Dexibuprofen 300 mg Film-coated Tablets

This medicine is a non-steroidal anti-inflammatory drug/analgesic

Dexibuprofen tablets are used in adults and children and adolescents from 8 years of age.

For the symptomatic treatment of

- pain and inflammation in osteoarthritis/arthrosis,

- Menstrual pain (primary dysmenorrhoea),

- Mild to moderate pain, such as musculoskeletal pain, headache or toothache, painful swelling and inflammation after injury

- and for the short-term symptomatic treatment of rheumatoid arthritis when other, longer-term therapy options (basic therapy: disease-modifying antirheumatic drugs, DMARDs) are not being considered.

Posology

The dosage should be adjusted to the severity of the disorder and the complaints of the patient. Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).

The maximum single dose is 400 mg, the maximum daily dose is 1200 mg dexibuprofen.

For individual dosage tablets with 200 mg, 300 mg and 400 mg dexibuprofen are available. The 200 mg and 400 mg tablets can be divided into equal halves, score on the tablets makes it possible to divide the tablets before administration so as to assist with swallowing.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses. Dividing the tablets may not provide an exact "half" dose.

Osteoarthritis/arthrosis and rheumatoid arthritis

The recommended dose is 600 to 900 mg dexibuprofen daily, divided in up to three single doses.

The dose may be increased up to 1200 mg dexibuprofen per day in patients with acute conditions.

Primary dysmenorrhea

The recommended dose is 600 to 900 mg of dexibuprofen daily, divided in up to three single doses

Mild to moderate pain

The recommended dose is 600 mg dexibuprofen daily, divided in up to three single doses.

If clearly needed in patients with acute pain conditions (e.g. in surgical extraction of teeth) the dose may be transiently increased up to 1200 mg dexibuprofen per day.

Children and adolescents

Only limited studies are available for the treatment of children and adolescents. Therefore, treatment should only be for a short time and at the lowest effective dose.

Dexibuprofen tablets are not suitable for children up to 8 years of age. Dexibuprofen 300 mg tablets are not suitable for children and adolescents.

Generally received

Children from 8 - 12 years: 100 mg dexibuprofen (1/2 film-coated tablet dexibuprofen 200 mg) 1 to 3 times daily.

Adolescents from 12 to 18 years: 200 mg dexibuprofen 1 to 3 times daily (1 film-coated tablet dexibuprofen 200 mg or ½ film-coated tablet dexibuprofen 400 mg).

There should be an interval of 4 to 6 hours between doses.

Elderly patients (65 years and older)

No special dosage modifications are required in the elderly. However, individual dose reduction and assessment has to be considered due to increased susceptibility to GI adverse reactions in the elderly (see section 4.4).

Hepatic dysfunction

Patients with mild to moderate hepatic impairment should start treatment at a lower dose and be closely monitored. Dexibuprofen should not be used in patients with severe hepatic impairment (see section 4.3).

Renal dysfunction

The starting dose should be reduced in patients with mild to moderate renal impairment. Dexibuprofen must not be used in patients with severe renal impairment (glomerular filtration rate, GFR < 30 ml/min) (see section 4.3).

Method of administration

For oral use.

The tablets can be taken with or without a meal (see section 5.2). In general, NSAIDs (non-steroidal anti-inflammatory drugs) are preferably taken with a meal to reduce gastrointestinal irritation, particularly during chronic use. However, a later onset of action in some patients may be anticipated when the tablets are taken with or directly after a meal.

Dexibuprofen must not be administered in patients:

- with hypersensitivity to dexibuprofen, to any other NSAID, or to any of the excipients of the product (see section 6.1.)

- in whom substances with a similar action (e.g. acetylsalicylic acid or other NSAIDs) precipitate attacks of asthma, bronchospasm, acute rhinitis, or cause nasal polyps, urticaria or angioneurotic oedema.

- with a history of gastrointestinal bleeding or perforation, related to previous NSAID therapy.

- with active, or a history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

- with cerebrovascular bleeding or other active bleedings.

- with active Crohn's disease or active ulcerative colitis.

- with severe heart failure.

- with severe renal dysfunction (GFR < 30 ml/min).

- with severely impaired hepatic function.

- from the beginning of 6th month of pregnancy (see section 4.6).

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2 and GI and cardiovascular and cerebrovascular risks below).

