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 Actron. The patient should be followed for several days because gastrointestinal ulceration and hemorrhage may occur.
None known.
Not applicable
None.
Actron 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 Actron 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 Actron, 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 Actron, 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 Actron, 438 in pain and 122 with fever. In the pain studies, Actron 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, Actron 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 Actron 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 Actron Treatment Group in Pain Studies*
| Event | Actron | 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 Actron-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 Actron Treatment Group in All-Cause Fever Study
| Event | Actron | 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 Actron in controlled clinical trials. The most common adverse reactions (incidence greater than or equal to 2%) in pediatric patients treated with Actron 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 Actron. 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 Actron 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 Actron 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
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Ireland
HPRA Pharmacovigilance
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Fax: +353 1 6762517
Website: www.hpra.ie
e-mail: [email protected]
Clinical Trials ExperienceThe most frequently reported adverse events with Actron were as shown in Table 1.
Table 1. Adverse Events within 30 Days of Therapy in the Multicenter Study*
| Adverse Event | % Incidence | |
| Actron | 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 Actron than on placebo, and greater than 2 events on Actron. ** 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 Actron.
Pharmacotherapeutic group: Propionic acid derivatives.
ATC Code: M01AE
Actron is a phenylpropionic acid derivative NSAID that has demonstrated its efficacy by inhibition of prostaglandin synthesis. In humans, Actron reduces inflammatory pain, swelling and fever. Furthermore, Actron reversibly inhibits platelet aggregation.
Experimental data suggest that Actron 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 Actron 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 Actron 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 Actron 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 Actron 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 Actron 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 Actron.
Actron 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 Actron is about 2 hours.
In limited studies, Actron 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 Actron 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, Actron 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 Actron determined in a study with volunteers are presented below.
Table 4: Pharmacokinetic Parameters of Intravenous Ibuprofen
| 400 mg* Actron Mean (CV%) | 800 mg* Actron 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 Actron 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 Actron 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.
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
Not applicable.
Not applicable
None.
Administrative dataAs for all parenteral products, ampoules of Actron 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 Actron 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 Actron 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 Actron, 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.
