin.

Biotransformation

Ibuprofen is metabolized in the liver into two inactive metabolites, and those together with the unchanged ibuprofen are excreted by the kidneys either as such or as conjugates.

Elimination

The excretion through the kidneys is fast and complete. The elimination half-life is approximately 2 hours.

Linearity/non-linearity

Ibuprofen shows a linearity in the AUC of the plasmatic concentration-time after a single administration of ibuprofen (in a range of 200-800 mg).

Pharmacokinetic / pharmacodinamic relationship

A correlation between plasmatic levels of ibuprofen, its pharmacodynamic properties and its overall safety profile exists. Ibuprofen pharmacokinetic is stereoselective after an intravenous or oral administration.

The mechanism of action and the pharmacology of intravenous ibuprofen do not differ from the mechanism of oral ibuprofen.

5.3 Preclinical safety data

The subchronic and chronic toxicity of ibuprofen in animal trials showed up mainly in the form of lesions and ulcers in the gastrointestinal tract. In vitro and in vivo studies gave no clinically relevant evidence of the mutagenic potential of ibuprofen. In studies in rats and mice no evidence of carcinogenic effects of ibuprofen was found.

Ibuprofen led to an inhibition of ovulation in rabbits and impaired implantation in various animal species (rabbit, rat, mouse). Experimental studies in rats and rabbits have shown that ibuprofen crosses the placenta. Following the administration of maternotoxic doses, an increased incidence of malformations (ventricular septal defects) occurred in the offspring of rats.

6. Pharmaceutical particulars
6.1 List of excipients

Trometamol

Sodium chloride

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

2 years.

From a microbiological point of view, the product should be used immediately after first opening.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Pack sizes: Packs of 20 and 50 polyolefin bags of 100 ml with an aluminium overwrapping.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Before administration the product should be inspected visually to detect any particle or change in colouration.

The remaining solution should not be used, it should be discarded. For instructions about administration see section 4.2.

The active substance ibuprofen occurs frequently in surface water, any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Dr. Reddy's Laboratories (UK) Ltd.

6 Riverview Road

Beverley

East Yorkshire

HU17 0LD

United Kingdom

8. Marketing authorisation number(s)

PL 08553/0619

9. Date of first authorisation/renewal of the authorisation

06/09/2019

10. Date of revision of the text

01/2021