Dexibuprofen

The effects of anticoagulants on bleeding time can be potentiated by NSAIDs. If concomitant treatment can not be avoidedblood 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.

The risk of gastrointestinal ulceration may be increased by the concomitant administration of NSAIDs and corticosteroids.

The initial dosage should be reduced in patients with mild to moderate impaired renal function.

Patients with mild to moderate hepatic dysfunction should start therapy at reduced doses and be closely monitored.

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).

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

Drugs increasing potassium plasma levels: As with other NSAIDs, concomitant treatment with drugs increasing potassium plasma levels, like potassium-sparing diuretics, ACE inhibitors, angiotensin-II receptors antagonists, immunosuppressants like cyclosporin or tacrolimus, trimethoprime, heparins, etc. may be associated with increased serum potassium levels; hence serum potassium levels should be monitored.

Concomitant administration of ibuprofen may impair inhibition of platelet aggregation by low-dose acetylsalicylic acid.

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.

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

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

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.

Methotrexate used at doses lower than 15 mg/week

Ibuprofen has been reported to 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 coadministration. 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.

Ibuprofen 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.

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.

Caution is required in patients suffering from, or with a previous history of, bronchial asthma since NSAIDs can cause bronchospasm in such patients.

In the treatment of patients with heart failure or hypertension, the risk of fluid retention 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.

For dexibuprofen, no clinical data on exposed pregnancies are available. Animal studies with ibuprofen and other NSAIDs have shown reproductive toxicity.

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/fetal development, and as the consequences of inhibiting the synthesis of prostaglandins are not fully known, dexibuprofen, like other drugs of this class, should only be administered in the first 5 months of pregnancy if clearly needed, in the lowest effective dose and as short as possible.

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

• the fetus to:
  • cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension),
  • renal dysfunction, which may progress to renal failure with oligo-hydroamniosis, * the mother and the neonate, at the end of pregnancy, to:
  • possible prolongation of bleeding time,
  • inhibition of uterine contractions resulting in delayed or prolonged labour.

Therefore, from the beginning of the 6^th month of pregnancy onward dexibuprofen is contraindicated.

The use of dexibuprofen, as with any drug substance known to inhibit cyclooxygenase/prostaglandin synthesis is not recommended in women attempting to conceive.

Ibuprofen is slightly excreted in human milk. Breast-feeding is possible with dexibuprofen if dosage is low and the treatment period is short.

During treatment with dexibuprofen the patient’s reaction capacity may be reduced when dizziness or fatigue 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 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.

It should be noted that the adverse events listed below include those reported predominantly for racemic ibuprofen, even though in some cases the adverse event has either not yet been observed with dexibuprofen or has not yet been reported in the frequency mentioned.

Gastrointestinal

Very common (>1/10): Dyspepsia, diarrhoea.

Common (>1/100, <1/10): Nausea, vomiting, abdominal pain.

Uncommon (>1/1,000, <1/100): Gastrointestinal ulcers and bleeding, ulcerative stomatitis.

Rare (>1/10,000, <1/1,000): Gastrointestinal perforation, flatulence, constipation, esophagitis, esophageal strictures. Exacerbation of diverticular disease, unspecific haemorrhagic colitis, colitis ulcerosa or Crohn’s disease.

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

Skin and hypersensitivity reaction

Common: Rash.

Uncommon: Urticaria, pruritus, purpura (including allergic purpura), angiooedema, rhinitis, bronchospasm.

Rare: Anaphylactic reaction

Very rare (<1/10,000): Erythema multiforme, epidermal necrolysis, systemic lupus erythematosus, alopecia, photosensitivity reactions, severe skin reactions like Stevens-Johnson-Syndrome, acute toxic epidermal necrolysis (Lyell-Syndrome) and allergic vasculitis.

Generalized hypersensitivity reactions have not yet been reported with dexibuprofen but their occurrence cannot be excluded considering the clinical experience with racemic ibuprofen. The symptoms may include fever with rash, abdominal pain, headache, nausea and vomiting, signs of liver injury and 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 case of a severe generalized hypersensitivity reaction swelling of face, tongue and larynx, bronchospasm, asthma, tachycardia, hypotension and shock can occur.

Central nervous system

Common: Fatigue or drowsiness, headache, dizziness, vertigo.

Uncommon: Insomnia, anxiety, restlessness, visual disturbances, tinnitus.

Rare: Psychotic reaction, agitation, irritability, depression, confusion or disorientation, reversible toxic amblyopia, impaired hearing.

Very rare: Aseptic meningitis (see hypersensitivity reactions).

Haematological

Bleeding time may be prolonged. Rare cases of blood disorders include: Thrombocytopenia, leucopenia, granulocytopenia, pancytopenia, agranulocytosis, aplastic anemia or haemolytic anaemia.

Cardiovascular

Peripheral oedema has been reported in association with dexibuprofen treatment.

Patients with hypertension or renal impairment seem to be predisposed to fluid retention.

Hypertension or cardiac failure (especially in the elderly) may occur.

Renal

According to the experience with NSAIDs in general, interstitial nephritis, nephrotic syndrome or renal failure cannot be excluded.

Hepatic

Rare cases of abnormal liver function, hepatitis and jaundice have been observed with racemic ibuprofen.

Others

In very rare cases infection related inflammation may be aggravated.