In children ingestion of more than 400mg/kg may cause symptoms. In adults the dose response effect is less clear cut. The half-life in overdose is 1.5-3 hours.
Symptoms
Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as vertigo, headache, respiratory depression, dyspnoea, drowsiness, occasionally excitation and disorientation or coma. Occasionally patents develop convulsions. In serious poisoning, hypotension, hyperkalaemia, and metabolic acidosis may occur and the prothrombin time / INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.
Management
Should be symptomatic and supportive and include maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.
In children ingestion of more than 400mg/kg may cause symptoms. In adults the dose response effect is less clear cut. The half-life in overdose is 1.5-3 hours.
Symptoms:
Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning metabolic acidosis may occur and the prothrombin time/INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.
Management:
Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.
In case of overdose, get medical help or contact a Poison Control Center right away.
Toxicity
Signs and symptoms of toxicity have generally not been observed at doses below 100 mg/kg in children or adults. However, supportive care may be needed in some cases. Children have been observed to manifest signs and symptoms of toxicity after ingestion of 400 mg/kg or greater.
Symptoms
Most patients who have ingested significant amounts of ibuprofen will manifest symptoms within 4 to 6 hours.
The most frequently reported symptoms of overdose include nausea, vomiting, abdominal pain, lethargy and drowsiness. Central nervous system (CNS) effects include headache, tinnitus, dizziness, convulsion, and loss of consciousness. Nystagmus, metabolic acidosis, hypothermia, renal effects, gastrointestinal bleeding, coma, apnoea, diarrhoea and depression of the CNS and respiratory system have also been rarely reported. Disorientation, excitation, fainting and cardiovascular toxicity, including hypotension, bradycardia and tachycardia have been reported. In cases of significant overdose, renal failure and liver damage are possible. Large overdoses are generally well tolerated when no other drugs are being taken.
Therapeutic measures
Patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose.
Good urine output should be ensured.
Renal and liver function should be closely monitored.
Patients should be observed for at least four hours after ingestion of potentially toxic amounts.
Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition.
Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare.
Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
For additional information about overdosage treatment contact a poison control center at 1-800-222-1222.
No case of overdose has been reported with intravenous ibuprofen in preterm newborn infants.
However, overdose has been described in infants and children administered oral ibuprofen: CNS depression, seizures, gastrointestinal disturbances, bradycardia, hypotension, apnoea, abnormal renal function, haematuria have been observed.
Massive overdose (up to more than 1000 mg/kg) has been reported to induce coma, metabolic acidosis, and transient renal failure. All patients recovered with conventional treatment. Only one recorded death has been published: after an overdose of 469 mg/kg, a 16-month old child developed an apnoeic episode with seizures and a fatal aspiration pneumonia.
The management of ibuprofen overdose is primarily supportive.
The following signs and symptoms have occurred in individuals (not necessarily in premature infants) following an overdose of oral ibuprofen: breathing difficulties, coma, drowsiness, irregular heartbeat, kidney failure, low blood pressure, seizures, and vomiting. There are no specific measures to treat acute overdosage with Ibuprofeno Vent3. The patient should be followed for several days because gastrointestinal ulceration and hemorrhage may occur.
Hypersensitivity to Ibuprofeno Vent3 or any of the constituents in the product.
Ibuprofeno Vent3 is contra-indicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angiodema or urticaria) in response to aspirin or other non-steroidal anti-inflammatory drugs.
Active or previous peptic ulcer (two or more episodes of proven ulceration or bleeding).
History of upper gastrointestinal bleeding or perforation, related to previous NSAID therapy.
Patients with severe hepatic failure, renal failure or severe heart failure (NYHA Class IV).
Use in last trimester of pregnancy.
Hypersensitivity to ibuprofen or any of the excipients in the product.
Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema, or urticaria) in response to aspirin or other non-steroidal anti-inflammatory drugs.
Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).
History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
Severe heart failure (NYHA Class IV), renal failure or hepatic failure
Last trimester of pregnancy
No information provided.
Brufen is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients.
Brufen should not be used in patients who have previously shown hypersensitivity reactions (e.g. asthma, urticaria, angioedema or rhinitis) after taking ibuprofen, aspirin or other NSAIDs.
Brufen is also contraindicated in patients with a history of gastrointestinal bleeding or perforation, related to previous NSAID therapy. Brufen should not be used in patients with active, or history of, recurrent peptic ulcer or gastrointestinal haemorrhage (two or more distinct episodes of proven ulceration or bleeding).
Brufen should not be given to patients with conditions involving an increased tendency to bleeding.
Brufen is contraindicated in patients with severe heart failure (NYHA Class IV), hepatic failure and renal failure.
Brufen is contraindicated during the last trimester of pregnancy.
Ibuprofeno Vent3 is contraindicated in the following patients:
- Hypersensitivity to the active substance or to any of the excipients;
- Life-threatening infection;
- Active bleeding, especially intracranial or gastrointestinal haemorrhage;
- Thrombocytopenia or coagulation defects;
- Significant impairment of renal function;
- Congenital heart disease in which patency of the ductus arteriosus is necessary for satisfactory pulmonary or systemic blood flow (e.g. pulmonary atresia, severe tetralogy of Fallot, severe coarctation of the aorta);
- Known or suspected necrotising enterocolitis;
Ibuprofeno Vent3 is contraindicated in:
None known.
Not applicable
None.
Ibuprofeno Vent3 solution must not be in contact with any acidic solution such as certain antibiotics or diuretics. A rinse of the infusion line must be performed between each product administration.
Hypersensitivity reactions have been reported and these may consist of
a) Non specific allergic reactions and anaphylaxis,
b) Respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea or
c) Various skin reactions, e.g. pruritus, urticaria, angioedema, and more rarely, exfoliative and bullous dermatoses (including epidermal necrolysis, and erythema multiforme).
The list of the following adverse effects relates to those experienced with Ibuprofeno Vent3 at OTC doses, from short-term use. In chronic conditions, under long-term treatment, additional adverse effects may occur.
| Infections and infestations | Very rare: | Aseptic meningitis |
| Blood and lymphatic disorders | Very rare: | Haematopoietic disorders (anaemia, hemolytic anemia, aplastic anemia), leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, nose and skin bleeding. |
| Immune system disorders | Uncommon: | Hypersensitivity reactions with urticaria and pruritus. |
| Very rare: | In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with Ibuprofeno Vent3, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed. Severe hypersensitivity reactions. Symptoms could be: facial, tongue and larynx swelling, dyspnoea, tachycardia, hypotension, (anaphylaxis, angioedema or severe shock). Exacerbation of asthma and bronchospasm. | |
| Psychiatric disorders | Very rare: | Nervousness |
| Nervous System | Uncommon: | Headache |
| Eye disorders | Very rare: | Visual disturbance |
| Ear and labyrinth disorders | Very rare: | Tinnitus and vertigo |
| Cardiac disorders | Very rare: | Cardiac failure |
| Vascular disorders | Very rare: | Hypertension |
| Respiratory, thoracic and mediastinal disorders | Very rare: | Asthma, broncospasm, dyspnoea and wheezing |
| Gastrointestinal disorders | Uncommon: | Abdominal pain, abdominal distension, dyspepsia and nausea. |
| Rare: | Diarrhoea, flatulence, constipation and vomiting. | |
| Very rare: | Peptic ulcer, perforation or gastrointestinal haemorrhage, melaena, haematemesis, sometimes fatal, particularly in the elderly. Exacerbation of ulcerative colitis and Crohn's disease. Mouth ulceration. | |
| Hepatobiliary disorders | Very rare: | Liver disorders, especially in long-term treatment, hepatitis and jaundice. |
| Skin and subcutaneous tissue disorders | Uncommon: | Various skin rashes. |
| Very rare: Not known: | Severe forms of skin reactions such as bullous reactions, including Stevens-Johnson Syndrome, erythema multiforme and toxic epidermal necrolysis can occur. Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) | |
| Renal and urinary disorders | Very rare: | Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema. Haematuria, interstitial nephritis, nephritic syndrome, proteinuria |
| General disorders and administration site conditions | Very rare: | Oedema, peripheral oedema. |
| Investigations | Very rare: | Decreased hematocrit and hemoglobin levels. |
Clinical studies suggest that use of Ibuprofeno Vent3, particularly at a high dose (2400mg/day) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).
