•           Inflammatory and degenerative forms of rheumatism: rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, osteoarthritis and spondylarthritis,

•           Painful syndromes of the vertebral column,

•           Non- articular rheumatism.

•           Acute attacks of gout.

•           Painful post-traumatic and post-operative inflammation and swelling, e.g. following dental or orthopedic surgery.

•           Painful and/or inflammatory gynecological conditions, e.g. primary dysmenorrhea or adnexitis.

•           As an adjunct in acute painful inflammatory infections of the ear, nose or throat, e.g. pharyngotonsillitis, otitis.

In keeping with standard therapeutic principles, the underlying disease should be treated with specific therapy, as appropriate. Fever alone is not an indication.

As a general recommendation, the dose should be individually adjusted. Adverse 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).

For oral administration

General Target population - Adults:

The starting dose for Voltaren gastro-resistant tablets is usually dose is 100 to 150 mg/day. In milder cases and for long-term therapy, 75 to 100 mg/day are usually sufficient.

The total daily amount is generally given in 2 to 3 divided doses. In order to avoid nocturnal pain and morning stiffness, treatment with the gastro-resistant coated tablets during the daytime can be supplemented by the administration of a suppository at bedtime (up to a total maximum daily dose of 150 mg).

In primary dysmenorrhea, the daily dose should be individually adjusted and is generally 50 to 150 mg/ day. Treatment should be started at 50-100 mg/day and, if necessary, may gradually be increased over the course of several menstrual cycles to a maximum of 150 mg/day.

The gastro-resistant tablets should be swallowed with liquid, preferably before meals; they must not be divided or chewed.

Special populations

Pediatrics

For adolescents and for children aged 1 year or older, the daily dosage, depending on the severity of the disorder is 0.5 to 2 mg/kg body weight given in 2 to 3 divided doses,. For treatment of juvenile rheumatoid arthritis, the daily dose can be increased up to a maximum of 3 mg/kg body weight, iven in several divided doses.

The maximum daily dose of 150 mg should not be exceeded.

Voltaren must not be given to children under 1 year of age.

Voltaren 50 mg gastro-resistant tablets are not recommended for use in children Because of their dosage strength

Elderly patients (aged 65 or above)

No adjustment of the starting dose is generally required for elderly patients. However, caution is indicated on basic medical grounds, especially for frail elderly patients or those with a low body weight (see section 4.4 Special warnings and special precautions for use).

Established cardiovascular disease or significant cardiovascular risk factors

Treatment with Voltaren is generally not recommended in patients with established cardiovascular disease or uncontrolled hypertension. If needed, patients with established cardiovascular disease, uncontrolled hypertension or significant risk factors for cardiovascular disease should be treated with Voltaren only after careful consideration, and only at doses of up to 100 mg daily if treated for more than 4 weeks (see section 4.4 Special warnings and special precautions for use).

Renal impairment

Voltaren gastro-resistant tablets is contraindicated in patients with renal failure (GFR <15 ml/min/1.73 m2) (see section 4.3 Contraindications).

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 Voltaren gastro-resistant tablets to patients with mild to moderate renal impairment (see sections 4.4 Special warnings and special precautions for use).

Hepatic impairment

Voltaren gastro-resistant tablets is contraindicated in patients with hepatic failure (see section 4.3 Contraindications).

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 Voltaren gastro-resistant tablets to patients with mild to moderate hepatic impairment (see sections 4.4 Special warnings and special precautions  for use).

General warning for the use of systemic non-steroidal anti-inflammatory drugs

Gastrointestinal ulceration, bleeding or perforation may occur at any time during treatment with non-steroidal anti-inflammatory drugs (NSAIDs), whether COX-2 selective or not, even in the absence of warning symptoms or a predisposing history. To minimise this risk, the lowest effective dose should be given for the shortest possible duration of treatment.

Placebo-controlled studies have shown an increased risk of thrombotic cardiovascular and cerebrovascular complications with certain COX-2 selective inhibitors. It is not yet known whether this risk correlates directly with the COX-1 / COX-2 selectivity of individual NSAIDs. As no comparable clinical study data are available at present for long-term treatment with the maximum dosage of diclofenac, the possibility of a similarly elevated risk cannot be ruled out. Until such data becomes available, a careful risk-benefit assessment must be carried out prior to using diclofenac in patients with clinically confirmed coronary heart disease, cerebrovascular disorders, peripheral arterial occlusive disease or considerable risk factors (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking). Due to this risk, too, the lowest effective dose should be given for the shortest possible duration of treatment.