Concomitant use of dexibuprofen with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided (see section 4.5).

Gastrointestinal risks

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

Gastrointestinal bleeding, ulceration and perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID dose, in patients with a history of ulcers, particularly if complicated with haemorrhage or perforation (see section 4.3), alcoholism 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 acetylsalicylic acid, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).

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

Caution should be advised in patients receiving concomitant medication 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 acetylsalicylic acid (see section 4.5).

When GI bleeding or ulceration occurs in patients receiving Dexibuprofen, the treatment should be withdrawn.

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

Hypersensitivity

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug.

Caution is advised in patients with bronchial asthma (acute or in the past), seasonal allergic rhinitis, nasal congestion (e.g. nasal polyps), chronic obstructive pulmonary disease or chronic respiratory infections, since NSAIDs may induce bronchospasm in these patients (see section 4.3). Severe acute hypersensitivity reactions (e.g. anaphylactic shock) are observed very rarely. Therapy must be discontinued at the first sign of a hypersensitivity reaction after taking dexibuprofen. Medically necessary measures corresponding to the symptoms must be initiated by competent persons.

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at a 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). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g. ≤ 1200 mg daily) is associated with an increased risk of myocardial infarction. Although data on the arterial thrombotic risk of dexibuprofen are limited, it can be assumed that the risk with high doses of dexibuprofen (1200 mg/day) is similar to that associated with high doses of ibuprofen (2400 mg/day).

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 dexibuprofen after careful consideration and high doses (1200 mg/day) should be avoided.

Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking particularly when high doses of dexibuprofen (1200 mg/day) are required.

Cases of Kounis syndrome have been reported in patients treated with dexibuprofen. Kounis syndrome has been defined as cardiovascular symptoms secondary to an allergic or hypersensitive reaction associated with constriction of coronary arteries and potentially leading to myocardial infarction.

Renal effects

Renal tubular acidosis and hypokalaemia may occur following acute overdose and in patients taking ibuprofen products over long periods at high doses (typically greater than 4 weeks), including doses exceeding the recommended daily dose.

Caution is required in patients suffering hepatic and renal disease; in hypertensive patients, in the elderly or in patients taking concomitant diuretics or other medicinal products affecting renal function; the risk of fluid retention, oedema and a deterioration in renal function must be taken into account. If used in these patients, the dose of dexibuprofen should be kept as low as possible and renal function should be regularly monitored.

In patients with dehydration in the extracellular space from any cause, e.g. during the peri- or post-operative phases of major surgical interventions, appropriate caution is required when using NSAIDs because of possible bleeding, electrolyte and volume complications. Monitoring of renal function is recommended as a precautionary measure in these cases.

As with all NSAIDs, dexibuprofen can increase plasma levels of urea and creatinine. As with other NSAIDs, dexibuprofen can be associated with adverse effects on the renal system, which can lead to glomerular nephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome and acute renal failure (see section 4.2, 4.3 and 4).

In general the habitual use of analgesics, especially the combination of different analgesic drug substances, can lead to lasting renal lesions with the risk of renal failure (analgesic nephropathy). Thus combinations with dexibuprofen or other NSAIDs (including OTC products and selective COX-2 inhibtors) should be avoided.

Liver

As with other NSAIDs, dexibuprofen can cause transient small increases in some liver parameters, and also significant increases in SGOT and SGPT. In case of a relevant increase in such parameters, therapy must be discontinued (see section 4.2 and 4.3).

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs), including exfoliative dermatitis, erythema multiforme, Steven-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported in association with the use of ibuprofen (see section 4.8). Most of these reactions occurred within the first month.

If signs and symptoms suggestive of these reactions appear Dexibuprofen should be withdrawn immediately and an alternative treatment considered (as appropriate).

Coagulation

In common with other NSAIDs dexibuprofen may reversibly inhibit platelet aggregation and function and prolong bleeding time. Caution should be exercised in patients with haemorrhagic diathesis and other coagulation disorders and when dexibuprofen is given concurrently with oral anticoagulants (see section 4.5).

Data from preclinical studies suggest that inhibition of platelet aggregation by low-dose acetylsalicylic acid may be impaired if NSAIDs such as dexibuprofen are administered concurrently. This interaction could reduce the cardiovascular-protective effect. Therefore if concomitant administration of low dose acetylsalicylic acid is indicated special precaution is required if duration of treatment exceeds short term use (see section 4.5 and 5.1).

