Lenbucod 10 mg/200 mg/350 mg FC tablets.

LENBUCOD is indicated for the relief of mild to moderate pain of inflammatory origin, with or without fever, for a maximum period of five days.

Posology
DO NOT EXCEED THE RECOMMENDED DOSAGE.
Use the lowest effective dose for the shortest possible duration of treatment.

Adults and children over the age of 12 years:
Take one (1) to two (2) tablets, six (6) hourly if necessary.
Do not take more than six (6) tablets in a 24-hour period.
Consult your health care provider if you require further treatment after five days.

Paediatric population
LENBUCOD is contraindicated in children under the age of 12 years (see section 4.3).

Method of administration
For oral administration.

LENBUCOD is contraindicated in:

• Hypersensitivity to paracetamol, ibuprofen, codeine or to any of the excipients listed in section 6.1.
• A history of previous hypersensitivity reactions (e.g. urticaria, rhinitis, asthma or angioedema), in response to aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs).
• A history of gastrointestinal perforation, ulceration or bleeding (PUBs) related to previous NSAIDs, including LENBUCOD.
• Patients with an active, or a history of recurrent gastrointestinal ulcer, haemorrhage or perforations (two or more distinct episodes of proven ulceration or bleeding).
• Patients with cerebrovascular bleeding or other active bleeding.
• Unclarified disturbances in blood-formation.
• Severe hepatic impairment, severe hepatic failure, or severe renal failure (see section 4.4).
• Cardiovascular disease.
• Severe heart failure (NYHA Class IV), heart failure secondary to chronic lung disease.
• During an attack of bronchial asthma, uncontrolled asthma, acute asthma or bronchospasm.
• Nasal polyps associated with aspirin-induced bronchospasms.
• After operations on the biliary tract, acute alcoholism, head injuries, and conditions where intracranial pressure is raised, respiratory depression, especially in the presence of cyanosis and excessive bronchial secretion.
• Concurrent use with monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping such treatment (see section 4.5).
• Concurrent use with coumarin anticoagulants (see section 4.5).
• Substantial dehydration (caused by vomiting, insufficient fluid intake or diarrhoea).
• The third trimester of pregnancy (from 28 weeks onwards), relating to the risk of oligohydramnios/ foetal renal dysfunction and premature closure of the foetal ductus arteriosus due to NSAIDs, and the risk of foetal respiratory complications due to codeine (see sections 4.4 and 4.6).
• In women who are breast feeding (see section 4.6).
• Children under the age of 12 years.
• Children (0 u2013 18 years of age) who undergo tonsillectomy or adenoidectomy surgery for obstructive sleep apnoea syndrome due to an increased risk of developing serious and life-threatening adverse reactions (see section 4.4).

Ibuprofen as in LENBUCOD
Before administering LENBUCOD, the benefit-risk ratio should be carefully considered in the following conditions: mixed connective tissue diseases or Systemic Lupus Erythematosus (SLE); congenital disturbances of porphyrin metabolism (e.g. acute intermittent porphyria); and the first and second trimester of pregnancy (see section 4.6).

Special care has to be taken in the following cases:

• Diseases affecting the gastrointestinal system including chronic inflammatory intestinal disease (e.g. ulcerative colitis, Crohnu2019s disease).
• Hypertension.
• Reduced renal function.
• Hepatic dysfunction.
• Disturbed haematopoiesis.
• Blood coagulation defects.
• Hay fever, allergies, chronic swelling of nasal mucosa, adenoids, chronic obstructive airway disease or bronchial asthma.
• Immediately after major surgical interventions.

Elderly
The elderly have an increased frequency of adverse reactions to NSAIDs, such as ibuprofen as contained in LENBUCOD, especially gastrointestinal bleeding, perforation or ulceration (PUBs), which may be fatal. Elderly patients are more likely to develop adverse hepatic or renal effects, and if gastrointestinal ulceration or bleeding occurs it is more likely to cause serious consequences.

Gastrointestinal bleeding, ulceration and perforation
Gastrointestinal bleeding, ulceration or perforation, can occur with all NSAIDs at any stage during the course of treatment (which can be fatal), with or without warning symptoms or having a history of previous gastrointestinal events. The risk of gastrointestinal perforation, ulceration or bleeding (PUBs) is higher with increasing doses of LENBUCOD, in patients with a history of ulcers, and the elderly. Treatment in these patients should be commenced on the lowest dose available.