The renal effects of NSAIDs include fluid retention with oedema and/or arterial hypertension. For this reason,

diclofenac should be used with caution in patients with cardiac impairment and other conditions that predispose to fluid retention. Caution is also indicated in patients who take concomitant diuretics or ACE inhibitors, or who are at increased risk of hypovolaemia.

The consequences are generally more serious in the elderly. If gastrointestinal bleeding or ulceration occurs in patients undergoing treatment with Voltaren, the medicinal product should be withdrawn.

Cutaneous reactions

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome) and drug rash with eosinophilia and systemic symptoms (DRESS) have been reported very rarely in association with the use of NSAIDs, including Voltaren (see section 4.8 Undesirable effects). Patients appear to be at the highest risk at the start of treatment, with : the onset of the reaction occurring in within the first month of treatment. Voltaren should be discontinued at the first sign of rash, mucosal lesions or any other signs of hypersensitivity.

Allergic reactions

As with other NSAIDs, allergic reactions – including anaphylactic/anaphylactoid reactions – may occur in rare cases, even without prior exposure to diclofenac.

Cases of Kounis syndrome have been reported in patients treated with NSAIDs. Kounis syndrome involves cardiovascular symptoms due to an allergic or hypersensitivity reaction, including narrowing of the coronary arteries, and may potentially lead to a myocardial infarction.

Masking signs of infection

Its pharmacodynamic properties mean that, like other NSAIDs, Diclofenac may mask the signs and symptoms of infection.

Precautions

General

The concomitant use of Voltaren gastro-resistant tablets with systemic NSAIDs including cyclooxygenase-2 selective inhibitors, should be avoided due to the potential for additive adverse effects (see section 4.5 Interaction with other medicinal products and other forms of interaction).

Caution is required in the elderly on basic medical grounds. In particular it is recommended that the lowest effective dosage be used in frail elderly patients or those with a low body weight.

Voltaren gastro-resistant tablets contain lactose. Patients with rare hereditary galactose intolerance, severe lactase deficiency or glucose – galactose malabsorption should not take Voltaren gastro-resistant tablets. .

Respiratory effects (Pre-existing asthma)

In patients with asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (i.e. nasal polyps), chronic obstructive pulmonary diseases or chronic infections of the respiratory tract (especially if linked to allergic rhinitis- like symptoms), reactions on NSAIDs like asthma exacerbations (analgesic intolerance / analgesic- induced asthma), Quincke’s oedema or urticaria are more frequent than in other patients. Therefore, particular caution is required in such patients (emergency readiness). This also applies to patients with allergic reactions – e.g. rash, pruritus or urticaria – to other substances.

Gastrointestinal effects

As with all NSAIDs, including diclofenac, close medical surveillance is required and particular caution should be exercised when prescribing Voltaren gastro-resistant tablets in patients with symptoms indicative of gastrointestinal (GI) disorders or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation, (see section 4.8 Undesirable effects). The risk of GI bleeding is higher with increasing NSAID doses and in patients with a history of ulcer (particularly if complicated with bleeding or perforation) and in the elderly patients.

Treatment should be initiated and maintained at the lowest effective dose in order to reduce the risk of GI toxicity in patients with a history of ulcer (particularly if complicated by bleeding or perforation), and in elderly pateints,

Combination therapy with protective agents (e.g. proton pump inhibitors or misoprostol) should be considered for these patients, and also for patients requiring concomitant use of low-dose acetylsalicylic acid (ASA), or other drugs likely to increase gastrointestinal risk.

Patients with a history of GI toxicity, particularly  elderly patients, should report any unusual abdominal symptoms (especially GI bleeding). Caution required in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants, anti-platelet agents or selective serotonin-reuptake inhibitors (see section 4.5 Interaction with other medicinal products and other forms of interaction).

NSAIDs, including diclofenac, can be associated with an increased risk of a gastrointestinal anastomosis leak. Caution is required with the use of Voltaren after gastrointestinal surgery and close medical monitoring is recommended.