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 at www.mhra.gov.uk/yellowcard.
Adverse events which have been associated with Ibuprofen are given below, listed by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to <1/1000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse events are presented in order of decreasing seriousness.
The list of the following adverse events relates to those experienced with ibuprofen at OTC doses for short-term use. In the treatment of chronic conditions, under long-term treatment, additional adverse events may occur.
The adverse events observed most often are gastrointestinal in nature. Adverse events are mostly dose-dependent, in particular the risk of occurrence of gastrointestinal bleeding is dependent on the dosage range and duration of treatment.
Clinical studies suggest that use of ibuprofen, particularly at a high dose 2400mg/day) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke),.
| System Organ Class | Frequency | Adverse Event |
| Blood and Lymphatic System Disorders | Very rare: | Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising. |
| Immune System Disorders |
Uncommon Very rare
Not Known | Hypersensitivity reactions consisting of1: Urticaria and pruritus Severe hypersensitivity reactions. Symptoms could be facial, tongue and laryngeal swelling, dyspnoea, tachycardia, hypotension (anaphylaxis, angioedema or severe shock). Respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea. |
| Nervous System Disorders | Uncommon Very rare | Headache Aseptic meningitis2 |
| Cardiac Disorders | Not Known | Cardiac failure and oedema |
| Vascular Disorders | Not Known | Hypertension |
| Gastrointestinal Disorders | Uncommon Rare Very rare
Not Known | Abdominal pain, nausea, dyspepsia Diarrhoea, flatulence, constipation and vomiting Peptic ulcer, perforation or gastrointestinal haemorrhage, melaena, haematemesis, sometimes fatal, particularly in the elderly. Ulcerative stomatitis, gastritis |
| Hepatobiliary Disorders | Very rare | Liver disorders |
| Skin and Subcutaneous Tissue Disorders | Uncommon Very rare | Various skin rashes Severe forms of skin reactions such as bullous reactions including Stevens-Johnson syndrome, erythema multiforme and toxic epidermal necrolysis can occur. |
| Renal and Urinary Disorders | Very rare
Not Known | Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema. Renal insufficiency |
| Investigations | Very rare | Decreased haemoglobin levels |
Description of Selected Adverse Reactions
1 Hypersensitivity reactions have been reported following treatment with ibuprofen. These may consist of (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract activity comprising asthma, aggravated asthma, bronchospasm, dyspnoea or (c) assorted skin disorders, including rashes of various types pruritus, urticaria, purpura, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).
2The pathogenic mechanism of drug-Induced aseptic meningitis is not fully understood. However, the available data on NSAID-related aseptic meningitis points to a hypersensitivity reaction (due to a temporal relationship with drug intake, and disappearance of symptoms after drug discontinuation). Of note, single cases of symptoms of aseptic meningitis (such as stiff neck, headache, nausea, vomiting, fever or disorientation) have been observed during treatment with ibuprofen, in patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease).
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 at: www.mhra.gov.uk/yellowcard
No information provided.
See WARNINGS Section.
Gastrointestinal disorders: The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, gastrointestinal haemorrhage and exacerbation of colitis and Crohn's disease have been reported following ibuprofen administration. Less frequently, gastritis, duodenal ulcer, gastric ulcer and gastrointestinal perforation have been observed.
Immune system disorders: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reaction and anaphylaxis, (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and, very rarely, erythema multiforme, bullous dermatoses (including Stevens- Johnson syndrome and toxic epidermal necrolysis).
Cardiac disorders and vascular disorders: Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment. Clinical studies suggest that use of ibuprofen, particularly at high dose (2400 mg/day) may be associated with a small increased risk of arterial thrombotic events such as myocardial infarction or stroke .
Infections and infestations: Rhinitis and aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus and mixed connective tissue disease) with symptoms of stiff neck, headache, nausea, vomiting, fever or disorientation.
Exacerbation of infection-related inflammations coinciding with the use of NSAIDs has been described. If signs of an infection occur or get worse during use of Ibuprofen the patient is therefore recommended to go to a doctor without delay.
Skin and subcutaneous tissue disorders: In exceptional cases, severe skin infections and soft-tissue complications may occur during a varicella infection (see also "Infections and infestations")
The following adverse reactions possibly related to ibuprofen and displayed by MedDRA frequency convention and system organ classification. Frequency groupings are classified according to the subsequent conventions: 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) and Not known (cannot be estimated from the available data).
| System organ class | Frequency | Adverse reaction |
| Infections and infestations | Uncommon | Rhinitis |
| Rare | Meningitis aseptic | |
| Blood and lymphatic system disorders | Rare | Leukopenia, thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia , haemolytic anaemia |
| Immune system disorders | Rare | Anaphylactic reaction |
| Psychiatric disorders | Uncommon | Insomnia, anxiety |
| Rare | Depression, confusional state | |
| Nervous system disorders | Common | Headache, dizziness |
| Uncommon | Paraesthesia, somnolence | |
| Rare | Optic neuritis | |
| Eye disorders | Uncommon | Visual impairment |
| Rare | Toxic optic neuropathy | |
| Ear and labyrinth disorders | Uncommon | Hearing impaired , tinnitus, vertigo |
| Respiratory, thoracic and mediastinal disorders | Uncommon | Asthma, bronchospasm, dyspnoea |
| Gastrointestinal disorders | Common | Dyspepsia, diarrhoea, nausea, vomiting, abdominal pain, flatulence, constipation, melaena, haematemesis, gastrointestinal haemorrhage |
| Uncommon | Gastritis, duodenal ulcer, gastric ulcer, mouth ulceration, gastrointestinal perforation | |
| Very rare | Pancreatitis | |
| Not known | Exacerbation of Colitis and Crohn´s disease | |
| Hepatobiliary disorders | Uncommon | Hepatitis, jaundice, hepatic function abnormal |
| Very Rare | Hepatic failure | |
| Skin and subcutaneous tissue disorders | Common | Rash |
| Uncommon | Urticaria, pruritus, purpura, angioedema, photosensitivity reaction | |
| Very rare | Severe forms of skin reactions ( e.g. Erythema multiforme, bullous reactions, including Stevens-Johnson syndrome,and toxic epidermal necrolysis) | |
| Renal and urinary disorders | Uncommon | Nephrotoxity in various forms e.g.Tubulointerstitial nephritis, nephrotic syndrome and renal failure |
| General disorders and administration site conditions | Common | Fatigue |
| Rare | Oedema | |
| Cardiac disorders | Very rare | Cardiac failure, myocardial infarction |
| Vascular disorders | Very rare | Hypertension |
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 at: www.mhra.gov.uk/yellowcard
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared directly to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adult PopulationDuring clinical development, 560 patients were exposed to Ibuprofeno Vent3, 438 in pain and 122 with fever. In the pain studies, Ibuprofeno Vent3 was started intra-operatively and administered at a dose of 400 mg or 800 mg every six hours for up to three days. In the fever studies, Ibuprofeno Vent3 was administered at doses of 100 mg, 200 mg, or 400 mg every four or six hours for up to 3 days. The most frequent type of adverse reaction occurring with oral ibuprofen is gastrointestinal.
Pain StudiesThe incidence rates of adverse reactions listed in the following table were derived from multi-center, controlled clinical studies in post-operative patients comparing Ibuprofeno Vent3 to placebo in patients also receiving morphine as needed for post-operative pain.
Table 1: Post-operative Patients with Adverse Reactions Observed in ≥ 3% of Patients in any Ibuprofeno Vent3 Treatment Group in Pain Studies*
| Event | Ibuprofeno Vent3 | 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%) |
| Hemorrhage | 13 (10%) | 13 (4%) | 16 (6%) |
| Dizziness | 8 (6%) | 13 (4%) | 5 (2%) |
| Edema peripheral | 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%) |
| * All patients received concomitant morphine during these studies. |
Fever studies were conducted in febrile hospitalized patients with malaria and febrile hospitalized patients with varying causes of fever. In hospitalized febrile patients with malaria, the adverse reactions observed in at least two Ibuprofeno Vent3-treated patients included abdominal pain and nasal congestion.