It should also be considered to combine therapy with protective medicines such as misoprostol or proton pump inhibitors. Combination therapy should also be used for patients concomitantly using low-dose acetylsalicylic acid (aspirin) (or any other medicines likely to increase gastrointestinal risk (see section 4.5). Patients with a history of gastrointestinal toxicity, particularly the 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 medicines which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin or heparin, selective serotonin reuptake inhibitors or anti-platelet medicines such as acetylsalicylic acid (aspirin) (see section 4.5).

The concomitant use of Ibuprofen, as in LENBUCOD, along with NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided due to the increased risk of ulceration or bleeding (see section 4.5).

When gastrointestinal bleeding or ulceration occurs in patients receiving LENBUCOD, treatment with it should be stopped. LENBUCOD should be given with caution to patients with a history of gastrointestinal disease (e.g. ulcerative colitis, Crohnu2019s disease, hiatus hernia, gastro-oesophageal reflux disease, angiodysplasia) as the condition may be exacerbated (see section 4.8).

Cardiovascular and cerebrovascular effects
Caution is advised in patients with a history of hypertension and/or heart failure as fluid retention and oedema have been reported in association with LENBUCOD therapy. In view of the LENBUCODu2019s inherent potential to cause fluid retention, heart failure may be precipitated in some compromised patients.

Severe skin reactions
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported (see section 4.8). Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Acute generalised exanthematous pustulosis (AGEP) has been reported. LENBUCOD should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. Exceptionally, varicella virus can be the origin of serious cutaneous and soft tissues infectious complications. It is advisable to avoid use of LENBUCOD in case of varicella virus.

Drug reaction with eosinophillia and systemic symptoms
Drug Reaction with Eosinophillia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as ibuprofen as contained in LENBUCOD. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, haematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophillia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue LENBUCOD and evaluate the patient immediately.

Ibuprofen as in LENBUCOD
Concomitant use of ibuprofen and the following medicines should be avoided.

• Acetylsalicylic acid (aspirin)
  Concomitant administration of ibuprofen, as in LENBUCOD and acetylsalicylic acid (aspirin) is not generally recommended because of the potential of increased adverse effects. Data suggests that the concomitant use may competitively inhibit the effect of low dose acetylsalicylic acid (aspirin) on platelet aggregation. Although there are uncertainties regarding extrapolation of these data to the clinical situation, the possibility that the long-term and regular concomitant use can reduce the cardio protective effect of low-dose acetylsalicylic acid (aspirin) cannot be excluded. No clinically relevant effect is considered to be likely for occasional LENBUCOD use.
• Other NSAIDs including cyclooxygenase-2 selective inhibitors
  As a result of synergistic effects, the concurrent use of several NSAIDs can increase the risk of gastrointestinal ulcers and haemorrhage. Co-administration of ibuprofen, as in LENBUCOD, with other NSAIDs should therefore be avoided (see section 4.4). Use of two or more NSAIDs concomitantly could result in an increase in side effects.
• Anti-coagulants
  LENBUCOD may enhance the effects of anti-coagulants such as warfarin or heparin (see section 4.4). It is recommended that the coagulation state of the patients must be monitored during combination treatment.
• Methotrexate
  The combined use of methotrexate with LENBUCOD, may lead to an increased and prolonged plasma concentration of methotrexate. The concomitant administration of ibuprofen within 24 hours before or after the administration of methotrexate can lead to an increase in the toxic effects due to the increased methotrexate plasma concentration. The risk for methotrexate toxicity is increased. NSAIDs, such as ibuprofen, as in LENBUCOD, inhibits the tubular secretion of methotrexate and certain metabolic interactions can occur resulting in reduced clearance of methotrexate. Therefore, combination therapy of LENBUCOD and high doses of methotrexate should be avoided. It is advised to monitor for potential risks of medication interactions, even on low dose treatment with methotrexate especially in patients with impaired renal function.

Concomitant use of ibuprofen and the following medicines should be taken only with caution:

• Corticosteroids
  Increased risk of gastrointestinal perforation, ulceration or bleeding (PUBs) (see section 4.4).
• Anti-platelet medicines (e.g. clopidogrel and ticlopidine) and selective serotonin reuptake inhibitors (SSRIs)
  Increased risk of gastrointestinal bleeding and ulceration (see section 4.4).
• Antihypertensives, beta blockers and diuretics
  NSAIDs, such as ibuprofen, as in LENBUCOD, may reduce the antihypertensive effect of ACE inhibitors, beta blockers, angiotensin-II antagonists and diuretics. In patients with reduced kidney function (e.g. dehydrated patients or elderly patients with reduced kidney function), the concomitant use of an ACE inhibitor, beta blocker or angiotensin II antagonist with a cyclooxygenase-inhibiting medicine can lead to further impairment of kidney function and may result in acute renal failure. This is usually reversible. The combination of these therapies should therefore only be used with caution, especially in elderly patients. Patients should be advised to consider periodic monitoring of the kidney values and drink sufficient amounts of liquid with the onset of combination therapy.
• The concomitant administration of LENBUCOD and potassium-sparing diuretics or ACE-inhibitors can result in hyperkalaemia. Careful monitoring of potassium levels is necessary. Diuretics can also increase the risk of nephrotoxicity of LENBUCOD.
• Captopril
  Studies have shown that ibuprofen, as in LENBUCOD, counteracts the increased sodium excreting effects of captopril.
• Aminoglycosides
  LENBUCOD may decrease the excretion of aminoglycosides, and increase their toxicity.
• Antidiabetic medicines (e.g. sulphonylureas)
  The hypoglycaemic effects of antidiabetic medicines may be increased. Monitoring of blood glucose levels is advised in the case of simultaneous treatment.
• Digoxin, phenytoin and lithium
  LENBUCOD may exacerbate cardiac failure, decrease the rate of glomerular filtration and increase levels of cardiac glycoside (digoxin) in the plasma. Combined administration of LENBUCOD with digoxin, phenytoin or lithium can increase the serum level of these medicines. Checking the serum lithium level, serum digoxin and serum phenytoin levels are generally not required on correct use (over 3 or 4 days maximum).
• Ciclosporin and tacrolimus
  Concomitant administration of ciclosporin and certain NSAIDs leads to the risk of developing nephrotoxicity and kidney damage. This effect cannot be ruled out for the combination of ciclosporin and ibuprofen, as in LENBUCOD, either.
• Cholestyramine
  Combination therapy of cholestyramine and ibuprofen, as in LENBUCOD, causes a prolonged and reduced (25 %) absorption of ibuprofen. These medicines should be administered at least one hour apart.
• Mifepristone
  The use of NSAIDs, including ibuprofen as in LENBUCOD, within an interval period of eight to twelve days after mifepristone administration, can reduce the effect of mifepristone. The reduction in mifepristone efficacy is theoretically associated with the antiprostaglandin properties of LENBUCOD.
• Probenecid or sulfinpyrazone
  May cause a delay in the elimination of ibuprofen as in LENBUCOD. The uricosuric action of these medicines is decreased.
• Quinolone antibiotics
  LENBUCOD can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs, such as ibuprofen as in LENBUCOD, and quinolones may have a higher risk of developing convulsions.
• Zidovudine
  When NSAIDs, such as ibuprofen as in LENBUCOD, are given with zidovudine, there is an increased risk of haematological toxicity. In HIV positive haemophiliacs receiving concurrent treatment with these medicines, there is evidence of an increased risk of haemarthrosis and haematoma. It is advised to monitor blood counts of patients one to two weeks after starting combination therapy.
• Ritonavir
  May elevate the plasma concentrations of NSAIDs, such as ibuprofen as in LENBUCOD.
• Bone marrow depressants
  The leukopenic and/or thrombocytopenic effects of these medicines may be increased.
• Alcohol, bisphosphonates and oxpentifylline
  The risk of bleeding and ulceration is increased with co-administration of LENBUCOD and alcohol, bisphosphonates or oxypentifylline.
• Baclofen
  Elevated baclofen toxicity.
• CYP2C9 Inhibitors
  Ibuprofen (CYP2C9 substrate), and co-administration of medicines such as voriconazole and fluconazole (CYP2C9 inhibitors) increases the exposure to ibuprofen (as in LENBUCOD). In a study with voriconazole and fluconazole (CYP2C9 inhibitors) an increased S (+) ibuprofen, as in LENBUCOD, exposure by approximately 80 % to 100 % has been shown. Reduction of the LENBUCOD dose should be considered when potent CYP2C9 inhibitors are administered concomitantly, particularly when high-dose LENBUCOD is administered with either voriconazole or fluconazole.
• Herbal extracts
  The concomitant use with Ginkgo biloba may potentiate the risk of bleeding effects of NSAIDu2019s (e.g., ibuprofen as in LENBUCOD).

LENBUCOD is not recommended for use by women in early pregnancy and is contraindicated in the third trimester (28 weeks of gestation onwards). LENBUCOD is contraindicated in breastfeeding women. (see sections 4.3 and 4.4).