Hepatic effects

Close medical surveillance is required when giving Voltaren gastro-resistant tablets to patients with impaired hepatic function, as their condition may be exacerbated. (see section 4.8 Undesirable effects).

As with all NSAIDs, including diclofenac, levels of one or more liver enzymes may rise during treatment with Voltaren This has been observed very frequently with diclofenac in clinical studies (in approximately 15% of patients), but is very rarely accompanied by clinical symptoms. Most of these cases involve borderline increases. Frequently (in 2.5% of cases) the increases observed were moderate (≥ 3 to < 8 times the upper limit of normal), while the incidence of marked increases (≥ 8 times the upper limit of normal) remained around 1%. Elevated liver enzyme levels were accompanied by clinically manifest liver damage in 0.5% of cases in the above-mentioned clinical studies. Elevated enzyme levels were generally reversible after discontinuation of the drug.

As with other NSAIDs long-term treatment with Voltaren gastro-resistant tablets required for regular monitoring of liver enzyme levels.

Voltaren gastro-resistant tablets should be discontinued, If abnormal liver function tests persist or worsen, if clinical signs or symptoms suggestive of liver disease develop, or if other manifestations occur (e.g. eosinophilia, rash).

In addition to elevated liver enzymes, there have been rare reports of severe hepatic reactions, including jaundice and fulminant hepatitis, hepatic necrosis and hepatic failure which, in isolated cases, had a fatal outcome.

Hepatitis may develop without prodromal symptoms. Caution is required when using Voltaren gastro-resistant tablets in patients with hepatic porphyria, since it may trigger an attack.

Renal effects

Owing to the importance of prostaglandins in maintaining renal blood flow, prolonged treatment with high doses of NSAIDs, including diclofenac, frequently (1–10%) results in oedema and hypertension., particular caution is required in patients with impaired cardiac or renal function, in patient with history of hypertension, in elderly patient, in patients receiving concomitant treatment with diuretics or medicinal products that may significantly impact renal function, and in patients with substantial extracellular volume depletion from any cause, e.g. before or after major surgery (see section 4.3 Contraindications).

Monitoring of renal function is recommended as a precautionary measure when using Voltaren gastro-resistant tablets in such cases. Patients usually recover to their pre-treatment state following discontinuation of therapy.

Cardiovascular effects

Treatment with NSAIDs including diclofenac, particularly at high doses and for prolonged periods , may be associated with a slightly increased risk of serious cardiovascular thrombotic events (including myocardial infarction and stroke).

Treatment with Voltaren is generally not recommended in patients with established cardiovascular disease (heart failure, established ischaemic heart disease, peripheral arterial disease) or uncontrolled hypertension. If needed, patients with established cardiovascular disease, uncontrolled hypertension or significant risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus and smoking) should be treated with Voltaren only after careful consideration and only at doses of up to 100 mg daily if treated for more than 4 weeks.

As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, the lowest effective daily dose should be used for the shortest duration possible. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically, especially when treatment continues for more than 4 weeks.

Patients should remain alert for the signs and symptoms of serious arterial thromboembolic events (e.g. chest pain, shortness of breath, weakness, slurring of speech), which can occur without warnings. Patients should be instructed to see a physician immediately in case of such an event.

Haematological effects

As with other NSAIDs, complete blood counts during long-term treatment with Voltaren gastro-resistant tablets.

Like other NSAIDs, Voltaren gastro-resistant tablets may temporarily inhibit platelet aggregation. Patients with coagulation disorder should be closely monitored.

The following interactions include those observed with Voltaren gastro-resistant tablets and/or other pharmaceutical forms of diclofenac.

Observed interactions to be considered

 CYP2C9 inhibitors:

Caution is required when co- administering diclofenac with potent CYP2C9  inhibitors (such as voriconazole), this could result in a significant increase in peak plasma concentrations and exposure to diclofenac .

Enzyme inhibitors

CYP2C9 inducers: Caution is required when co-administering diclofenac with CYP2C9 inducers (such as rifampicin). This could result in a significant decrease in plasma concentration and exposure to diclofenac.

Lithium: diclofenac may raise plasma concentrations of co-administered lithium. Monitoring of the serum lithium level is recommended.

