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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Slofenac 100mg SR

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 100mg diclofenac sodium.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Modified release tablets

Pale red, round biconvex tablets, marked S28 on one side and plain on the other.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Rheumatoid arthritis; osteoarthritis; acute gout; low back pain; relief of pain in fractures; acute musculo-skeletal disorders and trauma including periarthritis (particularly frozen shoulder), bursitis, tendinitis, tenosynovitis, dislocations, sprains and strains; ankylosing spondylitis; and the control of pain and inflammation in orthopaedic, dental and other minor surgery.

4.2    Posology and method of administration

Posology

Adults: One 75mg tablet once or twice a day.

The recommended maximum daily dose of Slofenac tablet is 150mg.

Paediatrics: Not suitable for use in children.

Elderly: Nonsteroidal anti-inflammatory drugs should be used with particular caution in elderly patients who generally are more prone to adverse reactions. In particular it is recommended that the lowest effective dosage be used in frail elderly patients or those with a low body weight (see also Precautions) and the patient should be monitored regularly for GI bleeding during NSAID therapy.

Renal impairment: Diclofenac is contraindicated in patients with severe renal impairment (see section 4.3). No specific studies have been carried out in patients with renal impairment, therefore, no specific dose adjustment recommendations can be made. Caution is advised when administering diclofenac to patients with mild to moderate renal impairment (see section 4.3 and 4.4).

Henatic impairment: Diclofenac is contraindicated in patients with severe hepatic impairment (see section 4.3). 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 (see section 4.3 and 4.4).

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4 Special warnings and precautions for use)

Method of administration:

For Oral administration.

Tablets should be swallowed whole with liquid, preferably with or after food.

4.3 Contraindications

Slofenac tablets are contraindicated in the following situations:

•    Hypersensitivity to the active substance or any of the excipients listed in section 6.1

•    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, renal and cardiac failure (see section 4.4 - Special warnings and precautions for use).

•    During the last trimester of pregnancy (See section 4.6 - Fertility pregnancy and lactation).

•    Active, gastric or intestinal ulcer, bleeding or perforation.

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

•    Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding)

•    Established congestive heart failure (NYHA II-IV), ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease.

4.4 Special warnings and precautions for use

General

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).

The concomitant use of diclofenac tablets 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 (see section 4.5 Interactions).

As with other nonsteroidal anti-inflammatory drugs including diclofenac, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug (see section 4.8 Undesirable effects).

Like other NSAIDs, diclofenac may mask the signs and symptoms of the infection due to its pharmacodynamics properties.

Elderly:

Caution is indicated in the elderly on basic medical grounds. In particular, it is recommended that the lowest effective dose be used in frail elderly patients or those with a low body weight (see section 4.2 Posology and Method of administration).

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

Cardiovascular, Renal and Hepatic Impairment:

The administration of an NS AID 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, the elderly or those recovering from major surgery. Renal function should be monitored in these patients (See also section 4.3 - Contraindications).

Caution in patients with a history of hypertension and/or heart failure as fluid retention and oedema have been reported in association with NS AID therapy.

Diclofenac should be stopped if liver function tests show abnormalities which persist or worsen, or if liver disease develops or if other symptoms such as eosinophilia or rash occur.

Diclofenac sodium may trigger an attack in patients with hepatic porphyria. Hepatitis may occur with diclofenac without prodromal symptoms.

Monitoring of renal function, hepatic function (elevation of liver enzymes may occur) and blood counts should be performed on long-term NSAID patients, as a precautionary measure.

Gastrointestinal bleeding, ulceration and perforation:

GI 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 GI events.

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

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.

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 (SSRIs) or anti-platelet agents such as aspirin (See section 4.5 Interactions).

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation and in the elderly. These patients should commence treatment on the lowest dose available and gastroprotective agents such as proton pump inhibitors should be considered.

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).

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).

Female fertility:

The use of diclofenac sodium 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 sodium should be considered (see section 4.6 Fertility, pregnancy and lactation).

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 the use of diclofenac, particularly at high dose (150mg daily) and in long term treatment may beassociated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with diclofenac after careful consideration. As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be reevaluated periodically.

Pre-existing asthma:

In patients with asthma, seasonal allergic rhinitis, swelling of nasal mucosa (i.e nasal ployps), chronic obstructive pulmonary disease or chronic infections of respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions on NSAIDS like asthma exacerbations (so called intolerance to analgesics/analgesics asthma), Quincke’s oedema or urticarial are more frequent than in other patients. Therefore, special precaution is recommended in such patients (readiness for emergency). This is applicable as well for patients who are allergic to other substances, e.g with skin reactions, pruritus or urticarial.

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.

Skin effects:

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, including Diclofenc (see section 4.8 Undesirable effects). Patients appear to be at highest risk of these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of the treatment. Diclofenac should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.