Masking of symptoms of underlying infections

Dexibuprofen 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 Dexibuprofen is administered for fever or pain relief in relation to infection, monitoring of infection is advised. In nonhospital settings, the patient should consult a doctor if symptoms persist or worsen.

Additional warnings and precautions for use

Patients receiving long-term treatment with dexibuprofen should be monitored as a precautionary measure (renal, hepatic functions and haematologic function/blood counts).

Dexibuprofen should only be given with care to patients with systemic lupus erythematosus and mixed connective tissue disease, because such patients may be predisposed to NSAID induced renal and CNS side effects, including aseptic meningitis (see section 4.8).

During long-term, high dose, off-label treatment with analgesics, headaches can occur which must not be treated with higher doses of the medicinal product.

Drugs known to inhibit cyclooxygenase/prostaglandin synthesis may impair fertility reversibly and are not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of dexibuprofen should be considered (see section 4.6).

Information on sodium content

This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. is essentially 'sodium-free'.

The information in this section is based upon previous experience with other NSAIDs. In general, NSAIDs should be used with caution with other drugs that can increase the risk of gastrointestinal ulceration or gastrointestinal bleeding or renal impairment.

Concomitant use not recommended:

Anticoagulants

NSAIDs may enhance the effect of anti-coagulants, such as warfarin . Blood coagulation tests (INR, bleeding time) should be performed during the initiation of dexibuprofen treatment and the dosage of the anticoagulant should be adjusted if necessary (see section 4.4).

Methotrexate used at doses of 15 mg/week or more:

If NSAIDs and methotrexate are given within 24 hours of each other plasma levels of methotrexate may increase, via a reduction in its renal clearance thus increasing the potential for methotrexate toxicity. Therefore, in patients receiving high-dose treatment with methotrexate, the concomitant use of dexibuprofen is not recommended.

Lithium:

NSAIDs can increase the plasma levels of lithium, by reducing its renal clearance. The combination is not recommended . Frequent lithium monitoring should be performed if the combination proves necessary. The possibility of reducing the dose of lithium should be considered.

Other NSAIDs and salicylates (acetylsalicylic acid as a pain reliever ):

The concomitant use with other NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided, since simultaneous administration of different NSAIDs can increase the risk of gastrointestinal ulceration and haemorrhage (see section 4.4).

Acetylsalicylic Acid:

Concomitant administration of dexibuprofen and acetylsalicylic acid is generally not recommended due to the potential for increased side effects.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when both are administered concomitantly. Although there are uncertainties regarding the 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. A clinically relevant interaction is unlikely with occasional use of ibuprofen (see section 5.1). Although no data are available for dexibuprofen, it can be assumed that there is a similar interaction between dexibuprofen (= S(+)-ibuprofen) (which is the pharmacologically active enantiomer of ibuprofen) and low-dose acetylsalicylic acid.

Combinations that require careful use:

Thrombolytics, ticlopidine and other antiplatelet agents:

Dexibuprofen inhibits platelet aggregation via inhibition of platelet cyclooxygenase. Therefore, caution is required when dexibuprofen is combined with thrombolytics, ticlopidine and other antiplatelet agents, because of the risk of increased antiplatelet effect.

Antihypertensives:

NSAIDs may reduce the efficacy of beta-blockers, possibly due to inhibition of the formation of vasodilatory prostaglandins.

The concomitant use of NSAIDs and ACE inhibitors or angiotensin-II receptor antagonists may be associated with an increased risk of acute renal failure, especially in patients with pre-existing impairment of renal function. When given to the elderly and/or dehydrated patients, such a combination can lead to acute renal failure by acting directly on glomerular filtration. At the beginning of the treatment, a careful monitoring of renal function is recommended.

Furthermore, chronic administration of NSAIDs can theoretically reduce the antihypertensive effect of angiotensin-II receptor antagonists, as reported with ACE inhibitors. Therefore, caution is required when using such a combination and at the start of treatment, renal function should be carefully monitored (and patients should be encouraged to maintain adequate fluid intake).

Ciclosporin, tacrolimus, sirolimus and aminoglycoside antibiotics:

Concomitant administration with NSAIDs may increase the risk of nephrotoxicity on account of reduced synthesis of prostaglandins in the kidney. During combination treatment renal function must be closely monitored, especially in the elderly.