Pregnancy
Ibuprofen as in LENBUCOD
Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1 %, up to approximately 1,5 %. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post- implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, LENBUCOD should not be given unless clearly necessary. If LENBUCOD is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low, and duration of treatment as short, as possible.

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

• cardiopulmonary toxicity (with premature closure of the foetal ductus arteriosus in utero, and in persistent pulmonary hypertension of the new-born,
• renal dysfunction, which may progress to renal failure with oligo-hydramniosis (see section 4.4).

And may expose the mother and the neonate, at the end of pregnancy to:

• possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.
• inhibition of uterine contractions resulting in the onset of labour may be delayed and its duration increased.

Use of NSAIDs, including LENBUCOD, can cause premature closure of the foetal ductus arteriosus and foetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, the use of LENBUCOD dose and duration between 20 and 28 weeks of gestation should be limited and avoided in the third trimester (28 weeks of gestation and later) (see sections 4.3 and 4.4).

Codeine phosphate as in LENBUCOD
LENBUCOD contains codeine phosphate, a narcotic analgesic. Use of narcotic analgesics during pregnancy is associated with foetal adverse effects, which include physical dependence and withdrawal, retardation of growth, and neonatal respiratory depression with high doses. Codeine is contraindicated in the third trimester of pregnancy (see section 4.3).

Breastfeeding
Ibuprofen as in LENBUCOD
Ibuprofen, as in LENBUCOD, is excreted in human breast milk in low concentrations. With therapeutic doses during short term treatment the risk for influence on infant seems unlikely. If, however, longer treatment is prescribed, early weaning should be considered.

Codeine phosphate as in LENBUCOD
LENBUCOD contains codeine phosphate. Breast-fed infants of mothers taking codeine may be at an increased risk of toxicity from its metabolite morphine. LENBUCOD is contraindicated in breastfeeding women (see section 4.3).

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

LENBUCOD has a minor influence on the ability to drive or use machines. Adverse reactions such as dizziness, drowsiness and visual disturbances have been reported (see section 4.8).

a. Summary of the safety profile
Ibuprofen as in LENBUCOD
The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, heamatemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (see section 4.4), have been reported following administration. Gastritis has been observed, less frequently.

Clinical studies suggest that use of ibuprofen, as in LENBUCOD, particularly at a high dose (2 400 mg/day) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4). Oedema, hypertension, and cardiac failure have been reported in association with NSAID treatment, such as ibuprofen, as in LENBUCOD.