Digoxin: diclofenac may increase plasma concentrations of co-administered digoxin. Monitoring of the serum digoxin level is recommended.

Diuretics and antihypertensive agents: As with other NSAIDs, co-administration of diclofenac with diuretics or antihypertensive agents (e.g. beta-blockers, angiotensin converting enzyme (ACE) inhibitors) may cause a decrease in their antihypertensive effect.

the combination should be administered with caution and patients, especially the elderly pateints, should have their blood pressure monitored regularly . Patients should be adequately hydrated and attention should be paid to monitoring of renal function on initiating  combination therapy and regularly thereafter, particularly with diuretics and ACE inhibitors due to the increased risk of nephrotoxicity. (see section 4.4 Special warnings and special precautions for use).

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

Drugs known to cause hyperkalemia: Concomitant treatment with potassium-sparing diuretics, ciclosporin, tacrolimus or trimethoprim may be associated with increased plasma potassium levels, which should therefore be monitored frequently (see section 4.4 Special warnings and special precautions for use).

Quinolone antibiotics: There have been isolated reports of convulsions which may have been due to concomitant use of quinolones and NSAIDs.

Anticipated interactions to be considered

Other NSAIDs and corticosteroids: Concomitant administration of diclofenac with other systemic NSAIDs or corticosteroids may increase the frequency of gastrointestinal adverse effects (see section 4.4 Special warnings and special precautions for use).

Anticoagulants and anti-platelet agents: Caution is required since co-administration could increase the risk of bleeding (see section 4.4 Special warnings and special precautions for use).

Although clinical investigations do not appear to indicate that diclofenac affects the action of anticoagulants, there have been reports of an increased risk of bleeding in patients receiving diclofenac and anticoagulants concomitantly. Close monitoring of such patients is therefore recommended.

Selective serotonin reuptake inhibitors (SSRIs): Co-administration of systemic NSAIDs and SSRIs may increase the risk of gastrointestinal bleeding (see section 4.4 Special warnings and special precautions for use).

Anti-diabetics 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 both hypoglycaemic and reactions following administration of diclofenac, requiring adjustment of  the dosage of the antidiabetic agents. For this reason, monitoring of the blood glucose level is recommended as a precautionary measure during concomitant therapy.

There have also been isolated reports of metabolic acidosis when diclofenac was co-administered with, especially in patients with pre-existing renal impairment.

Methotrexate: Caution is required when NSAIDs, including diclofenac, are administered less than 24 hours before or after treatment with methotrexate, because blood levels of methotrexate may rise and the toxicity may increase.

Phenytoin: Monitoring of phenytoin plasma concentrations is recommended if phenytoin is used concomitantly with diclofenac 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.

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

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

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.

Fertility

Voltaren gastro-resistant tablets may impair female fertility and is not recommended in women attempting to conceive. Consideration should be given to stopping diclofenac in women who are having difficulty conceiving, or in those being tested for infertility.

In animals, based on relevant data, impairment of male fertility cannot be ruled out (see section 5.3 "Preclinical data"). The relevance of this finding for humans is unclear.

Pregnancy

Inhibition of prostaglandin synthesis may have a negative impact on pregnancy and/or embryofetal development. Data from epidemiological studies suggest an elevated risk of miscarriage and of cardiac malformation and gastroschisis following administration of a prostaglandin synthetase inhibitor during early pregnancy. The risk is assumed to rise with the dose and the duration of therapy.

In animals, administration of a prostaglandin synthetase inhibitor has been shown to result in increased pre-implantation and post-implantation loss and embryofetal lethality. In addition, increased incidences of various malformations, including cardiovascular malformations, have been reported in animals given a prostaglandin synthetase inhibitor during organogenesis (see section 5.3 "Preclinical data").

During the first and second trimesters of pregnancy,  diclofenac should not be given unless absolutely necessaryIf diclofenac is used by a woman attempting to conceive, or during the first or second trimesters of pregnancy, the dose should be kept as low – and the duration of treatment as short – as possible.