Corticosteroids:

Concomitant use of NSAIDs and corticosteroids may increase the risk of gastrointestinal ulceration and bleeding (see section 4.4)

Digoxin:

NSAIDs can increase the plasma levels of digoxin and increase the risk of digoxin toxicity.

Methotrexate used at doses lower than 15 mg/week:

Dexibuprofen may increase methotrexate levels. If dexibuprofen is used in combination with low doses of methotrexate, then the patient's blood count should be monitored carefully, particularly during the first weeks of co-administration. An increased surveillance is required in the presence of even mildly impaired renal function, notably in the elderly, and renal function should be monitored to anticipate any reductions in the clearance of methotrexate.

Phenytoin:

Some NSAIDs may displace phenytoin from protein-binding sites, possibly leading to increased phenytoin serum levels and toxicity. Although clinical evidence for this interaction is limited, phenytoin dosage adjustment, based on monitoring of plasma concentrations and/or observed signs of toxicity, is recommended.

Phenytoin, phenobarbital and rifampicin:

Concomitant administration of CYP2C8 and CYP2C9 inducing agents may lower the effects of dexibuprofen.

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs):

Increased risk of gastrointestinal bleeding.

Thiazides, thiazide-related substances, loop diuretics and potassium-sparing diuretics:

Concurrent use of an NSAID and a diuretic may increase the risk of renal failure secondary to a reduction in renal blood flow.

With concomitant use, the antihypertensive effect may be reduced (see section 4.4).

Drugs increasing potassium plasma levels:

NSAIDs have been reported to increase serum potassium levels. Therefore, caution is required during concomitant treatment with other drugs that increase potassium plasma levels (such as potassium sparing diuretics, ACE inhibitors, angiotensin-II receptor antagonists, immunosuppressants like cyclosporin or tacrolimus, trimethoprim and heparins) and serum potassium levels should be monitored.

Oral anti-diabetic drugs:

Concomitant use of an NSAID and sulphonylurea may cause fluctuations in blood glucose level. Therefore, appropriate monitoring may be required.

Zidovudine (Azidothymidine):

Concomitant use of NSAIDs and zidovudine has been reported to increase the risk of hemarthrosis and haematoma in patients with haemophilia.

Pemetrexed:

High doses of NSAIDs may increase the concentration of pemetrexed. In patients with impaired renal function, concomitant use of NSAIDs at high doses should be avoided two days before and two days after pemetrexed administration.

Alcohol:

Excessive alcohol consumption during NSAID-therapy may increase gastro-intestinal adverse effects.

Fertility

NSAIDs may impair fertility reversibly and are not recommended in women attempting to conceive (see section 4.4).

Pregnancy:

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/fetal development.

Data from epidemiological studies suggest an increased risk of miscarriage, 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 postimplantation loss and embryo-fetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period (see section 5.3).

From the 20th week of pregnancy onward, dexibuprofen use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, during the first and second trimester of pregnancy NSAIDs should not be given unless clearly necessary. If NSAIDs are 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. Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to dexibuprofen for several days from gestational week 20 onward. Dexibuprofen should be discontinued if oligohydramnios or ductus arteriosus constriction are found.

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

- cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension),

- renal dysfunction (see above), which may progress to renal failure with oligo-hydroamniosis,

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

- possible prolongation of bleeding time, an antiaggregating effect which may occur even at very low doses,

- inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, dexibuprofen is contraindicated during the third trimester of pregnancy (see sections 4.3 and 5.3).

Lactation

Ibuprofen is slightly excreted in human milk. Breast-feeding is possible with dexibuprofen if dosage is low and the treatment period is short. However, if longer use or higher doses are prescribed, early weaning should be considered.

During treatment with dexibuprofen the patient's reaction capacity may be reduced when dizziness, fatigue, drowsiness, vertigo or visual disturbances appear as side effects. This should be taken into consideration when increased alertness is required, e.g. when driving or operating machinery.

For a single dose or short term use of dexibuprofen no special precautions are necessary.

Clinical experience has shown that the risk of undesirable effects induced by dexibuprofen is comparable to that of racemic ibuprofen. The most common adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4).

Clinical bridging and other studies with a duration of about 2 weeks show a frequency of about 8 to 20% of patients with mostly mild GI-events and a much lower frequency in low risk populations e.g. during short term use or if used occasionally.