Haematological effects:

During prolonged treatment with diclofenac, as with other NSAIDs, monitoring of the blood count is recommended. Slofenac may reversibly inhibit platelet aggregation (see anticoagulants in section 4.5 Interactions). Patient with defetcs of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored)

4.5 Interaction with other medicinal products and other forms of interaction

Other NSAIDs including cyclooxygenase-2 selective inhibitors. : 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 (including aspirin) as this may increase the risk of adverse effects (See section 4.3 Contraindications).

Diuretics and Anti-hypertensives agents: Like other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensive agents (eg. Beta-blockers, angiotensin converting enzymes (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.

Drugs known to cause hyperkalemia: Increased serum potassium levels may result when diclofenac is given concomitantly with potassium-sparing diuretics, ciclosporin, tacrolimus or trimethoprim Serum potassium levels should therefore be monitored frequently.

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

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

Lithium: Diclofenac may increase plasma concentrations of lithium (by impairment of its excretion from the kidneys). Monitoring of the serum lithium level is recommended.

Methotrexate:

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.

Ciclosporin: NSAIDs may increase ciclosporin nephrotoxicity as a result of their effect on renal prostaglandins.

Mifepristone:    NSAIDs should not be used for 8-12 days after

mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Corticosteroids: Increased risk of GI bleeding (See section 4.4 -Special warnings and precautions for use).

Anti-coagulants and anti-platelet agents: Caution is recommended since concomitant administration could increase the risk of bleeding (see section 4.4 Special warnings and precautions for use) as diclofenac may reversibly inhibit platelet aggregation. Monitoring is recommended to ensure the desired response to the anticoagulant is maintained as there are rare reports of increased risk of haemorrhage with combined diclofenac and anticoagulant therapy (See section 4.4 - Special warnings and precautions for use).

Selective serotonin reuptake inhibitors (SSRIs): Concomitant administration of SSRI's may increase the risk of gastrointestinal bleeding (see section 4.4 Special warnings and precautions for use).

Quinolone antibiotics: 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.

Tacrolimus: 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.

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

Colestipol and cholestyramine: 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

Potent CYP2C9 inhibitors: 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.

Oral antidiabetic agents: It has been reported that hypo- and hyperglycaemic effects have occurred rarely when diclofenac and oral antidiabetic agents

have been given together and adjustment of the hypoglycaemic may be required. For this reason, monitoring of the blood glucose level is recommended as a precautionary measure during concomitant therapy.

4.6 Fertility, pregnancy and lactation

Pregnancy:

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 or 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 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 organogenetic period. If Slofenac is used by a woman attempting to conceive, or during the 1st trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus 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 the pregnancy, 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 Consequently, Diclofenac is contraindicated during the third trimester of pregnancy.

Lactation:

Like other NSAIDs, diclofenac passes into breast milk in small amounts. Therefore Diclofenac should not be administered during breast feeding in order to avoid undesirable effects in the infant (see section 5.2 Pharmacokinetic properties).

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 may have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of diclofenac should be considered. See section 4.4 Special warnings and precautions for use, regarding female fertility.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Adverse reactions are ranked under the heading of frequency, the most frequent first, using the following convention: very common: (>1/10); common (>    1/100,    <1/10); uncommon (>    1/1,000,    <1/100); rare

(>1/10,000, <1/1000); very rare (<1/10,000); not known: cannot be estimated from available data.

The following undesirable effects include those reported with other shortterm or long- term use.

Blood and lymphatic	system disorders
Very rare	Thrombocytopenia, leucopoenia, anaemia (including haemolytic and aplastic anaemia), agranulocytosis
Immune system disorders
Rare	Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock).
Very rare	Angioneurotic oedema (including face oedema).
Psychiatric disorders
Very rare	Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder.
Nervous system disorders

Common	Headache, dizziness.
Rare	Somnolence, tiredness
Very rare	Paraesthesia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis, taste disturbances, cerebrovascular accident.
Unknown	Confusion, hallucinations, disturbances of sensation, malaise.
_Eye disorders_
Very rare	Visual disturbance, vision blurred, diplopia
Unknown	Optic neuritis.
Ear and labyrinth disorders
Common	Vertigo
Very rare	Tinnitus, hearing impaired
Cardiac disorders
Very rare	Palpitations, chest pain, cardiac failure, myocardial infarction.
Vascular disorders
Very rare	Hypertension, hypotension, vasculitis
Respiratory, thoracic and mediastinal disorders
Rare	Asthma (including dyspnoea).
Very rare	Pneumonitis
Gastrointestinal disorders
Common	Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia.
Rare	Gastritis, gastrointestinal haemorrhage, haematemesis, diarrhoea haemorrhagic, melaena, gastrointestinal ulcer with or without bleeding or perforation (sometimes fatal particularly in the elderly).
Very rare	Colitis (including haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, oesophageal disorder, diaphragm-like intestinal strictures, pancreatitis
Hepatobiliary disorders
Common	Transaminases increased.
Rare	Hepatitis, jaundice, liver disorder

Very rare	Fulminant hepatitis, hepatic necrosis, hepatic failure.
Skin and subcutaneous tissue disorders
Common	Rash.
Rare	Urticaria.
Very rare	Bullous eruptions, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), dermatitis exfoliative, loss of hair, photosensitivity reaction, purpura, allergic purpura, pruritus.
Renal and urinary disorders
Very rare	Acute renal failure, haematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis_
General disorders and administration site conditions
Rare	Oedema
Reproductive system and breast disorders
Very rare	Impotence.