In hospitalized febrile patients (all causes), adverse reactions observed in more than two patients in any given treatment group are presented in the table below.
Table 2: Patients with Adverse Reactions Observed in ≥ 3% of Patients in any Ibuprofeno Vent3 Treatment Group in All-Cause Fever Study
| Event | Ibuprofeno Vent3 | 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%) |
| Hypotension | 0 | 2 (7%) | 3 (10%) | 1 (4%) |
| Diarrhea | 3 (10%) | 3 (10%) | 2 (7%) | 2 (7%) |
| Pneumonia bacterial | 3 (10%) | 1 (3%) | 2 (7%) | 0 |
| Blood LDH increased | 3 (10%) | 2 (7%) | 1 (3%) | 1 (4%) |
| Thrombocythemia | 3 (10%) | 2 (7%) | 1 (3%) | 0 |
| Bacteremia | 4 (13%) | 0 | 0 | 0 |
A total of 143 pediatric patients ages 6 months and older have received Ibuprofeno Vent3 in controlled clinical trials. The most common adverse reactions (incidence greater than or equal to 2%) in pediatric patients treated with Ibuprofeno Vent3 were infusion site pain, vomiting, nausea, anemia and headache.
Data are currently available on approximately 1,000 preterm newborn from both the literature concerning ibuprofen and clinical trials with Ibuprofeno Vent3. Causality of adverse events reported in the preterm newborn is difficult to assess since they may be related to the haemodynamic consequences of the patent ductus arteriosus as well as to direct effects of ibuprofen.
Reported adverse reactions are listed below, by system organ class and by frequency. Frequencies are defined as: very common (> 1/10), common (>1/100, <1/10) and uncommon (>1/1,000, <1/100).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
| Blood and lymphatic system disorders | Very common: Thrombocytopenia, Neutropenia |
| Nervous system disorders | Common: Intraventricular haemorrhage, Periventricular leukomalacia |
| Respiratory, thoracic and mediastinal disorders | Very common: Bronchopulmonary dysplasia* Common: Pulmonary haemorrhage Uncommon: Hypoxemia* |
| Gastrointestinal disorders | Common: Necrotizing enterocolitis, Intestinal perforation Uncommon: Gastrointestinal haemorrhage Unknown: Gastric perforation |
| Renal and urinary disorders | Common: Oliguria, Fluid retention, Haematuria Uncommon: Acute renal failure |
| Investigations | Very Common: Blood creatinine increased, Blood sodium decreased |
| * see below | |
In a clinical curative trial involving 175 preterm newborn infants less than 35 weeks of gestational age, the incidence of bronchopulmonary dysplasia at 36 weeks post-conceptional age was 13/81 (16%) for indomethacin versus 23/94 (24%) for ibuprofen.
In a clinical trial where Ibuprofeno Vent3 was administered prophylactically during the first 6 hours of life, severe hypoxemia with pulmonary hypertension was reported in 3 newborn infants less than 28 weeks of gestational age. This occurred within one hour of the first infusion and was reversed within 30 minutes after the inhalation of nitric oxide. There have also been post-marketing reports of pulmonary hypertension where Ibuprofeno Vent3 was administered to premature neonates in the therapeutic setting.
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
United Kingdom
Website: www.mhra.gov.uk/yellowcard
Ireland
HPRA Pharmacovigilance
Earlsfort Terrace
Dublin 2
Ireland
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail: [email protected]
Clinical Trials ExperienceThe most frequently reported adverse events with Ibuprofeno Vent3 were as shown in Table 1.
Table 1. Adverse Events within 30 Days of Therapy in the Multicenter Study*
| Adverse Event | % Incidence | |
| Ibuprofeno Vent3 | Placebo | |
| Sepsis | 43 | 37 |
| Anemia | 32 | 25 |
| Total Bleeding** | 32 | 29 |
| Intraventricular Hemorrhage, Grades 1/2 | 15 | 13 |
| Intraventricular Hemorrhage, Grades 3/4 | 15 | 10 |
| Other Bleeding | 6 | 13 |
| Intraventricular Hemorrhage, All Grades | 29 | 24 |
| Apnea | 28 | 26 |
| Gastrointestinal Disorders | 22 | 18 |
| non-Necrotizing Enterocolitis | ||
| Total Renal Events** | 21 | 15 |
| Renal Failure | 1 | 3 |
| Renal Insufficiency, Impairment | 6 | 4 |
| Urine Output Reduced | 3 | 1 |
| Blood Creatinine Increased | 3 | 1 |
| Blood Urea Increased with Hematuria | 1 | 1 |
| Blood Urea Increased | 7 | 4 |
| Respiratory Infection | 19 | 13 |
| Skin Lesion/Irritation | 16 | 6 |
| Hypoglycemia | 12 | 6 |
| Hypocalcemia | 12 | 9 |
| Respiratory Failure | 10 | 4 |
| Urinary Tract Infection | 9 | 4 |
| Adrenal Insufficiency | 7 | 1 |
| Hypernatremia | 7 | 4 |
| Edema | 4 | 0 |
| Atelectasis | 4 | 1 |
| * Within 30 days of therapy, with an event rate greater on Ibuprofeno Vent3 than on placebo, and greater than 2 events on Ibuprofeno Vent3. ** A given subject may have experienced more than one specific event within these adverse event categories. Only the most severe grade of IVH counted for a given subject. |
Compared to placebo, there was a small decrease in urinary output in the ibuprofen group on days 2-6 of life, with a compensatory increase in urine output on day 9. In other studies, adverse events classified as renal insufficiency including oliguria, elevated BUN, elevated creatinine, or renal failure were reported in ibuprofen treated infants.
Additional Adverse EventsThe adverse events reported in the multicenter study and of unknown association include tachycardia, cardiac failure, abdominal distension, gastroesophageal reflux, gastritis, ileus, inguinal hernia, injection site reactions, cholestasis, various infections, feeding problems, convulsions, jaundice, hypotension, and various laboratory abnormalities including neutropenia, thrombocytopenia, and hyperglycemia.
Post-Marketing ExperienceThe following adverse reactions have been identified from spontaneous post-marketing reports or published literature: gastrointestinal perforation, necrotizing enterocolitis, and pulmonary hypertension. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency, or establish a causal relationship to drug exposure.
No relevant information additional to that already contained elsewhere in the SmPC.
No relevant information, additional to that contained elsewhere in the SPC.
None stated.
There are no preclinical data considered relevant to clinical safety beyond data included in other sections of this Summary of Product Characteristics. With the exception of an acute toxicity study, no further studies have been carried out in juvenile animals with Ibuprofeno Vent3.
GSL
For the relief of mild to moderate pain including rheumatic and muscular pain, backache, neuralgia, migraine, headache, dental pain, dysmenorrhoea, feverishness and for the relief of the symptoms of cold and influenza.
For the relief of migraine-headaches, backache, dental pain, neuralgia and period pains as well as rheumatic and muscular pains.
Ibuprofeno Vent3 relieves pain and reduces inflammation and temperature as well as relieving headaches and other types of pain. It also relieves cold and flu symptoms.
PurposePain reliever/fever reducer
UsesIbuprofeno Vent3 is indicated for its analgesic and anti-inflammatory effects in the treatment of rheumatoid arthritis (including juvenile rheumatoid arthritis or Still's disease), ankylosing spondylitis, osteoarthritis and other non-rheumatoid (seronegative) arthropathies.
In the treatment of non-articular rheumatic conditions, Ibuprofeno Vent3 is indicated in periarticular conditions such as frozen shoulder (capsulitis), bursitis, tendinitis, tenosynovitis and low back pain; Ibuprofeno Vent3 can also be used in soft-tissue injuries such as sprains and strains.
Ibuprofeno Vent3 is also indicated for its analgesic effect in the relief of mild to moderate pain such as dysmenorrhoea, dental and post-operative pain and for symptomatic relief of headache including migraine headache.