When assessing side effects, the following frequency information is used as a basis:

Table 1 Frequencies of side effects

Infections and infestation

Very rare: Infection related inflammation may be aggravated (necrotising fasciitis).

Blood and lymphatic system disorders

Bleeding time could be prolonged.

Rare: Cases of blood disorders including thrombocytopenia, leukopenia, granulocytopenia, pancytopenia, agranulocytosis, aplastic anaemia or haemolytic anaemia.

Immune system disorders

Uncommon: Purpura (including allergic purpura), angioedema.

Rare: Anaphylactic reaction.

Very rare: Generalized hypersensitivity reactions, including symptoms like fever with rash, abdominal pain, headache, nausea and vomiting, signs of liver injury, even aseptic meningitis. In the majority of cases in which aseptic meningitis has been reported with ibuprofen, some form of underlying auto-immune disease (such as systemic lupus erythematosus or other collagen diseases) was present as a risk factor. In the case of a severe generalized hypersensitivity reaction swelling of face, tongue and larynx, bronchospasm, asthma, tachycardia, hypotension and shock can occur.

Psychiatric disorders

Uncommon: Anxiety.

Rare: Psychotic reaction, depression, irritability.

Nervous system disorders

Common: Drowsiness, headache, dizziness, vertigo.

Uncommon: Insomnia, restlessness.

Rare: Disorientation, confusion, agitation.

Very rare: Aseptic meningitis (see immune system disorders).

Eye disorders

Uncommon: Visual disturbances.

Rare: Reversible toxic amblyopia.

Ear and labyrinth disorders

Uncommon: Tinnitus.

Rare: Impaired hearing.

Cardiac Disorders

Not known: Kounis syndrome

Heart and vascular diseases

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

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) (see section 4.4). Although data on the arterial thrombotic risk of dexibuprofen are limited, it can be assumed that the risk with high doses of dexibuprofen (1200 mg/day) is similar to that associated with high doses of ibuprofen (2400 mg/day).

Gastrointestinal disorders

Very common: Dyspepsia, abdominal pain.

Common: Diarrhoea, nausea, vomiting.

Uncommon: Gastrointestinal ulcers and bleeding, gastritis, ulcerative stomatitis, melaena.

Rare: Gastrointestinal perforation, flatulence, constipation, esophagitis, oesophageal strictures, exacerbation of diverticular disease, unspecific haemorrhagic colitis, ulcerative colitis or Crohn's disease.

If gastrointestinal blood loss occurs, this may cause anaemia and haematemesis.

Skin and subcutaneous tissue disorders

Common: Rash.

Uncommon: Urticaria, pruritus.

Very rare: Severe cutaneous adverse reactions (SCARs) (including Erythema multiforme, exfoliative dermatitis, bullous reactions including Stevens-Johnson-Syndrome, and toxic epidermal necrolysis (Lyell-Syndrome)), systemic lupus erythematosus, alopecia, photosensitivity reactions and allergic vasculitis.

Not known: Drug reaction with eosinophilia and systemic symptoms (DRESS). Acute generalized exanthematous pustulosis (AGEP)

Respiratory, thoracic and mediastinal disorders

Uncommon: Rhinitis, bronchospasm.

Metabolism and Nutrition Disorders

Not known: Decreased Appetite, Hypokalaemia*

Renal and urinary disorder

Very rare: Interstitial nephritis, nephrotic syndrome or acute renal failure papillary necrosis,

Not known: Ureteric colic, dysuria, Renal tubular acidosis*

*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.

Hepatobiliary disorders

Rare: Abnormal liver function, hepatitis and jaundice.

General disorders

Common: Fatigue.

Fluid retention: patients with hypertension or renal impairment seem to be predisposed.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

Dexibuprofen has a low acute toxicity and patients have survived after single doses as high as 54 g of ibuprofen (equivalent to approximately 27 g of dexibuprofen). Most overdoses have been asymptomatic. There is a risk of symptoms at doses > 80 - 100 mg/kg ibuprofen.

Symptoms of an overdose

The onset of symptoms usually occurs within 4 hours. Mild symptoms are most common, including abdominal pain, nausea, vomiting, lethargy, drowsiness, headache, nystagmus, tinnitus and ataxia. Rarely, moderate or severe symptoms include gastrointestinal bleeding, hypotension, hypothermia, metabolic acidosis, seizures, impaired kidney function, coma, adult respiratory distress syndrome and transient episodes of apnoea (in very young children following large ingestions). In severe poisoning, metabolic acidosis can occur.