Oligohydramnios/neonatal renal impairment

Use of NSAIDs in the 20th week of pregnancy or later may lead to fetal renal impairment, which may cause oligohydramnios and, in some cases, neonatal renal impairment. These adverse effects occur, on average, after days to weeks of treatment, although in rare cases oligohydramnios has been reported as early as 48 hours after initiation of NSAID treatment. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some post-marketing cases of neonatal renal impairment invasive procedures such as exchange transfusion or dialysis were required. Consider ultrasound monitoring of the amniotic fluid if Voltaren treatment lasts longer than 48 hours. Discontinue Voltaren if oligohydramnios occurs and follow up according to clinical practice.

Third trimester

diclofenac is contraindicated during the third trimester of pregnancy

All prostaglandin synthetase inhibitors may:

- expose the fetus to the following risks:

cardiopulmonary toxicity (with premature closure of the ductus arteriosus, and pulmonary hypertension, also see section 5.3 "Preclinical data");

renal dysfunction, which may progress to renal failure with oligohydramnios.

- expose the mother and child to the following risks:

possible prolongation of bleeding time, an effect of inhibition of platelet aggregation even at very low doses; inhibition of uterine contractions, resulting in delayed or prolonged labour.

Breast-feeding

As with other NSAIDs, small amounts of diclofenac passes into the breast milk. . As a precaution, diclofenac should therefore, not be used

by women who are breast-feeding. If treatment is essential, the infant should be switched to bottle feeding.

Patients experiencing visual disturbances, light-headedness, dizziness, drowsiness, or other central nervous system disturbances while taking Voltaren gastro-resistant tablets should refrain from driving or using machines.

The following adverse effects include those reported with Voltaren gastro-resistant tablets and/or other pharmaceutical forms of diclofenac, during either short-term or long-term use.

Frequencies

Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Table 1 Adverse drug reactions

* The frequency reflects data from long-term treatment with a high dose (150 mg/day).

Meta-analysis of controlled clinical studies and pharmacoepidemiological data point towards a small increased risk of arterial thromboembolic events (for example myocardial infarction or stroke) associated with the use of diclofenac, particularly at a high dose (150 mg daily) and during long-term treatment (See section 4.4 Special warnings and precautions for use)

Visual effects

Visual disturbances such as visual impairment, blurred vision and diplopia appear to be NSAID class effects and are usually reversible on discontinuation. A likely mechanism for the visual disturbances is the inhibition of prostaglandin synthesis and other related compounds that alter the regulation of retinal blood flow resulting in potential changes in vision. If such symptoms occur during diclofenac treatment, an ophthalmological examination may be considered to exclude other causes.

Reporting of suspected adverse reactions

To report any side effect(s):

·         Saudi Arabia

-          The National Pharmacovigilance Centre (NPC):

o SFDA call center: 19999

o E-mail: npc.drug@sfda.gov.sa

o Website: https://ade.sfda.gov.sa  

-          Patient Safety Department Novartis Consulting AG - Saudi Arabia:

o Toll Free Number: 8001240078

o Phone: +966112658100

o Fax: +966112658107

o Email: adverse.events@novartis.com

•    Other GCC States:

-  Please contact the relevant competent authority.

To report any complaint(s) : complaints.ksa@novartis.com

Symptoms

There is no typical clinical picture resulting from diclofenac overdosage. Overdose may cause symptoms such as vomiting, gastrointestinal bleeding, diarrhoea, light-headedness, tinnitus or convulsions. acute renal failure and liver damage are possible in the event of significant intoxication .

Therapeutic measures

Treatment of acute intoxication 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.

Specific measures such as forced diuresis, dialysis, or haemoperfusion are unlikely to be helpful in eliminating NSAIDs, including diclofenac, due to the 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.

 (ATC code: M01A B05).

Mechanism of action

Voltaren gastro-resistant tablets contains diclofenac sodium, a non-steroidal compound with pronounced antirheumatic, anti-inflammatory, analgesic and antipyretic properties.

Inhibition of prostaglandin biosynthesis, which has been demonstrated experimentally, and is considered fundamental to the mechanism of action of diclofenac . Prostaglandins play a major role in causing inflammation, pain, and fever. in vitro, at concentrations equivalent to those attained in humans. Voltaren does not suppress proteoglycan biosynthesis in cartilage.