Ibuprofeno Vent3 is indicated in adults and pediatric patients six months and older for the:
Treatment of a haemodynamically significant patent ductus arteriosus in preterm newborn infants less than 34 weeks of gestational age.
Ibuprofeno Vent3 is indicated to close a clinically significant patent ductus arteriosus (PDA) in premature infants weighing between 500 and 1500 g, who are no more than 32 weeks gestational age when usual medical management (e.g., fluid restriction, diuretics, respiratory support, etc.) is ineffective. The clinical trial was conducted among infants with an asymptomatic PDA. However, the consequences beyond 8 weeks after treatment have not been evaluated; therefore, treatment should be reserved for infants with clear evidence of a clinically significant PDA.
Pharmacotherapeutic group: Propionic acid derivatives.
ATC Code: M01AE
Ibuprofeno Vent3 is a phenylpropionic acid derivative NSAID that has demonstrated its efficacy by inhibition of prostaglandin synthesis. In humans, Ibuprofeno Vent3 reduces inflammatory pain, swelling and fever. Furthermore, Ibuprofeno Vent3 reversibly inhibits platelet aggregation.
Experimental data suggest that Ibuprofeno Vent3 may competitively inhibit the effect of low dose aspirin (acetylsalicylic acid) on platelet aggregation when they are dosed concomitantly. Some pharmacodynamics studies show that when single doses of Ibuprofeno Vent3 400mg were taken within 30 min after immediate release aspirin (acetylsalicylic acid) dosing (81 mg), a decreased effect of aspirin (acetylsalicylic acid) on the formation of thromboxane or platelet aggregation occurred. Although there are uncertainties regarding extrapolation of these data to the clinical situation, the possibility that regular, long-term use of Ibuprofeno Vent3 may reduce the cardioprotective effect of low-dose aspirin (acetylsalicylic acid) cannot be excluded. No clinically relevant effect is considered to be likely for occasional Ibuprofeno Vent3 use.
ATC Code: M01AE01
Ibuprofen is a propionic acid derivative NSAID that has demonstrated its efficacy by inhibition of prostaglandin synthesis. In humans, ibuprofen reduces inflammatory pain, swellings and fever. Furthermore, ibuprofen reversibly inhibits platelet aggregation.
Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose aspirin (acetylsalicylic acid) on platelet aggregation when they are dosed concomitantly. Some pharmacodynamics studies show that when single doses of ibuprofen 400mg were taken within 8 h before or within 30 min after immediate release aspirin dosing (81mg), a decreased effect of (acetylsalicylic acid) on the formation of thromboxane or platelet aggregation occurred. 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.
Pharmacotherapeutic classification: Anti-inflammatory and antirheumatic products, nonsteroidal; propionic acid derivatives.
ATC code: M01AE01
Ibuprofen is a propionic acid derivative with analgesic, anti-inflammatory and antipyretic activity. The drug's therapeutic effect as an NSAID is thought to result from its inhibitory effect on the enzyme cyclo-oxygenase, which results in a marked reduction in prostaglandin synthesis.
Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. Some pharmacodynamic studies show that when single doses of ibuprofen 400mg were taken within 8 hours before or within 30 minutes after immediate release aspirin dosing (81mg), a decreased effect of aspirin on the formation of thromboxane or platelet aggregation occurred. 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.
Pharmacotherapeutic group: other cardiac preparations, ATC code: C01 EB16
Ibuprofen is a NSAID that possesses anti-inflammatory, analgesic and antipyretic activity. Ibuprofen is a racemic mixture of S(+) and R(-) enantiomers. In vivo and in vitro studies indicate that the S(+) isomer is responsible for the clinical activity. Ibuprofen is a non selective inhibitor of cyclo-oxygenase, leading to reduced synthesis of prostaglandins.
Since prostaglandins are involved in the persistence of the ductus arteriosus after birth, this effect is believed to be the main mechanism of action of ibuprofen in this indication.
In a dose-response study of Ibuprofeno Vent3 in 40 preterm newborn infants, the ductus arteriosus closure rate associated to the 10-5-5 mg/kg dose regimen was 75% (6/8) in neonates of 27-29 weeks' gestation and 33% (2/6) in neonates of 24-26 weeks' gestation.
Prophylactic use of Ibuprofeno Vent3 in the first 3 days of life (starting within 6 hours of birth) in preterm newborn infants less than 28 weeks of gestational age was associated with increased incidence of renal failure and pulmonary adverse events including hypoxia, pulmonary hypertension, pulmonary haemorrhage, as compared to curative use. Conversely, a lower incidence of neonatal grade III-IV intraventricular haemorrhage and of surgical ligation was associated with prophylactic use of Ibuprofeno Vent3.
Ibuprofeno Vent3 is rapidly absorbed following administration and is rapidly distributed throughout the whole body. The excretion is rapid and complete via the kidneys.
Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an empty stomach. When taken with food, peak levels are observed after 1 to 2 hours. These times may vary with different dosage forms.
The half life of Ibuprofeno Vent3 is about 2 hours.
In limited studies, Ibuprofeno Vent3 appears in the breast milk in very low concentrations.
Ibuprofen is rabidly absorbed following administration and is rapidly distributed throughout the whole body. The excretion is rapid and complete via the kidneys.
Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an empty stomach. When taken with food, peak levels are observed after 1 to 2 hours. These times may vary with different dosage forms.
Elimination half-life is approximately 2 hours.
In limited studies, ibuprofen appears in the breast milk in very low concentrations.
The pharmacokinetic profile of Ibuprofeno Vent3 compared with that of conventional-release 400mg tablets showed that the sustained-release formulation reduced the peaks and troughs characteristic of the conventional-release tablets and gave higher levels at 5, 10, 15 and 24 hours. Compared with conventional-release tablets, the area under the plasma concentration time curve for sustained-release tablets was almost identical.
Both mean plasma profiles and the pre-dose plasma levels showed no major differences between the young and elderly age groups. In several studies, Ibuprofeno Vent3 produced a double peak plasma profile when taken under fasting conditions. The elimination half-life of ibuprofen is approximately 2 hours. Ibuprofen is metabolised in the liver to two inactive metabolites and these, together with unchanged ibuprofen, are excreted by the kidney either as such or as conjugates. Excretion by the kidney is both rapid and complete. Ibuprofen is extensively bound to plasma proteins.
Ibuprofen is a racemic mixture of [-]R- and [+]S-isomers. In vivo and in vitro studies indicate that the [+]S-isomer is responsible for clinical activity. The [-]R-form, while thought to be pharmacologically inactive, is slowly and incompletely (~60%) interconverted into the active [+]S species in adults. The [-]R-isomer serves as a circulating reservoir to maintain levels of active drug. The pharmacokinetic parameters of Ibuprofeno Vent3 determined in a study with volunteers are presented below.
Table 4: Pharmacokinetic Parameters of Intravenous Ibuprofen
| 400 mg* Ibuprofeno Vent3 Mean (CV%) | 800 mg* Ibuprofeno Vent3 Mean (CV%) | |
| Number of Patients | 12 | 12 |
| AUC (mcg•h/mL) | 109.3 (26.4) | 192.8 (18.5) |
| Cmax (mcg/mL) | 39.2 (15.5) | 72.6 (13.2) |
| KEL (1/h) | 0.32 (17.9) | 0.29 (12.8) |
| T½ (h) | 2.22 (20.1) | 2.44 (12.9) |
| AUC = Area-under-the-curve Cmax = Peak plasma concentration CV = Coefficient of Variation KEL = First-order elimination rate constant T½ = Elimination half-life * = 60 minute infusion time |
The pharmacokinetic parameters of Ibuprofeno Vent3 determined in a study with febrile pediatric patients are presented in Table 5. It was observed that the median Tmax was at the end of the infusion and that Ibuprofeno Vent3 had a shorter elimination half-life in pediatric patients compared to adults. The volume of distribution and clearance increased with age.
