Diclofenac Other names: Diclofenac sodium

Caution is recommended when co-prescribing diclofenac with potent CYP2C9 inhibitors (such as voriconazole), which could result in a significant increase in peak plasma concentrations and exposure to diclofenac due to inhibition of diclofenac metabolism.

Co-administration of diclofenac with corticosteroids may increase the risk of gastrointestinal bleeding or ulceration. Avoid concomitant use.

No specific studies have been carried out in patients with hepatic impairment, therefore, no specific dose adjustment recommendations can be made. Caution is advised when administering diclofenac to patients with mild to moderate hepatic impairment.

Clinical studies have shown that diclofenac can be given together with oral antidiabetic agents without influencing their clinical effect. However there have been isolated reports of hypoglycaemic and hyperglycaemic effects necessitating changes in the dosage of the antidiabetic agents during treatment with diclofenac. For this reason, monitoring of the blood glucose level is recommended as a precautionary measure during concomitant therapy.

Caution is recommended since concomitant administration of diclofenac with anticoagulants, anti-platelet agents could increase the risk of bleeding. Although clinical investigations do not appear to indicate that diclofenac has an influence on the effect of anticoagulants, there are isolated reports of an increased risk of haemorrhage in patients receiving diclofenac and anticoagulant concomitantly. Therefore, to be certain that no change in anticoagulant dosage is required, close monitoring of such patients is required. As with other nonsteroidal anti-inflammatory agents, diclofenac in a high dose can reversibly inhibit platelet aggregation.

Diclofenac may increase the anticoagulant effect of coumarin anticoagulants.

Concomitant use of cardiac glycosides and NSAIDs in patients may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Like other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensive agents (e.g. beta-blockers, angiotensin converting enzyme (ACE) inhibitors may cause a decrease in their antihypertensive effect via inhibition of vasodilatory prostaglandin synthesis.

Therefore, the combination should be administered with caution and patients, especially the elderly, should have their blood pressure periodically monitored. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy periodically thereafter, particularly for diuretics and ACE inhibitors due to the increased risk of nephrotoxicity.

Concomitant treatment of diclofenac with potassium-sparing diuretics, ciclosporin, tacrolimus or trimethoprim may be associated with increased serum potassium levels, which should therefore be monitored frequently.

Concomitantly, diclofenac may reduce the antihypertensive effect of beta-blockers and ACE inhibitors.

Convulsions may occur due to an interaction between quinolones and NSAIDs. This may occur in patients with or without a previous history of epilepsy or convulsions. Therefore, caution should be exercised when considering the use of a quinolone in patients who are already receiving an NSAID.

Concomitant administration of diclofenac with SSRI’s may increase the risk of gastrointestinal bleeding.

The concomitant use of diclofenac with systemic NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided due to the absence of any evidence demonstrating synergistic benefits and the potential for additive undesirable effects. Co-administration of diclofenac with other systemic NSAIDs may increase the risk of gastrointestinal bleeding or ulceration. Avoid concomitant use of two or more NSAIDs.

Diclofenac, as an inhibitor of CYP1A2, may reduce the metabolism of CYP1A2 substrates.

Like other drugs that inhibit prostaglandin synthetase activity, diclofenac sodium and other NSAIDs can precipitate bronchospasm if administered to patients suffering from, or with a previous history of bronchial asthma.

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

Co-administration of diclofenac with alendronic acid may increase the risk of gastric toxicity.

Diclofenac, like other NSAIDs, may increase the nephrotoxicity of ciclosporin due to the effect on renal prostaglandins. Therefore, it should be given at doses lower than those that would be used in patients not receiving ciclosporin.

These agents can induce a delay or decrease in absorption of diclofenac. Therefore, it is recommended to administer diclofenac at least one hour before or 4 to 6 hours after administration of colestipol/cholestyramine.

If digoxin used concomitantly, diclofenac may raise plasma concentrations of digoxin. Monitoring of the serum digoxin level is recommended.

If lithium used concomitantly, diclofenac may increase plasma concentrations of lithium. Monitoring of the serum lithium level is recommended.

Diclofenac can inhibit the tubular renal clearance of methotrexate hereby increasing methotrexate levels. Caution is recommended when NSAIDs, including diclofenac, are administered less than 24 hours before treatment with methotrexate, since blood concentrations of methotrexate may rise and the toxicity of this substance be increase. Cases of serious toxicity have been reported when methotrexate and NSAIDs including diclofenac are given within 24 hours of each other. This interaction is mediated through accumulation of methotrexate resulting from impairment of renal excretion in the presence of the NSAID.

NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

When using phenytoin concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin.

Rifampicin may increase the metabolism of diclofenac.

Tacrine metabolism can be reduced by diclofenac.

Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus. This might be mediated through renal antiprostagladin effects of both NSAID and calcineurin inhibitor.

Concomitant administration of telmisartan and diclofenac may increase the risk of acute renal failure and hyperkalaemia.

Diclofenac may antagonize the antihypertensive effect of timolol.

Diclofenac may reduce the metabolism and clearance of tizanidine.

Diclofenac may antagonize the antihypertensive effect of trandolapril.

Treprostinil may increase the risk of bleeding when co-administered with diclofenac.

Voriconazole can increase the concentration of diclofenac in blood serum by reducing its metabolism.

Antiplatelet effects of oral diclofenac may increase the risk of bleeding when co-administered warfarin.

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 including diclofenac.

Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high dose (150mg daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with diclofenac after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, and smoking).

Close medical surveillance and caution should be exercised in patients with ulcerative colitis, or with Crohn’s disease as these conditions may be exacerbated.

Diclofenac may reversibly inhibit platelet aggregation. Patients with defects of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.

Diclofenac may increase the anticoagulant activity of anisindione.

The use of diclofenac may impair female fertility and is not recommended in women attempting to conceive. In women who may have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of diclofenac should be considered.

The systemic concentration of diclofenac is lower after topical administration, compared to oral formulations.

With reference to experience from treatment with NSAIDs with systemic uptake, the following is recommended:

• 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 the dose and duration of therapy.
• Animal studies have shown reproductive toxicity. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and postimplantation 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, diclofenac should not be given unless clearly necessary. If diclofenac is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low (<30% of the body surface) and duration of treatment as short as possible (not longer than 3 weeks).

During the second and third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

• Functional renal injury in the foetus. From the 12th week: oligohydramnios (usually reversible after the end of treatment), or anamnios (particularly with prolonged exposure). After birth: kidney failure may persist (particularly with late or prolonged exposure).
• Pulmonary and cardiac toxicity in the foetus (pulmonary hypertension with premature closure of the ductus arteriosus). This risk exists from the beginning of the 6th month and increases if administration is close to full term.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the mother and the neonate, to:

• Possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.
• Inhibition of uterine contractions resulting in delayed or prolonged labour.
• Increased risk of oedema formation in the mother.

Consequently, diclofenac is contraindicated during the third trimester of pregnancy.

Buccal administration

Diclofenac mouthwash should not be used in pregnancy unless considered essential by the physician. There are no adequate and well-controlled studies to support its use.

Ocular administration

There are no data on the use of ocular diclofenac in pregnancy. Studies in animals with diclofenac have shown reproductive toxicity.

1^st and 2^nd Trimester: Animal studies have so far shown no risk to the foetus but no controlled studies in pregnant women are available.

3^rd Trimester: Voltarol Ophtha should not be used, due to a possible risk of premature closure of the ductus arteriosus and possible inhibition of contractions.

Like other NSAIDs, diclofenac passes into breast milk in small amounts. However, at the recommended therapeutic doses no effects on the suckling child are anticipated. Because of a lack of controlled studies in lactating women, the product should only be used during lactation under advice from a healthcare professional. Under this circumstance, diclofenac should not be applied on the breasts of nursing mothers, nor elsewhere on large areas of skin or for a prolonged period of time.

Buccal administration

Diclofenac mouthwash should not be used in pregnancy or lactation unless considered essential by the physician. There are no adequate and well-controlled studies to support its use.

Ocular administration

Diclofenac is excreted in breast milk. However, at therapeutic doses of ocular diclofenac no effects on the suckling child are anticipated. Use of ocular diclofenac is not recommended during breast feeding unless the expected benefits outweigh the possible risks.

Fertility

As with other NSAIDs, the use of diclofenac 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 diclofenac should be considered.

Oral / IV / IM / SC administration

Patients who experience visual disturbances, dizziness, vertigo, somnolence, central nervous system disturbances, drowsiness, or fatigue while taking NSAIDs should refrain from driving or operating machinery.

Cutaneous / Topical application

Cutaneous application of topical diclofenac has no influence on the ability to drive and use machines.

Diclofenac 140 mg medicated plaster has no influence on the ability to drive and use machines.

Buccal administration

Diclofenac mouthwash has no or negligible influence on the ability to drive and use machines.

Ocular administration

Patients with blurred vision should refrain from driving a vehicle or operating machines.