Source: Health Products Regulatory Authority (ZA) Revision Year: 2023 Publisher: Sandoz SA (Pty) Ltd<sup>1</sup>, Magwa Crescent West, Waterfall City, Jukskei View, Midrand, 2090 1 Company Reg. No.: 1990/001979/07
This product contains paracetamol which may be fatal in overdose. In the event of overdosage or suspected overdose and notwithstanding the fact that the person may be asymptomatic, the nearest doctor, hospital or Poison Centre must be contacted immediately.
Dosages in excess of those recommended may cause severe liver damage.
IBUPAIN FORTE is for short term use and is not recommended for use beyond 5 days.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2 and gastrointestinal and cardiovascular risks below).
Bronchospasm may be precipitated in patients suffering from or with a previous history of bronchial asthma or allergic disease.
Acute asthma attack or respiratory impairment or disease – may decrease respiratory drive and increase airway resistance in these patients.
The use of IBUPAIN FORTE with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).
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. In view of IBUPAIN FORTE’s inherent potential to cause fluid retention, heart failure may be precipitated in some compromised patients.
Clinical studies suggest that use of ibuprofen, particularly at a high dose (2400 mg/day) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g. ≤1200 mg/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 IBUPAIN FORTE 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.
Gastrointestinal 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 gastrointestinal events.
The risk of gastrointestinal Perforation, Ulceration or Bleeding (PUBs) is higher with increasing doses of IBUPAIN FORTE, in patients with a history of ulcers, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly.
These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other medicines likely to increase gastrointestinal risk (see below and section 4.5).
Patients with a history of gastrointestinal toxicity, 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 (see section 4.5).
When gastrointestinal bleeding or ulceration occurs in patients receiving IBUPAIN FORTE, the treatment with IBUPAIN FORTE should be stopped.
IBUPAIN FORTE should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease, hiatus hernia, gastro-oesophageal reflux disease, angiodysplasia) as their condition may be exacerbated (see section 4.8).
The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients (see also section 4.3).
There is a risk of renal impairment in dehydrated children and adolescents.
Severe hypokalaemia and renal tubular acidosis have been reported due to prolonged use of ibuprofen at higher than recommended doses. This risk is increased with the use of codeine/ibuprofen as patients may become dependent on the codeine component (see warning on Opioid use disorder, section 4.8 and section 4.9).
Presenting signs and symptoms included reduced level of consciousness and generalized weakness. Ibuprofen induced renal tubular acidosis should be considered in patients with unexplained hypokalaemia and metabolic acidosis.
Tolerance, physical and psychological dependence and opioid use disorder (OUD) may develop upon repeated administration of opioids such as codeine. Abuse or intentional misuse of IBUPAIN FORTE may result in overdose and/or death.
Serious clinical outcomes, including fatalities, have been reported in association with abuse and dependence with codeine/ibuprofen combinations, particularly when taken for prolonged periods at higher than recommended doses. These have included reports of gastrointestinal perforations, gastrointestinal haemorrhages, severe anaemia, renal failure, renal tubular acidosis and severe hypokalaemia associated with the ibuprofen component.
Patients should be informed about the risks and signs of OUD as well as serious clinical outcomes. If these signs occur, patients should be advised to contact their doctor.
Withdrawal symptoms, such as restlessness and irritability may occur once the drug is stopped.
Severe cutaneous adverse reactions such as toxic epidermal necrolysis (TEN), exfoliative dermatitis, Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), eosinophilia and systemic (DRESS)/Drug-induced hypersensitivity syndrome (DIHS) and fixed drug eruptions (FDE) have been reported in association with the use of NSAIDs (see section 4.8). 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. If a patient develops SCAR, treatment with IBUPAIN FORTE must immediately be discontinued at the first appearance of signs and symptoms of SCARs, such as skin rash, mucosal lesions, or any other sign of hypersensitivity and appropriate treatment instituted.
IBUPAIN FORTE can mask symptoms of infection, which may lead to delayed initiation of appropriate treatment and thereby worsening the outcome of the infection. This has been observed in bacterial community acquired pneumonia and bacterial complications to varicella. When IBUPAIN FORTE is administered for fever or pain relief in relation to infection, monitoring of infection is advised. In non-hospital settings, the patient should consult a doctor if symptoms persist or worsen.
The elderly have an increased frequency of adverse reactions to NSAIDs including IBUPAIN FORTE, especially gastrointestinal Perforation, Ulceration and Bleeding (PUBs) which may be fatal (see section 4.2).
Elderly patients may metabolise or eliminate opioid analgesics more slowly than younger adults. Codeine should be used with caution in the elderly and debilitated patients as they may be more susceptible to the respiratory depressant effects.