Table 5: Pharmacokinetic Parameters of 10 mg/kg Intravenous Ibuprofen, Pediatric Patients, by Age Group
| 6 months to < 2 years Mean (CV%) | 2 years to < 6 years Mean (CV%) | 6 years to 16 years Mean (CV%) | |
| Number of Patients | 5 | 12 | 25 |
| AUC (mcgh/mL) | 71.1 (37.1) | 79.2 (37.0) | 80.7 (36.9) |
| Cmax (mcg/mL) | 59.2 (34.8) | 64.2 (34.3) | 61.9 (26.6) |
| Tmax (min)* | 10 (10-30) | 12 (10-46) | 10 (10-40) |
| T½ (h) | 1.8 (29.9) | 1.5 (41.8) | 1.55 (26.4) |
| Cl (mL/h) | 1172.5 (38.9) | 1967.3 (56.0) | 4878.5 (71.0) |
| Vz (mL) | 2805.7 (20.1) | 3695.8 (30.0) | 10314.2 (67.4) |
| Cl/WT# (mL/hr/kg) | 133.7 (58.6) | 130.1 (82.4) | 109.2 (41.6) |
| Vz/WT# (mL/kg) | 311.2 (35.4) | 227.2 (41.7) | 226.8 (30.4) |
| *Median (minimum-maximum) #WT: body weight (kg) |
Ibuprofen, like most NSAIDs, is highly protein bound ( > 99% bound at 20 mcg/mL). Protein binding is saturable, and at concentrations > 20 mcg/mL binding is nonlinear. Based on oral dosing data, there is an age- or fever-related change in volume of distribution for ibuprofen.
Distribution
Although a great variability is observed in the premature population, peak plasma concentrations are measured around 35-40 mg/l after the initial loading dose of 10 mg/kg as well as after the last maintenance dose, whatever gestational and postnatal age. Residual concentrations are around 10-15 mg/l 24 hours after the last dose of 5 mg/kg.
Plasma concentrations of the S-enantiomer are much higher than those of the R-enantiomer, which reflects a rapid chiral inversion of the R- to the S-form in a proportion similar to adults (about 60%).
The apparent volume of distribution is on average 200 ml/kg (62 to 350 according to various studies). The central volume of distribution may depend on the status of the ductus and decrease as the ductus closes.
In vitro studies suggest that, similarly to other NSAIDs, ibuprofen is highly bound to plasma albumin, although this seems to be significantly lower (95 %) compared with adult plasma (99 %). Ibuprofen competes with bilirubin for albumin binding in newborn infant serum and, as a consequence, the free fraction of bilirubin may be increased at high ibuprofen concentrations.
Elimination
Elimination rate is markedly lower than in older children and adults, with an elimination half-life estimated at approximately 30 hours (16-43). The clearance of both enantiomers increases with gestational age, at least in the range of 24 to 28 weeks.
PK-PD relationship
In preterm newborns ibuprofen significantly reduced plasma concentrations of prostaglandins and their metabolites, particularly PGE2 and 6-keto-PGF-1-alpha. Low levels were sustained up to 72 hours in neonates who received 3 doses of ibuprofen, whereas subsequent re-increases were observed at 72 hours after only 1 dose of ibuprofen.
Caution is required in patients with certain conditions:
- Systemic lupus erythematosus as well as those with mixed connective tissue disease due to increased risk of aseptic meningitis.
- Gastrointestinal disorders and chronic inflammatory intestinal disease as these conditions may be exacerbated (ulcerative colitis, Crohn's disease).
- Caution is required prior to starting treatment in patients with a history of hypertension and or heart/failure. Oedema, hypertension and/or cardiac impairment as renal function may deteriorate and/or fluid retention occur.
- Renal impairment as renal function may deteriorate.
- Hepatic dysfunction.
Undesirable effects may be minimised by using the minimum effective dose for the shortest possible duration to control symptoms (see GI and cardiovascular risks below).
The elderly are at increased risk of the serious consequences of adverse reactions especially gastrointestinal bleeding and perforation which may be fatal.
Bronchospasm may be precipitated in patients suffering from or with a previous history of bronchial asthma or allergic disease.
Use with concomitant NSAIDs including cyclo-oxygenase-2 specific inhibitors should be avoided .
Cardiovascular and cerebrovascular effects
Clinical studies suggest that use of Ibuprofeno Vent3, particularly at high doses (2400 mg/day) 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 Ibuprofeno Vent3 (e.g. ≤1200mg 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 Ibuprofeno Vent3 after careful consideration 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 Ibuprofeno Vent3 (2400 mg/day) are required.
There is some evidence that drugs, which inhibit cyclooxygenase/ prostaglandin synthesis, may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment.
Gastro-intestinal (GI) bleeding, ulceration, or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI effects (including ulcerative colitis, Crohn's disease).
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation , and in the elderly. These patients should commence treatment on the lowest dose available.
Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.
Caution should be advised in patients receiving concomitant medications which could increase the risk of gastrotoxicity or bleeding, such as corticosteroids, or anticoagulants such as warfarin, selective serotonin uptake inhibitors or anti-platelet agents such as aspirin.
Where GI bleeding or ulceration occurs in patients receiving Ibuprofeno Vent3, the treatment should be withdrawn immediately.
Dermatological
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. Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Ibuprofeno Vent3 should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Patients with rare hereditary problems of fructose intolerance should not take this medicine as this product contains sucrose.
Each tablet contains 67mg of sucrose. This should be taken into account in patients with diabetes mellitus.
There is a risk of renal impairment in dehydrated children and adolescents, between the ages of 12-18 year olds.
The label will include:
12-18 years: if symptoms worsen, or persist for more than 3 days, or you get new symptoms consult your doctor.
Adults: if symptoms worsen, or persist for more than 10 days, or you get new symptoms consult your pharmacist or doctor.
Read the enclosed leaflet before taking this product.
Do not take if you:
- have ever had a stomach ulcer, perforation or bleeding
- are allergic to Ibuprofeno Vent3 (or anything else in this medicine), aspirin or other related painkillers
- are taking other NSAID painkillers, or aspirin with a daily dose above 75mg
- are in the last 3 months of pregnancy.
Speak to a pharmacist or your doctor before taking if you:
- have asthma, diabetes, high cholesterol, high blood pressure, had a stroke, heart, liver, kidney or bowel problems
- are a smoker
- are pregnant
The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.
Respiratory:
Bronchospasm may be precipitated in patients suffering from, or with a previous history of, bronchial asthma or allergic disease.
Other NSAIDs:
The use of Ibuprofen with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.
SLE and mixed connective tissue disease:
Systemic lupus erythematosus as well as those with mixed connective tissue disease - increased risk of aseptic meningitis
Renal:
Renal impairment as renal function may further deteriorate.
There is a risk of renal impairment in dehydrated children and adolescents
Hepatic:
Hepatic dysfunction
Cardiovascular and cerebrovascular effects:
Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.
Clinical studies suggest that use of ibuprofen, particularly at a high dose (2400mg/day) 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. ≤1200mg/day) 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 after careful consideration 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.
Impaired female fertility:
There is limited evidence that drugs which inhibit cyclo-oxygenase/ prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible upon withdrawal of treatment.
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.
GI bleeding, ulceration or perforation, which can be fatal has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of GI events.
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation , and in the elderly. These patients should commence treatment on the lowest dose available.
Patients with a history of GI toxicity, particularly the elderly, should report any unusual abdominal symptoms (especially GI 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 bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin.
When GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn.
Dermatological:
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. Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Ibuprofen should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Advice for patients with sugar-related disorders:
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Advice for patients on a controlled sodium diet:
This medicinal product contains 1.1 mmol (or 25.3 mg) of sodium per 2 doses (2 tablets). To be taken into consideration by patients on a controlled sodium diet.
The leaflet will include:
The quantity of sodium contained in 2 tablets is approximately 1.1mmol, ie about 25.3 mg. This quantity is to be taken into consideration by patients on a controlled sodium diet.
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
The label will include:
Read the enclosed leaflet before taking this product
Do not take if you:
- have (or have had two or more episodes of ) a stomach ulcer, perforation or bleeding
- are allergic to ibuprofen, to any of the ingredients, or to aspirin or other related painkillers
- are taking other NSAID pain killers or aspirin with a daily dose above 75mg
Speak to a pharmacist or your doctor before taking if you:
- have or have had asthma, diabetes, high cholesterol, high blood pressure, a stroke, heart, liver, kidney or bowel problems
- Are a smoker
- Are pregnant
If symptoms persist or worsen, or if new symptoms occur, consult your doctor or pharmacist.
