ACECLOFENAC-BPtablets

Clinical Particulars

Therapeutic Indications

Aceclofenac 100 mg Tablets are indicated for the relief of pain and inflammation in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.

Posology And Method Of Administration

Aceclofenac tablets are supplied for oral administration and should be swallowed whole with a sufficient quantity of liquid. Aceclofenac should be taken preferably with or after food.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).

Adults

The recommended dose is 200 mg daily, taken as two separate 100 mg doses, one tablet in the morning and one in the evening.

Children

There are no clinical data on the use of Aceclofenac in children and therefore it is not recommended for use in children.

Elderly

The pharmacokinetics of Aceclofenac are not altered in elderly patients, therefore it is not considered necessary to modify the dose or dose frequency.

As with other non-steroidal anti-inflammatory drugs (NSAIDs), caution should be exercised in the treatment of elderly patients, who are at increased risk of the serious consequences of adverse reactions, and who are more likely to be suffering from impaired renal, cardiovascular or hepatic function and receiving concomitant medication. The elderly should be monitored regularly for GI bleeding during NSAID therapy.

Renal insufficiency

There is no evidence that the dosage of Aceclofenac needs to be modified in patients with mild renal impairment, but as with other NSAIDs caution should be exercised (See also Precautions).

Hepatic insufficiency

There is some evidence that the dose of Aceclofenac should be reduced in patients with hepatic impairment and it is suggested that an initial daily dose of 100 mg be used.

Contraindications

Hypersensitivity to any of the constituents.

NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin, or other non-steroidal anti-inflammatory drugs.

Severe hepatic and cardiac failure (See section 4.4 - Special warnings and precautions for use).

Moderate to severe renal failure.

During the last trimester of pregnancy (See section 4.6 - Pregnancy and lactation)

Active or previous peptic ulcer.

History of upper gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

Use with concomitant NSAIDs including cyclooxygenase 2 specific inhibitors (See section 4.5 Interactions).

Special Warnings And Precautions For Use

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 risks below).

Elderly:

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

Respiratory disorders:

Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

Cardiovascular, Renal and Hepatic Impairment:

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 – Contraindications). Effects on renal function are usually reversible on withdrawal of Aceclofenac.

If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), Aceclofenac should be discontinued. Hepatitis may occur without prodromal symptoms.

Use of Aceclofenac in patients with hepatic porphyria may trigger an attack.

Gastrointestinal bleeding, ulceration and perforation:

GI bleeding, ulceration or 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 performation is higher with increasing NSAID doses, in patients with a history of ulcers, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients shouls 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 conconminant low dose asprin, 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 unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

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 some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for Aceclofenac.

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

Caution should be advised in patients receiving concomitant medications which could increase the risk of gastrotoxicity or bleeding, such as corticosteroids, or anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (See section 4.5).

When GI bleeding or ulceration occurs in patients receiving Aceclofenac 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 these conditions may be exacerbated (See section 4.8 – Undesirable effects).

Close medical surveillance is imperative in patients with bleeding diathesis or haematological abnormalities.

SLE and mixed connective tissue disease:

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (See section 4.8 – Undesirable effects).

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely 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. Aceclofenac should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Female fertility:

The use of Aceclofenac 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 Aceclofenac should be considered.

Hypersensitivity reactions:

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

Haematological:

Aceclofenac may reversibly inhibit platelet aggregation (See anticoagulants under 'Interactions').

Long-term treatment:

All patients who are receiving NSAIDs should be monitored as a precautionary measure e.g. renal function, hepatic function (elevation of liver enzymes may occur) and blood counts.

Interaction With Other Medicinal Products And Other Forms Of Interaction

Lithium: Aceclofenac, like many NSAIDs, may increase plasma concentrations of lithium.

Cardiac Glycosides: Through their renal effects, NSAIDs may increase plasma glycoside (including digoxin) levels, exacerbate cardiac failure and reduce the glomerular filtration rate in patients receiving glycosides.

Diuretics: Aceclofenac, like other NSAIDs, may inhibit the activity of diuretics. Although it was not shown to affect blood pressure control when co-administered with bendroflumethiazide, interactions with other diuretics cannot be ruled out. When concomitant administration with potassium-sparing diuretics is employed, serum potassium should be monitored. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Anticoagulants: Like other NSAIDs, Aceclofenac may enhance the activity of anticoagulants such as warfarin (See section 4.4 - Special warnings and precautions for use). Close monitoring of patients on combined anticoagulant and Aceclofenac therapy should be undertaken.

Antidiabetic agents: 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. Thus with Aceclofenac, consideration should be given to adjustment of the dosage of hypoglycaemic agents.

Methotrexate: Caution should be exercised if NSAIDs and methotrexate are administered within 24 hours of each other, since NSAIDs may increase methotrexate plasma levels, resulting in increased toxicity.

Mifepristone: NSAIDs should not be used for8-12days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Ciclosporin: Ciclosporin nephrotoxicity may be increased by the effect of NSAIDs on renal prostaglandins.

Quinolone antimicrobials: 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 a NSAID.