Overdose therapy

Treatment is symptomatic, and there is no specific antidote. Amounts not likely to produce symptoms (less than 50 mg/kg dexibuprofen) may be diluted with water to minimize gastrointestinal upset. In case of ingestion of a significant amount, activated charcoal should be administered.

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.

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

Gastric emptying by emesis should only be considered within 60 minutes of ingestion. Gastric lavage should only be considered if potentially life-threatening amounts of the dexibuprofen have been taken and the gastric lavage can be performed within 60 minutes of ingestion

Forced diuresis, haemodialysis or hemoperfusion do not seen to be of helpful because dexibuprofen is strongly bound to plasma proteins.

Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products, non-steroids, propionic acid derivatives.

ATC code: M01AE14

Dexibuprofen (=S(+)-Ibuprofen) is the pharmacologically active enantiomer of ibuprofen, a non-selective NSAID. By inhibiting prostaglandin synthesis, dexibuprofen has an analgesic, anti-inflammatory and antipyretic effect and inhibits platelet aggregation.

Bridging clinical studies in order to compare the efficacy of racemic ibuprofen and dexibuprofen in osteoarthritis over a treatment period of 15 days, in dysmenorrhea, including symptoms of pain and in dental pain have demonstrated at least “ non-inferiority” of dexibuprofen versus racemic ibuprofen at the recommended 1:2 dose ratio.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg was taken within 8 h before or within 30 min after immediate release aspirin dosing (81mg), a decreased effect of ASA on the formation of thromboxane or platelet aggregation occurred. Although there are uncertainties regarding the 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. A clinically relevant interaction is unlikely with occasional use of ibuprofen (see section 4.5). Although no data are available for dexibuprofen, it can be assumed that there is a similar interaction between dexibuprofen (= S(+)-ibuprofen) (which is the pharmacologically active enantiomer of ibuprofen) and low-dose acetylsalicylic acid.

Absorption

Following oral administration dexibuprofen is well absorbed primarily from the small intestine. Maximum plasma levels are reached about 2 hours after oral administration.

Distribution

The plasma protein binding of dexibuprofen is about 99 %.

Metabolism and elimination

After metabolic transformation in the liver (hydroxylation, carboxylation), the pharmacologically inactive metabolites are completely excreted, mainly by the kidneys (90%), but also in the bile. The elimination half-life is 1.8 – 3.5 hours.

Influence of simultaneous food intake

The administration of 400 mg dexibuprofen with a high fat meal delays the time to reach maximum concentrations (from 2.1 hours after fasting conditions to 2.8 hours after a high fat meal) and decreases the maximum plasma concentrations (from 20.6 to 18.1 µ g/ml, which is of no clinical relevance), but has no effect on the extent of absorption.

Patients with impaired renal and hepatic function

Pharmacokinetic studies with ibuprofen in patients with renal failure suggest a dosage reduction in these patients. Caution is also required due to inhibition of renal prostaglandin synthesis (see section 4.2 and 4.4).

Elimination of dexibuprofen is slightly lower in patients with liver cirrhosis.

“ Bridging” studies on single and repeated dose toxicity, reproduction toxicity and mutagenicity have shown that the toxicological profile of dexibuprofen is comparable to that of ibuprofen and reveal no other specific toxicological or carcinogenic hazards for humans.

Ibuprofen inhibited ovulation in the rabbit and impaired implantation in different animal species (rabbit, rat, mouse). Administration of prostaglandin synthesis inhibitors including ibuprofen (mostly in doses higher than used therapeutically) to pregnant animals has been shown to result in increased pre- and postimplantation loss, embryo-fetal lethality and increased incidences of malformations.

Colloidal anhydrous silica

Microcrystalline cellulose

Hypromellose

Croscarmellose Sodium

Purified Talc

Opadry II white

Purified water

Not applicable

2 years

Store below 25° C.

Dexibuprofen Film-coated Tablets, 300 mg

The packs are available in 10, 20, 30, 50, 60, 90, 100 tablets in blister pack of ALU-PVC/PVDC.

Not all pack sizes may be marketed.

No special requirements.