WARNINGSAllergy alert: Ibuprofen may cause a severe allergic reaction, especially in people allergic to aspirin. Symptoms may include:
If an allergic reaction occurs, stop use and seek medical help right away.
Stomach bleeding warning: This product contains an NSAID, which may cause severe stomach bleeding. The chance is higher if you:
Do not use
Ask a doctor before use if
Ask a doctor or pharmacist before use if you are
When using this product
Stop use and ask a doctor if
If pregnant or breast-feeding,
ask a health professional before use. It is especially important not to use ibuprofen during the last 3 months of pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery.
Keep out of reach of children.
PRECAUTIONSSee WARNINGS Section above.
). As with other NSAIDs, ibuprofen may mask the signs of infection.
The use of Brufen with concomitant NSAIDs, including cyclooxygenase-2 selective inhibitors, should be avoided due to the increased risk of ulceration or bleeding.
Elderly
The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal.
Paediatric population
There is a risk of renal impairment in dehydrated children and adolescents.
Gastrointestinal bleeding, ulceration and perforation
GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation , and in the elderly.).
Patients with a history of gastrointestinal disease, particularly when elderly, should report 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 bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin.
When GI bleeding or ulceration occurs in patients receiving Brufen, the treatment should be withdrawn.
NSAIDs should be given with care to patients with a history of ulcerative colitis or Crohn's disease as these conditions may be exacerbated.
Respiratory disorders and hypersensitivity reactions
Caution is required if Brufen 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 precipitate bronchospasm, urticaria or angioedema in such patients.
Cardiac, renal and hepatic impairment
The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure.).
Brufen should be given with care to patients with a history of heart failure or hypertension since oedema has been reported in association with ibuprofen administration.
Cardiovascular and cerebrovascular effects
Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.
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 such as myocardial infarction or stroke. Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g. ≤ 1200mg/day) 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 after careful consideration and high doses (2400mg/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 (2400mg/day) are required.
Renal effects
Caution should be used when initiating treatment with ibuprofen in patients with considerable dehydration.
As with other NSAIDs, long-term administration of ibuprofen has resulted in renal papillary necrosis and other renal pathologic changes. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependant reduction in prostaglandin formation and, secondarily, in renal blood flow, which may cause renal failure. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pre-treatment state.
SLE and mixed connective tissue disease
).
Dermatological effects
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. 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. Brufen should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Haematological effects
Ibuprofen, like other NSAIDs, can interfere with platelet aggregation and prolong bleeding time in normal subjects.
Aseptic meningitis
Aseptic meningitis has been observed on rare occasions in patients on ibuprofen therapy. Although it is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not have an underlying chronic disease.
Impaired female fertility
The use of Brufen may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Brufen should be considered.
WARNINGSIncluded as part of the PRECAUTIONS section.
PRECAUTIONS Cardiovascular Thrombotic EventsClinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as ibuprofen, increases the risk of serious gastrointestinal (GI) events.
Status Post Coronary Artery Bypass Graft (CABG) SurgeryTwo large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG.
Post-MI PatientsObservational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of Ibuprofeno Vent3 in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If Ibuprofeno Vent3 is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
Gastrointestinal Bleeding, Ulceration, And PerforationNSAIDs, including ibuprofen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can 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 on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months and in about 2%-4% of patients treated for one year. However, even short-term therapy is not without risk.
Risk Factors For GI Bleeding, Ulceration And PerforationPatients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these 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; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.
Strategies to Minimize the GI Risks in NSAID-treated patients:
Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs, including ibuprofen.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms).If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue Ibuprofeno Vent3 immediately, and perform a clinical evaluation of the patient.
HypertensionNSAIDs, including Ibuprofeno Vent3, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs.
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
Heart Failure And EdemaThe Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of ibuprofen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]).
Avoid the use of Ibuprofeno Vent3 in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If Ibuprofeno Vent3 is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
Renal Toxicity And Hyperkalemia Renal ToxicityLong-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of Ibuprofeno Vent3 in patients with advanced renal disease. The renal effects of Ibuprofeno Vent3 may hasten the progression of renal dysfunction in patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating Ibuprofeno Vent3. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of Ibuprofeno Vent3. Avoid the use of Ibuprofeno Vent3 in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If Ibuprofeno Vent3 is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
HyperkalemiaIncreases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemicÂhypoaldosteronism state.
Anaphylactic ReactionsIbuprofen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to ibuprofen and in patients with aspirin-sensitive asthma.
Seek emergency help if anaphylactic reaction occurs.
Exacerbation Of Asthma Related To Aspirin SensitivityA subpopulation 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. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, Ibuprofeno Vent3 is contraindicated in patients with this form of aspirin sensitivity. When Ibuprofeno Vent3 is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
Serious Skin ReactionsNSAIDs, including ibuprofen, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of Ibuprofeno Vent3 at the first appearance of skin rash or any other sign of hypersensitivity. Ibuprofeno Vent3 is contraindicated in patients with previous serious skin reactions to NSAIDs.
Premature Closure Of Fetal Ductus ArteriosusIbuprofen may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Ibuprofeno Vent3, in pregnant women starting at 30 weeks of gestation (third trimester).
Hematologic ToxicityAnemia has occurred in NSAID-treated patients. This may be due to occult or gross GI blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with Ibuprofeno Vent3 has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including Ibuprofeno Vent3 may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorder, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding.
Ibuprofeno Vent3 must be diluted prior to use. Infusion of the drug product without dilution can cause hemolysis.
Masking Of Inflammation And FeverThe pharmacological activity of Ibuprofeno Vent3 in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.
Laboratory MonitoringBecause serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically.
Ophthalmological EffectsBlurred or diminished vision, scotomata, and changes in color vision have been reported with oral ibuprofen. Discontinue ibuprofen if a patient develops such complaints, and refer the patient for an ophthalmologic examination that includes central visual fields and color vision testing.
Aseptic MeningitisAseptic meningitis with fever and coma has been observed in patients on oral ibuprofen therapy. Although it is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not have underlying chronic disease. If signs or symptoms of meningitis develop in a patient on ibuprofen, give consideration to whether or not the signs or symptoms are related to ibuprofen therapy.
Patient Counseling InformationAdvise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Patients, families, or their caregivers should be informed of the following information before initiating therapy with Ibuprofeno Vent3 and periodically during the course of ongoing therapy.
Cardiovascular Thrombotic EventsAdvise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately.
Gastrointestinal Bleeding, Ulceration, And PerforationAdvise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding.
HepatotoxicityInform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop Ibuprofeno Vent3 and seek immediate medical therapy.
Heart Failure And EdemaAdvise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur.
Anaphylactic ReactionsInform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur.
Serious Skin ReactionsAdvise patients to stop Ibuprofeno Vent3 immediately if they develop any type of rash and to contact their healthcare provider as soon as possible.
Female FertilityAdvise females of reproductive potential who desire pregnancy that NSAIDs, including Ibuprofeno Vent3, may be associated with a reversible delay in ovulation
Fetal ToxicityInform pregnant women to avoid use of Ibuprofeno Vent3 and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus.
Avoid Concomitant Use Of NSAIDsInform patients that the concomitant use of Ibuprofeno Vent3 with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.
Use Of NSAIDS And Low-Dose AspirinInform patients not to use low-dose aspirin concomitantly with Ibuprofeno Vent3 until they talk to their healthcare provider.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility CarcinogenesisLong-term studies in animals to evaluate the carcinogenic potential of ibuprofen have not been conducted.
MutagenesisIn published studies, ibuprofen was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay).
Impairment Of FertilityIn a published study, dietary administration of ibuprofen to male and female rats 8-weeks prior to and during mating at dose levels of 20 mg/kg (0.06-times the MRHD based on body surface area comparison) did not impact male or female fertility or litter size.