b. Tabulated summary of adverse reactions
Ibuprofen as in LENBUCOD
SYSTEM ORGAN CLASS
FREQUENCY
ADVERSE REACTIONS
Infections and infestations
Less frequent
Rhinitis, aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus and mixed connective tissue disease) with symptoms of stiff neck, nausea, vomiting, fever or disorientation
Blood and lymphatic system disorders
Less frequent
Haematopoietic disorders (leucopoenia, pancytopenia, agranulocytosis, thrombocytopenia with or without purpura, aplastic anaemia, haemolytic anaemia, anaemia, neutropenia). The first symptoms or signs may include: fever, sore throat, surface mouth ulcers, flu-like symptoms, severe fatigue, nasal and skin bleeding
Frequency unknown
Neutropenia
Immune system disorders
Less frequent
Hypersensitivity reactions such as urticaria, pruritus, purpura and exanthema as well as asthma attacks (sometimes with hypotension), severe hypersensitivity reactions. The symptoms may include: facial oedema, swelling of the tongue, internal laryngeal swelling with constriction of the airways, dyspnoea, tachycardia, fall of blood pressure to the point of life-threatening shock
Metabolism and nutrition disorders
Frequency unknown
Hypokalaemia**
Psychiatric disorders
Less frequent
Confusional state, nervousness, insomnia, depression, anxiety, hallucination
Nervous system disorders
Frequent
Dizziness
Less frequent
Drowsiness, headache, somnolence, fatigue, agitation, irritability
Frequency unknown
Paraesthesia
Eye disorders
Less frequent
Blurred vision, other ocular reactions
Frequency unknown
Visual impairment, toxic optic neuropathy
Ear and labyrinth disorders
Less frequent
Tinnitus
Frequency unknown
Impaired hearing, vertigo
Cardiac disorders
Less frequent
Heart failure may be precipitated in compromised patients, angina pectoris, cardiac dysrhythmias, palpitations, myocardial infarction, acute pulmonary oedema
Frequency unknown
Oedema, hypertension
Respiratory, thoracic and mediastinal disorders
Less frequent
Rhinitis, bronchospasm
Frequency unknown
Alveolitis, pulmonary eosinophilia
Gastrointestinal disorders
Frequent
Gastrointestinal disorders, such as heartburn, dyspepsia, abdominal cramps and pain, nausea, vomiting, flatulence, diarrhoea, constipation
Less frequent
Peptic ulcers, perforation or gastro-intestinal bleeding, sometimes fatal; gastrointestinal ulcers, sometimes with bleeding and perforation (see section 4.4), occult blood loss which may lead to anaemia, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohnu2019s disease, inflammatory bowel disease, complications of colonic diverticula (perforation, fistula), gastritis, oesophagitis, pancreatitis, intestinal strictures, bloating, decreased appetite
Hepato - biliary disorders
Less frequent
Abnormalities of liver function tests, hepatitis, jaundice, liver dysfunction, liver damage, especially in long-term use, hepatic failure
Frequency unknown
Hepatotoxicity
Skin and subcutaneous tissue disorders
Frequent
Skin rash, pruritus
Less frequent
Photosensitivity reaction, severe forms of skin reactions (erythema multiforme, exfoliative dermatitis, bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, alopecia, necrotising fasciitis
Frequency unknown
Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), Acute generalised exanthematous pustulosis (AGEP)
Renal and urinary disorders
Less frequent
Impairment of renal function, acute reversible renal failure, haematuria, renal papillary necrosis in long-term use (see section 4.4), development of oedema especially in patients with arterial hypertension or renal insufficiency, nephrotic syndrome, interstitial nephritis which can be associated with renal failure
Frequency unknown
Renal tubular acidosis**
General disorders and administration site conditions
Frequency unknown
Malaise
Investigations
Less frequent
Increase of blood urea nitrogen, serum transaminases and alkaline phosphatase, decrease in haemoglobin and haematocrit values, inhibition of platelet aggregation, prolonged bleeding time, decrease of serum calcium, increase in serum uric acid
Paracetamol as in LENBUCOD
SYSTEM ORGAN CLASS
FREQUENCY
ADVERSE REACTIONS
Blood and lymphatic system disorders
Less frequent
Haematological reaction (including agranulocytosis, thrombocytopenia, neutropenia, pancytopenia, leukopenia)
Immune system disorders
Frequency unknown
Drug-induced hypersensitivity syndrome (DIHS) (see section 4.4)*
Hepato - biliary disorders
Less frequent
Hepatitis, pancreatitis
Skin and subcutaneous tissue disorders
Less frequent
Hypersensitivity reactions resulting in reversible skin rash (which may be accompanied by fever and mucosal lesions) or blood disorders dermatitis, erythematous or urticarial rash accompanied by fever and mucosal lesions
Frequency unknown
Fixed drug eruptions (FDE) (see section 4.4)*
Renal and urinary disorders
Less frequent
Renal colic, renal failure, sterile pyuria
Codeine phosphate as in LENBUCOD
SYSTEM ORGAN CLASS
FREQUENCY
ADVERSE REACTIONS
Psychiatric disorders
Less frequent
Euphoria
Nervous system disorders
Less frequent
Confusion, drowsiness, restlessness, changes in mood, vertigo, raised intracranial pressure
Eye disorders
Less frequent
Miosis, blurred or double vision
Cardiac disorders
Less frequent
Bradycardia, palpitations, orthostatic hypotension
Respiratory, thoracic and mediastinal disorders
Less frequent
Respiratory depression
Gastrointestinal disorders
Less frequent
Nausea, vomiting, constipation, dry mouth, acute pancreatitis*
Hepato - biliary disorders
Less frequent
Biliary spasm
Skin and subcutaneous tissue disorders
Less frequent
Sweating, facial flushing, urticaria, pruritus
Renal and urinary disorders
Less frequent
Micturition difficulties, ureteric spasm
General disorders and administration site conditions
Less frequent
Hypothermia
*post-marketing experience: Less frequent increased risk of abdominal pain, including pancreatitis has been reported. The following side effects have been reported and frequencies are unknown: Fixed drug eruptions (FDE) and drug-induced hypersensitivity syndrome (DIHS) (see section 4.4). **Renal tubular acidosis and hypokalaemia have been reported in the post-marketing setting typically following prolonged use of the ibuprofen component at higher than recommended doses due to dependence on the codeine component. c. Description of selected adverse reactions
Ibuprofen
Acute reversible renal failure has been reported. Hypersensitivity reactions have been reported following treatment with ibuprofen, as in LENBUCOD. These may consist of (a) nonspecific 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). The pathogenic mechanism of medicine-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 medicine intake, and disappearance of symptoms after medicine 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 autoimmune disorders (such as systemic lupus erythematosus, mixed connective tissue disease).