Do not take concurrently with any other codeine containing compounds.
Care is advised in the administration of codeine to patients with hypotension, hypothyroidism, adrenocortical insufficiency, shock, obstructive bowel disorders, acute abdominal conditions (e.g. peptic ulcer), recent gastrointestinal surgery, gallstones, myasthenia gravis, and a history of peptic ulcer or convulsions and also in patients with a history of drug abuse. The habitual intake of analgesics, especially the combination of different analgesics may cause permanent kidney damage with the risk of renal failure (analgesic nephropathy).
Long-term, inappropriate use of high doses of analgesics may cause headaches, which may not be treated by increasing doses of the medicinal product.
Gallbladder disease or gallstones – may cause biliary tract spasm.
Alcoholism, drug abuse or dependence:
DEPENDENCE MAY DEVELOP WITH PROLONGED USE OF HIGH DOSES.
Exceeding the prescribed dose, together with prolonged and continuous use of this medication, may lead to dependency and addiction. This may result in withdrawal symptoms, such as restlessness and irritability once IBUPAIN FORTE is stopped.
Risk of respiratory depression and further increase in intracranial pressure.
IBUPAIN FORTE may also cause sedation and pupillary changes that may obscure the clinical course of head injury.
Increased risk of respiratory depression and prolonged central nervous system depression.
Codeine is metabolised by the liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect will not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an extensive or ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at commonly prescribed doses. These patients convert codeine into morphine rapidly resulting in higher than expected serum morphine levels.
General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life-threatening and very rarely fatal.
Estimates of prevalence of ultra-rapid metabolisers in different populations are summarized below:
| Population | Prevalence % |
|---|---|
| African/Ethiopian | 29% |
| African American | 3,4% to 6,5% |
| Asian | 1,2% to 2% |
| Caucasian | 3,6% to 6,5% |
| Greek | 6,0% |
| Hungarian | 1,9% |
| Northern European | 1% to 2% |
There have been reports in the published literature that codeine given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life-threatening adverse events including death (see also section 4.3). All children received doses of codeine that were within the appropriate dose range; however there was evidence that these children were either ultra-rapid or extensive metabolisers in their ability to metabolise codeine to morphine.
Codeine is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of morphine toxicity.
Regular use of NSAIDs such as IBUPAIN FORTE during the third trimester of pregnancy, may result in premature closure of the foetal ductus arteriosus in utero, and possibly, in persistent pulmonary hypertension of the new-born. The onset of labour may be delayed and its duration increased.
The use of NSAIDs around 20 weeks gestation or later in pregnancy may cause a rare but serious foetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Complications of prolonged oligohydramnios include limb contractures and delayed lung maturation, which may require invasive procedures such as exchange transfusion or dialysis, in some cases.
IBUPAIN FORTE should be used with caution in the following:
Dosages of IBUPAIN FORTE in excess of those recommended may cause severe liver damage.
IBUPAIN FORTE should not be taken with other medicines containing paracetamol, ibuprofen, acetylsalicylic acid, salicylates or with any other anti-inflammatory drugs (NSAIDs) unless under a doctor’s instruction.
Concomitant administration of ibuprofen and acetylsalicylic acid (aspirin) is not generally recommended because of the potential of increased adverse effects.
Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly. Although there are uncertainties regarding extrapolation of these data to the clinical situation, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).
Increased risk of gastrointestinal perforation, ulceration or bleeding (PUBs) (see section 4.4).
IBUPAIN FORTE may enhance the effects of anticoagulants, such as warfarin (see section 4.4).
Increased risk of gastrointestinal bleeding (see section 4.4).
Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse effects (see section 4.4).
NSAIDs may diminish the effect of these medicines. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of an ACE inhibitor or angiotensin II antagonist and agents that inhibit cyclooxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients taking a coxib concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter. Diuretics can increase the risk of nephrotoxicity of NSAIDs.
NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
Decreased elimination of lithium.
Decreased elimination of methotrexate.
Increased risk of nephrotoxicity.
Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.
NSAIDs should not be used for 8–12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.
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 second or third trimester of pregnancy, NSAIDs including celecoxib/ibuprofen may cause foetal renal dysfunction which may result in reduction of amniotic fluid volume or oligohydramnios in severe cases.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:
An association between abnormalities of the respiratory tract and the use of codeine during the first three months of pregnancy was found in humans. Evidence for other malformations was also found in epidemiological studies with narcotic analgesics, including codeine. Codeine may therefore only be used during pregnancy, especially during the first three months, if clearly indicated and after a careful benefit-risk assessment.
In case of imminent birth or preterm birth, the use of codeine is contraindicated since codeine crosses the placental barrier and can cause neonatal respiratory depression.