Clinical trial and epidemiological data consistently point towards an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) associated with the use of diclofenac, particularly at high dose (150mg daily) and in long term treatment. (see section 4.3 and 4.4 for Contraindications and Special warnings and special precautions for use)

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.

4.9 Overdose

a)    Symptoms

There is no typical clinical picture resulting from diclofenac over dosage. Over dose can cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting or convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.

b)    Therapeutic measures

Management of acute poisoning with NSAIDs, including diclofenac, essentially consists of supportive measures and symptomatic treatment. Supportive measures and symptomatic treatment should be given for

complications such as hypotension, renal failure, convulsions, gastrointestinal disorder, and respiratory depression.

Special measures such as forced diuresis, dialysis or haemo-perfusion are probably of no help in eliminating NSAIDs, including diclofenac, due to high protein binding and extensive metabolism.

Activated charcoal may be considered after ingestion of a potentially toxic overdose, and gastric decontamination (e.g. vomiting, gastric lavage) after ingestion of a potentially life threatening overdose.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products; ATC Code: M01A B05

Diclofenac sodium is a non-steroidal, anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. It is an inhibitor of prostaglandin synthetase.

5.2 Pharmacokinetic properties

Absorption

The same amount of active substance is released and absorbed from SR tablets as from enteric-coated tablets. Mean peak plasma concentrations of diclofenac are reached at 4 hours, 0.4 ± 0.184pg/ml (0.4pg/mL =1.25pmol/L) for 75mg SR tablets. 75mg SR tablets are modified release preparations and plasma concentrations of diclofenac of 13ng/mL (40nmol/L) can be recorded at 16 hours after administration. Absorption is unaffected by food.

Bioavailability:

The systemic availability of diclofenac from the SR formulations is on average 82% of that achieved with the same dose of enteric-coated tablets (possibly due to release rate dependent first-pass metabolism). As a result of the slower release of active substance, peak plasma concentrations are lower than for the equivalent enteric-coated tablets.

Pharmacokinetic behaviour does not change on repeated administration. Accumulation does not occur, provided the recommended dosage intervals are

observed. Trough levels of diclofenac in the plasma after 75mg SR twice daily are around 25ng/ml (80nmol/l).

Distribution

The active substance is 99.7% protein bound, mainly to albumin (99.4%).

Diclofenac enters the synovial fluid, where maximum concentrations are measured 2-4 hours after the peak plasma values have been attained. The apparent half-life for elimination from the synovial fluid is 3-6 hours. Two hours after reaching the peak plasma values, concentrations of the active substance are already higher in the synovial fluid than they are in the plasma and remain higher for up to 12 hours.

Diclofenac was detected in a low concentration (100 ng/mL) in breast milk in one nursing mother. The estimated amount ingested by an infant consuming breast milk is equivalent to a 0.03 mg/kg/day dose (see section 4.6 Fertility, pregnancy and lactation).

Metabolism

Biotransformation of diclofenac takes place partly by glucuronidation of the intact molecule, but mainly by single and multiple hydroxylation and methoxylation, resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two phenolic metabolites are biologically active, but to a much lesser extent than diclofenac.

Elimination

The total systemic clearance of diclofenac in plasma is 263 ± 56 mL/min (mean value ± SD). The terminal half-life in plasma is 1-2 hours. Four of the metabolites, including the two active ones, also have short plasma half-lives of 1-3 hours.

About 60% of the administered dose is excreted in the urine in the form of the glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted to glucuronide conjugates. Less than 1% is excreted as unchanged substance. The rest of the dose is eliminated as metabolites through the bile in the faeces.

Characteristics in patients

Elderly: No relevant age-dependent differences in the drug's absorption, metabolism, or excretion have been observed, other than the finding that in five elderly patients, a 15 minute iv infusion resulted in 50% higher plasma concentrations than expected with young healthy subjects.

Patients with renal impairment: In patients suffering from renal impairment, no accumulation of the unchanged active substance can be inferred from the single-dose kinetics when applying the usual dosage schedule. At a creatinine clearance of less than 10 mL/min, the calculated steady-state plasma levels of the hydroxy metabolites are about 4 times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.

Patients with hepatic disease: In patients with chronic hepatitis or non-decompensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in patients without liver disease.

5.3 Preclinical safety data

None stated.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Talc

Ethylcellulose Magnesium stearate Povidone Stearic acid

Hydroxypropyl methylcellulose Diethyl phthalate Titanium dioxide (E171)

Red iron oxide (E172)

Yellow iron oxide (E172) Polyethylene glycol 4000

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

10 DATE OF REVISION OF THE TEXT

25/03/2015