Treatment is symptomatic and supportive (see section 4.4).
Ibuprofen as in LENBUCOD
Most patients who have ingested significant amounts of ibuprofen (as in LENBUCOD), will manifest symptoms within four to six hours.

Symptoms
The most frequently reported symptoms of overdose include nausea, abdominal pain, lethargy, vomiting, blurred vision, drowsiness and other central nervous system (CNS) symptoms (such as headache, dizziness, tinnitus, convulsion, and loss of consciousness). Symptoms of overdose that have also been reported include nystagmus, metabolic acidosis, hypothermia, renal effects, gastrointestinal bleeding, coma, apnoea, diarrhoea and depression of the CNS and respiratory system have also been 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.

In more serious poisoning, toxicity is seen in the central nervous system, with symptoms such as vertigo, dizziness, drowsiness, occasionally excitation and loss of consciousness or coma. Children may also develop myoclonic cramps. In serious poisoning metabolic acidosis may occur, hypothermia and hyperkalaemia may also occur, and the prothrombin time/INR may be prolonged, probably due to interference with the actions of circulating clotting factors.

Prolonged use at higher than recommended doses may result in severe hypokalaemia and renal tubular acidosis. Symptoms may include reduced level of consciousness and generalised weakness (see section 4.4 and section 4.8).

Respiratory depression and cyanosis may occur. Exacerbation of asthma is possible in asthmatics.

Treatment
Patients should be treated symptomatically as required and supportive and the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Within one hour of ingestion of a potentially toxic amount oral administration of activated charcoal should be considered. 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 or lorazepam. Other measures may be indicated by the patientu2019s clinical condition. If ibuprofen has already been absorbed, alkaline substances should be administered to promote the excretion of the acid ibuprofen in the urine.

Bronchodilators should be given for asthma. No specific antidote is available.

Paracetamol as in LENBUCOD
Prompt treatment is essential. In the event of an overdosage, consult a doctor immediately, or take the person directly to a hospital. A delay in starting treatment may mean that the antidote is given too late to be effective. Evidence of liver damage is often delayed until after the time for effective treatment has lapsed.

Symptoms
Symptoms of paracetamol overdosage in the first 24 hours include pallor, nausea, vomiting, anorexia and possibly abdominal pain. Mild symptoms during the first two days of acute poisoning, do not reflect the potential seriousness of the overdosage. Liver damage may become apparent 12 to 48 hours, or later after ingestion, initially by elevation of the serum transaminase and lactic dehydrogenase activity, increased serum bilirubin concentration and prolongation of the prothrombin time. Liver damage may lead to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Abnormalities of glucose metabolism and metabolic acidosis may occur. Cardiac dysrhythmias have been reported.

Treatment
N-acetylcysteine should be administered to all cases of suspected overdose as soon as possible preferably within eight hours of overdosage, although treatment up to 36 hours after ingestion may still be of benefit, especially if more than 150 mg/kg of paracetamol was taken. An initial dose of 150 mg/kg N-acetylcysteine in 200 mL dextrose injection given intravenously over 15 minutes, followed by an infusion of 50 mg/kg in 500 mL dextrose injection over the next four hours, and then 100 mg/kg in 1 000 mL dextrose injection over the next sixteen hours. The volume of intravenous fluid should be modified for children. Although the oral formulation is not the treatment of choice, 140 mg/kg dissolved in water may be administered initially, followed by 70 mg/kg every four hours for seventeen doses. A plasma paracetamol level should be determined four hours after ingestion in all cases of suspected overdosage. Levels done before four hours may be misleading. Patients at risk of liver damage, and hence requiring continued treatment with N-acetylcysteine, can be identified according to their plasma paracetamol level. The plasma paracetamol level can be plotted against time since ingestion in the nomogram below. The nomogram should be used only in relation to a single acute ingestion. Those whose plasma paracetamol levels are above the u201cnormal treatment lineu201d, should continue N-acetylcysteine treatment with 100 mg/kg IV over sixteen hours repeatedly until recovery. Patients with increased susceptibility to liver damage as identified above, should continue treatment if concentrations are above the u201chigh risk treatment lineu201d. Prothrombin index correlates best with survival. Monitor all patients with significant ingestions for at least ninety-six hours.