In other studies, adult mice were administered ibuprofen intraperitoneally at a dose of 5.6 mg/kg/day (0.0085-times the MRHD based on body surface area comparison) for 35 or 60 days in males and 35 days in females. There was no effect on sperm motility or viability in males but decreased ovulation was reported in females.
Use In Specific Populations Pregnancy Risk SummaryUse of NSAIDs, including Ibuprofeno Vent3, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Ibuprofeno Vent3, in pregnant women starting at 30 weeks gestation (third trimester).
There are no adequate and well-controlled studies of Ibuprofeno Vent3 in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In published animal reproduction studies, there were no clear developmental effects at doses up to 0.4-times the maximum recommended human dose (MRHD) in the rabbit and 0.5-times in the MRHD rat when dosed throughout gestation. In contrast, an increase in membranous ventricular septal defects was reported in rats treated on Gestation Days 9 & 10 with 0.8-times the MRHD. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as ibuprofen, resulted in increased pre-and post-implantation loss. Advise a pregnant woman of the potential risk to a fetus.
Clinical ConsiderationsLabor or Delivery
There are no studies on the effects of Ibuprofeno Vent3 during labor or delivery. In animal studies, NSAIDs, including ibuprofen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
Animal DataIn a published study, female rabbits given 7.5, 20, or 60 mg/kg ibuprofen (0.04, 0.12, or 0.36-times the maximum recommended human daily dose of 3200 mg of ibuprofen based on body surface area) from Gestation Days 1 to 29, no clear treatment-related adverse developmental effects were noted. This dose was associated with significant maternal toxicity (stomach ulcers, gastric lesions). In the same publication, female rats were administered 7.5, 20, 60, 180 mg/kg ibuprofen (0.02, 0.06, 0.18, 0.54-times the maximum daily dose) did not result in clear adverse developmental effects. Maternal toxicity (gastrointestinal lesions) was noted at 20 mg/kg and above.
In a published study, rats were orally dosed with 300 mg/kg ibuprofen (0.912-times the maximum human daily dose of 3200 mg based on body surface area) during Gestation Days 9 and 10 (critical time points for heart development in rats). Ibuprofen treatment resulted in an increase in the incidence of membranous ventricular septal defects. This dose was associated with significant maternal toxicity including gastrointestinal toxicity. One incidence each of a membranous ventricular septal defect and gastroschisis was noted in fetuses from rabbits treated with 500 mg/kg (3-times the maximum human daily dose) from Gestation Day 9-11.
Lactation Risk SummaryNo lactation studies have been conducted with Ibuprofeno Vent3; however, limited published literature reports that, following oral administration, ibuprofen is present in human milk at relative infant doses of 0.06% to 0.6% of the maternal weight-adjusted daily dose. There are no reports of adverse effects on the breastfed infant and no effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Ibuprofeno Vent3 and any potential adverse effects on the breastfed infant from the Ibuprofeno Vent3 or from the underlying maternal condition.
Females And Males Of Reproductive Potential InfertilityFemales
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including Ibuprofeno Vent3, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin- mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including Ibuprofeno Vent3 in women who have difficulties conceiving or who are undergoing investigation of infertility.
Pediatric UseThe safety and effectiveness of Ibuprofeno Vent3 for the treatment of pain and fever in pediatric patients ages 6 months and older is supported by evidence of fever reduction from a multi-center, open-label study of hospitalized febrile pediatric patients along with safety data from exposure to Ibuprofeno Vent3 in 143 pediatric patients ages 6 months and older in two pediatric fever studies and one pediatric pain study, supportive data from other ibuprofen products approved in pediatric patients, and evidence from adequate and well controlled studies in adults. The effectiveness of Ibuprofeno Vent3 for the treatment of pain and fever has not been studied in pediatric patients less than 6 months of age..
Geriatric UseElderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects.
Clinical studies of Ibuprofeno Vent3 did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients are at increased risk for serious GI adverse events.
Before administration of Ibuprofeno Vent3 an adequate echocardiographic examination should be performed in order to detect a haemodynamically significant patent ductus arteriosus and to exclude pulmonary hypertension and ductal-dependent congenital heart disease.
Since prophylactic use in the first 3 days of life (starting within 6 hours of birth) in preterm newborn infants less than 28 weeks of gestational age was associated with increased pulmonary and renal adverse events, Ibuprofeno Vent3 should not be used prophylactically at any gestational age. In particular, severe hypoxemia with pulmonary hypertension was reported in 3 infants within one hour of the first infusion and was reversed within 30 min after start of inhaled nitric oxide therapy.
If hypoxaemia occurs during or following Ibuprofeno Vent3 infusion, close attention should be paid to pulmonary pressure.
Since ibuprofen was shown in vitro to displace bilirubin from its binding site to albumin, the risk of bilirubin encephalopathy in premature newborn infants may be increased. Therefore, ibuprofen should not be used in infants with marked elevated bilirubin concentration.
As a non-steroidal anti-inflammatory drug (NSAID), ibuprofen may mask the usual signs and symptoms of infection.).
Ibuprofeno Vent3 should be administered carefully to avoid extravasation and potential resultant irritation to tissues.
As ibuprofen may inhibit platelet aggregation, premature neonates should be monitored for signs of bleeding.
As ibuprofen may decrease the clearance of aminoglycosides, strict surveillance of their serum levels is recommended during co-administration with ibuprofen.
Careful monitoring of both renal and gastrointestinal function is recommended.
In preterm newborn infants less than 27 weeks of gestational age, the closure rate of the ductus arteriosus (33 to 50%) was shown to be low at the recommended dose regimen.
This medicinal product contains less than 1 mmol sodium (15 mg) per 2 ml, i.e. essentially 'sodium-free'.
WARNINGSIncluded as part of the "PRECAUTIONS" Section
PRECAUTIONS GeneralThere are no long-term evaluations of the infants treated with ibuprofen at durations greater than the 36 weeks post-conceptual age observation period. Ibuprofen’s effects on neurodevelopmental outcome and growth as well as disease processes associated with prematurity (such as retinopathy of prematurity and chronic lung disease) have not been assessed.
InfectionIbuprofeno Vent3 may alter the usual signs of infection. The physician must be continually on the alert and should use the drug with extra care in the presence of controlled infection and in infants at risk of infection.
Platelet AggregationIbuprofeno Vent3, like other non-steroidal anti-inflammatory agents, can inhibit platelet aggregation. Preterm infants should be observed for signs of bleeding. Ibuprofen has been shown to prolong bleeding time (but within the normal range) in normal adult subjects. This effect may be exaggerated in patients with underlying hemostatic defects (see CONTRAINDICATIONS).
Bilirubin DisplacementIbuprofen has been shown to displace bilirubin from albumin binding-sites; therefore, it should be used with caution in patients with elevated total bilirubin.
AdministrationIbuprofeno Vent3 should be administered carefully to avoid extravascular injection or leakage, as solution may be irritating to tissue.
Use In Specific Populations Pediatric UseSafety and effectiveness have only been established in premature infants.
None expected at recommended doses and duration of therapy.
None expected at recommended dose and duration of therapy.
Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.
Not relevant
For oral administration and short-term use only. Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.
Adults, the elderly, and children and adolescents over 12 years of age:
If in children and adolescents, between the age of 12 and 18 years, this medicinal product is required for more than 3 days, or if symptoms worsen, a doctor should be consulted.
For adults aged 18 years or older the minimum effective dose should be used for the shortest time necessary to relieve symptoms. If the product is required for more than 10 days or if the symptoms worsen, or persist, the patient should consult a pharmacist or a doctor.
1 or 2 tablets to be taken up to three times a day, as required. The tablets should be taken with water.
Leave at least 4 hours between doses and do not take more than 1200mg (6 tablets) in any 24 hour period.
Not to be given to children under 12 years of age.
For oral administration and short-term use only.
During short-term use, if symptoms persist or worsen the patient should be advised to consult a doctor.
Adults and children and adolescents between 12 and 18 years:
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.
If in children and adolescents between 12 and 18 years this medicinal product is required for more than 3 days, or if symptoms worsen a doctor should be consulted.
If in adults the product is required for more than 10 days, or if the symptoms worsen the patient should consult a doctor.