Other analgesics including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects (See section 4.3).

Anti-hypertensives: Reduced anti-hypertensive effect.

Corticosteroids: Increased risk of gastrointestinal ulceration or GI bleeding (See section 4.4).

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see section 4.4)

Zidovudine: 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.

Ritonavir: plasma concentration of Aceclofenac possibly increased by ritonavir.

Pregnancy And Lactation

Pregnancy:

Congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closure of the ductus arteriosus), use in the last trimester of pregnancy is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child (See section 4.3 Contraindications). NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus.

Animal studies indicate that there was no evidence of teratogenesis in rats although the systemic exposure was low and in rabbits, treatment with aceclofenac (10 mg/kg/day) resulted in a series of morphological changes in some foetuses.

Lactation:

There is no information on the secretion of Aceclofenac to breast milk; there was however no notable transfer of radio-labelled (¹⁴C) aceclofenac to the milk of lactating rats.

In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breast-feeding.

See section 4.4 Special warnings and precautions for use, regarding female fertility.

Effects On Ability To Drive And Use Machines

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.

Undesirable Effects

The majority of adverse reactions reported have been reversible and of a minor nature. The most frequent are gastro-intestinal disorders, in particular dyspepsia, abdominal pain, nausea and diarrhoea, and occasional occurrence of dizziness. Dermatological complaints including pruritus and rash and abnormal hepatic enzyme and serum creatinine levels have also been reported with the frequencies indicated in the following table.

If serious side effects occur, Aceclofenac should be withdrawn.

The following is a table of adverse reactions reported during clinical studies and after authorisation, grouped by System-Organ Class and estimated frequencies.

Other rare or very rare class-effects reported with NSAIDs in general are:

Gastrointestinal System – Duodenal ulcer, Gastrointestinal perforation

Urinary System – Interstitial nephritis

Central and Peripheral Nervous System – Optic neuritis

Psychiatric – Hallucination, Drowsiness, Confusion

Skin and Appendages – Epidermal necrolysis, Erythema multiforme, Exfoliative dermatitis

Respiratory – Aggravated asthma

Haematological – Aplastic anaemia

Others – Tinnitus, Photosensitivity, Malaise

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

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombic events (for example myocardial infarction or stroke (see section 4.4 Special warnings and precautions for use).

Other undesirable effects that have been reported are exacerbation of colitis and Crohn's disease, angioedema, aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation and also asthma (See section 4.4 Special warnings and precautions for use).

Overdose

There are no human data available on the consequences of Aceclofenac overdose.

Symptoms

Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.

b) Therapeutic measure

Patients should be treated symptomatically as required.

Within one hour of ingestion of a potentially toxic amount activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose.

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.

Other measures may be indicated by the patient's clinical condition.

Specific therapies such as forced diuresis, dialysis or haemoperfusion are probably of no help in eliminating NSAIDs due to their high rate of protein binding and extensive metabolism.

Pharmacological Properties

Pharmacodynamic Properties

ATC code: M01A B16

Aceclofenac is a non-steroidal agent with marked anti-inflammatory and analgesic properties.

The mode of action of aceclofenac is largely based on the inhibition of prostaglandin synthesis. Aceclofenac is a potent inhibitor of the enzyme cyclo-oxygenase, which is involved in the production of prostaglandins.

Pharmacokinetic Properties

After oral administration, aceclofenac is rapidly and completely absorbed as unchanged drug. Peak plasma concentrations are reached approximately1.25to3.00hours following ingestion. Aceclofenac penetrates into the synovial fluid, where the concentrations reach approximately 57% of those in plasma. The volume of distribution is approximately25 L.

The mean (geometrical) plasma elimination half-life is2.30hours. Aceclofenac is highly protein-bound (> 99%). Aceclofenac circulates mainly as unchanged drug. 4'-Hydroxyaceclofenac is the main metabolite detected in plasma. Approximately two-thirds of the administered dose is excreted via the urine, mainly as hydroxymetabolites.

No changes in the pharmacokinetics of aceclofenac have been detected in the elderly.

Preclinical Safety Data

The results from preclinical studies conducted with aceclofenac are consistent with those expected for NSAIDs. The principal target organ was the gastro-intestinal tract. No unexpected findings were recorded.

Aceclofenac was not considered to have any mutagenic activity in three in vitro studies and an in vivo study in the mouse.

Aceclofenac was not found to be carcinogenic in either the mouse or rat.

Pharmaceutical Particulars

Incompatibilities

Not applicable.

Shelf Life

3 years. Do not use after the expiry date.

Special Precautions For Storage

Store in the original package, in a dry, dark place, away from the reach of the children, at a temperature not exceeding 25°C.

Nature And Contents Of Container

Tablets 100 mg. 10 tablets in each blister. 1, 2 or 3 blisters in every package.

Special Precautions For Disposal And Other Handling

No special requirements.

Name and address of the manufacturer

SC “Balkan Pharmaceuticals” SRL

4 Gradescu str.

Chisinau, Republic of Moldova