During long-term use of codeine an opioid dependence of the foetus can develop. Withdrawal symptoms in the new-born after repeated use of codeine in the last trimester of pregnancy were reported.
A large amount of data on pregnant women indicate neither malformative, nor foeto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy, however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.
IBUPAIN FORTE should not be used during breastfeeding (see section 4.3).
At normal therapeutic doses codeine and its active metabolite may be present in breast milk at very low doses and is unlikely to adversely affect the breast fed infant. However, if the patient is an ultra-rapid metaboliser of CYP2D6, higher levels of the active metabolite, morphine, may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant, which may be fatal.
The use of ibuprofen 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 IBUPAIN FORTE should be considered.
Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after intake of IBUPAIN FORTE. If affected, patients should not drive or operate machinery.
Less frequent: 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 (see section 4.4).
Less frequent: Agranulocytosis, thrombocytopenia, leukopenia, neutropenia, pancytopenia, aplastic anaemia and haemolytic anaemia.
Less frequent: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (which could include facial, tongue and throat swelling, tachycardia, hypotension or severe shock) (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, more rarely exfoliative and bullous dermatoses (including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme).
Frequency not known: Decreased appetite, hypokalaemia.
Less frequent: Insomnia, anxiety, depression, confusion state, hallucination.
Less frequent: Dizziness, nervousness, headache, optic neuritis, paraesthesia, somnolence.
Less frequent: Visual impairment and toxic optic neuropathy.
Less frequent: Hearing impairment, tinnitus and vertigo.
Less frequent: Cardiac failure may be precipitated in compromised patients, angina pectoris, cardiac arrhythmias, oedema.
Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high dose (2400 mg daily), and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).
Less frequent: Hypertension.
Frequency not known: Respiratory tract reactivity comprising asthma, bronchospasm or dyspnoea.
The most commonly observed adverse events are gastrointestinal in nature.
Frequent: Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal. Dyspepsia, nausea, vomiting, diarrhoea, abdominal cramps and pain, bloating, flatulence, constipation, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease, gastritis.
Less frequent: Pancreatitis.
Less frequent: Hepatic function abnormal, hepatic failure, hepatitis and jaundice.
Less frequent: Skin rash, pruritus. Bullous reactions, including Stevens-Johnson syndrome, erythema multiforme and toxic epidermal necrolysis, photosensitivity reaction.
Frequency not known: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalised exanthematous pustulosis (AGEP).
Less frequent: Impairment of renal function, acute reversible renal failure (Especially in long-term use, associated with increased serum urea and oedema. Also includes papillary necrosis).
Frequency not known: Ureteric colic, dysuria, renal tubular acidosis.
Less frequent: Malaise, fatigue
Frequency not known: Hyperhidrosis, irritability.
Less frequent: Haematological reaction (including thrombocytopenia, leucopoenia, pancytopenia, neutropenia and agranulocytosis).
Less frequent: Hypersensitivity. Cutaneous hypersensitivity reactions including, among others, skin rashes and angioedema. Very rare cases of serious skin reactions have been reported. Anaphylactic reaction.
Less frequent: Hepatic enzyme increase, hepatic dysfunction.
Less frequent: Rash, pruritus, erythema, urticaria.
Very rare cases of serious skin reactions have been reported (including drug-induced Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Acute Generalised Exanthematous Pustulosis (AGEP)).
Less frequent: Bronchospasm*.
* There have been cases of bronchospasm with paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.
Less frequent: Renal colic, renal failure.
Less frequent: Hallucinations, dysphoria, euphoria, mood changes, restlessness, confusion.
Frequency not known: Nightmares.
Frequent: Drowsiness, dizziness, seizures, addiction, tolerance, dependence, headache, vertigo, malaise, sleep disturbances.
Frequency not known: Convulsion, intracranial pressure increased, dyskinesia.
Less frequent: Miosis, visual disturbances.
Frequency not known: Vision blurred, diplopia.
Less frequent: Bradycardia, palpitations, tachycardia.
Less frequent: Postural hypotension, hypothermia, facial flushing.
Less frequent: Respiratory depression.
Frequency not known: Cough suppression.
Frequent: Nausea, vomiting, constipation, pancreatitis.
Less frequent: Dry mouth.
Less frequent: Biliary spasm, liver disorder.
Frequency not known: Biliary colic.
Less frequent: Sweating, urticaria, pruritus, rashes.
Less frequent: Micturition difficulties, ureteric spasm or retention, dysuria (Increased frequency, decrease in amount).
Frequency not known: Muscle rigidity.
Less frequent: Haemoglobin decreased.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8. Suspected adverse reactions can also be reported directly to the HCR via https://pvi1j.solutions.iqvia.com or adverse.event.sac@sandoz.com
Not applicable.
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