Children and Adolescents between 12 and 18 years: Take 1 or 2 caplets with water, up to three times a day as required.
Adults: Take 1 or 2 caplets with water, up to three times a day as required.
Leave at least four hours between doses.
Do not take more than 6 caplets in any 24 hour period.
Not for use by children under 12 years of age.
DirectionsUndesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.
Adults and children over 12 years of age: Two tablets taken as a single daily dose, preferably in the early evening well before retiring to bed. The tablets should be swallowed whole with plenty of fluid and not chewed, broken, crushed or sucked on to avoid oral discomfort and throat irritation. In severe or acute conditions, total daily dosage may be increased to three tablets in two divided doses.
Children: Not recommended for children under 12 years.
Elderly: The elderly are at increased risk of serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy. If renal or hepatic function is impaired, dosage should be assessed individually.
For oral administration. It is recommended that patients with sensitive stomachs take Brufen with food. If taken shortly after eating, the onset of action of Brufen may be delayed. To be taken preferably with or after food.
Important Dosage And Administration InstructionsUse the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
After observing the response to initial therapy with Ibuprofeno Vent3, the dose and frequency should be adjusted to suit an individual patient's needs. Do not exceed 3200 mg total daily dose in adults. Do not exceed 40 mg/kg or 2,400 mg, whichever is less, total daily dose in pediatric patients less than 17 years of age.
To reduce the risk of renal adverse reactions, patients must be well hydrated prior to administration of Ibuprofeno Vent3. Ibuprofeno Vent3 must be diluted prior to administration.
Dilute to a final concentration of 4 mg/mL or less. Appropriate diluents include 0.9% Sodium Chloride Injection USP (normal saline), 5% Dextrose Injection USP (D5W), or Lactated Ringers Solution.
For weight-based dosing at 10 mg/kg ensure that the concentration of Ibuprofeno Vent3 is 4 mg/mL or less.
Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. If visibly opaque particles, discoloration or other foreign particulates are observed, the solution should not be used.
Diluted solutions are stable for up to 24 hours at ambient temperature (approximately 20° C to 25° C) and room lighting.
Adults For Analgesia (pain)The dose is 400 mg to 800 mg intravenously every 6 hours as necessary. Infusion time must be at least 30 minutes. Maximum daily dose is 3,200 mg.
For FeverThe dose is 400 mg intravenously, followed by 400 mg every 4 to 6 hours or 100 mg to 200 mg every 4 hours as necessary. Infusion time must be at least 30 minutes. Maximum daily dose is 3,200 mg.
Pediatric Patients For Analgesia (pain) And FeverAges 12 to 17 Years Of Age
The dose is 400 mg intravenously every 4 to 6 hours as necessary. Infusion time must be at least 10 minutes. Maximum daily dose is 2,400 mg.
Ages 6 Months To 12 Years Of Age
The dose is 10 mg/kg intravenously up to a maximum single dose of 400 mg every 4 to 6 hours as necessary. Infusion time must be at least 10 minutes. Maximum daily dose is 40 mg/kg or 2,400 mg, whichever is less.
Pediatric Dosing as Necessary for Fever and Pain
| Age Group | Dose | Dosing Interval | Min infusion time | Max daily dose |
| 6 months to less than 12 years | 10 mg/kg up to 400 mg max | Every 4 to 6 hours as necessary | 10 minutes | *40 mg/Kg or 2,400 mg |
| 12 to 17 years | 400 mg | Every 4 to 6 hours as necessary | 10 minutes | 2,400 mg |
| * Maximum daily dose is 40 mg/kg or 2,400 mg, whichever is less |
Treatment with Ibuprofeno Vent3 should only be carried out in a neonatal intensive care unit under the supervision of an experienced neonatologist.
Posology
A course of therapy is defined as three intravenous injections of Ibuprofeno Vent3 given at 24-hour intervals. The first injection should be given after the first 6 hours of life.
The ibuprofen dose is adjusted to the body weight as follows:
- 1st injection: 10 mg/kg,
- 2nd and 3rd injections: 5 mg/kg.
If anuria or manifest oliguria occurs after the first or second dose, the next dose should be withheld until urine output returns to normal levels.
If the ductus arteriosus does not close 48 hours after the last injection or if it re-opens, a second course of 3 doses, as above, may be given.
If the condition is unchanged after the second course of therapy, surgery of the patent ductus arteriosus may then be necessary.
Method of administration
For intravenous use only.
Ibuprofeno Vent3 should be administered as a short infusion over 15 minutes, preferably undiluted. If necessary, the injection volume may be adjusted with either sodium chloride 9 mg/ml (0.9%) solution for injection or glucose 50 mg/ml (5%) solution for injection. Any unused portion of the solution should be discarded.
The total volume of solution injected should take into account the total daily fluid volume administered.
Recommended DoseA course of therapy is three doses of Ibuprofeno Vent3 administered intravenously (administration via an umbilical arterial line has not been evaluated). An initial dose of 10 mg per kilogram is followed by two doses of 5 mg per kilogram each, after 24 and 48 hours. All doses should be based on birth weight. If anuria or marked oliguria (urinary output <0.6 mL/kg/hr) is evident at the scheduled time of the second or third dose of Ibuprofeno Vent3, no additional dosage should be given until laboratory studies indicate that renal function has returned to normal. If the ductus arteriosus closes or is significantly reduced in size after completion of the first course of Ibuprofeno Vent3, no further doses are necessary. If during continued medical management the ductus arteriosus fails to close or reopens, then a second course of Ibuprofeno Vent3, alternative pharmacological therapy, or surgery may be necessary.
Directions For UseFor intravenous administration only. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use Ibuprofeno Vent3 if particulate matter is observed.
After the first withdrawal from the vial, any solution remaining must be discarded because Ibuprofeno Vent3 contains no preservative.
For administration, Ibuprofeno Vent3 should be diluted to an appropriate volume with dextrose or saline. Ibuprofeno Vent3 should be prepared for infusion and administered within 30 minutes of preparation and infused continuously over a period of 15 minutes. The drug should be administered via the IV port that is nearest the insertion site. After the first withdrawal from the vial, any solution remaining must be discarded because Ibuprofeno Vent3 contains no preservative.
Since Ibuprofeno Vent3 is potentially irritating to tissues, it should be administered carefully to avoid extravasation.
Ibuprofeno Vent3 should not be simultaneously administered in the same intravenous line with Total Parenteral Nutrition (TPN). If necessary, TPN should be interrupted for a 15-minute period prior to and after drug administration. Line patency should be maintained by using dextrose or saline.
Not applicable.
Not applicable
None.
Administrative dataAs for all parenteral products, ampoules of Ibuprofeno Vent3 should be visually inspected for particulate matter and the integrity of the container prior to use. Ampoules are intended for single use only, any unused portions must be discarded.
Chlorhexidine must not be used to disinfect the neck of the ampoule as it is not compatible with the Ibuprofeno Vent3 solution. Therefore, for asepsis of the ampoule before use, ethanol 60% or isopropyl alcohol 70% is recommended.
When disinfecting the neck of the ampoule with an antiseptic, to avoid any interaction with the Ibuprofeno Vent3 solution, the ampoule must be completely dry before it is opened.
The required volume to be given to the infant should be determined according to body weight, and should be injected intravenously as a short infusion over 15 minutes, preferably undiluted.
Use only sodium chloride 9 mg/ml (0.9%) solution for injection or glucose 50 mg/ml (5%) solution to adjust injection volume.
The total volume of solution injected to preterm infants should take into account the total daily fluid volume administered. A maximal volume of 80 ml/kg/day on the first day of life should usually be respected; this should be progressively increased in the following 1-2 weeks (about 20 ml/kg birthweight/day) up to a maximal volume of 180 ml/kg birthweight/day.
Before and after administration of Ibuprofeno Vent3, to avoid contact with any acidic solution, rinse the infusion line over 15 minutes with 1.5 to 2 ml of either sodium chloride 9 mg/ml (0.9%) or glucose 50 mg/ml (5%), solution for injection.
After first opening of an ampoule, any unused portions must be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.