Clinical efficacy

In rheumatic diseases, the anti-inflammatory and analgesic properties of diclofenac elicit a clinical response characterised by improved function and marked relief of signs and symptoms such as pain at rest, pain on movement, morning stiffness and swelling of the joints. In post-traumatic and post-operative inflammatory conditions, Voltaren rapidly relieves both spontaneous pain and pain on movement, and reduces inflammatory swelling and wound oedema.

In clinical trials, the product has also been shown to exert a pronounced analgesic effect in moderate and severe pain of non-rheumatic origin. It can relieve the pain, and also reduce bleeding, in primary dysmenorrhoea.

Absorption

Diclofenac is completely absorbed from the gastro-resistant tablets after their passage through the stomach. Although absorption is rapid, its onset may be delayed due to the gastro-resistant coating of the tablet.

Mean peak plasma concentrations of 1.5 micrograms/mL are attained on average 2 hours after ingestion of one tablet of 50 mg.

The coated tablets pass through the stomach more slowly when ingested with or after a meal than when it is ingested before a meal, but the amount of diclofenac absorbed remains the same.

Since about half of diclofenac is metabolized during its first passage through the liver ("first pass" effect), the area under the concentration curve (AUC) following oral or rectal administration is about half that following an equivalent parenteral dose.

Pharmacokinetic behavior does not change after repeated administration. No accumulation occurs provided the recommended dosage intervals are observed.

The plasma concentrations attained in children given equivalent doses (mg/kg body weight) are similar to those obtained in adults.

Distribution

Diclofenac is 99.7% bound to serum proteins, mainly to albumin (99.4%). The apparent volume of distribution calculated is 0.12 to 0.17 L/kg.

Diclofenac enters the synovial fluid, where maximum concentrations are measured 2 to4 hours after peak plasma values have been reached. The apparent half-life for elimination from the synovial fluid is 3 to 6 hours. Two hours after reaching peak plasma levels, concentrations of the active substance are already higher in the synovial fluid than in the plasma, and they remain higher for up to 12 hours.

 A low concentration of Diclofenac (100ng/mL) was detected in the breast milk of one nursing mother. The estimated amount ingested by an infant consuming breast milk is equivalent to a 0.03 mg/kg/day dose.

Metabolism

Biotransformation of diclofenac is partly by glucuronidation of the intact molecule, but mainly by single and multiple hydroxylation and methoxylation, resulting in several phenolic metabolites (3'-hydroxy-,4'-hydroxy-,5- hydroxy-,4',5-dihydroxy- and 3'-hydroxy-4'-methoxy-diclofenac), most of which are subsequently converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, but to a much smaller extent than diclofenac itself.

Elimination

Total systemic clearance of diclofenac from plasma is 263 56 mL/min (mean value SD). The terminal half-life is 1 to 2 hours. Four of the metabolites, including the two that are active, also have short plasma half-lives of 1 to 3 hours. the virtually inactive. metabolite, 3'-hydroxy-4'-methoxy-diclofenac has a much longer plasma half-life.

About 60% of the dose is excreted in the urine as metabolites, Compared with Less than 1% as unchanged substance. The rest of the dose is eliminated as metabolites via the bile in the faeces.

Linearity/ Non - linearity

The amount absorbed is in linear proportion to the size of the dose.

Pharmacokinetics in Special populations

No relevant age-dependent differences in the drug’s absorption, metabolism, or excretion have been observed.

Renal impairment

In patients with renal impairment, the drug’s single-dose pharmacokinetics do not suggest any accumulation of unchanged active substance with the usual dosage schedule. In patients with a creatinine clearance of < 10mL/min, theoretical steady-state plasma levels of the metabolites are about 4 times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.

Hepatic impairment

In patients with hepatic impairment (chronic hepatitis or compensated cirrhosis), the pharmacokinetics and metabolism of diclofenac are the same as in patients without liver disease.

Preclinical data from safety pharmacology studies, acute and repeated dose toxicity studies and genotoxicity, mutagenicity and carcinogenicity studies with diclofenac revealed no evidence of a specific hazard for humans at the intended therapeutic doses.

The increased incidence of lymphomas (thymus) in mice, and subcutaneous fibromas, fibroadenomas (mammary gland) or C-cell adenomas (thyroid gland) in rats were all within the historical control range of the laboratory for the animal strain used, and are considered to have occurred by chance.

In all toxicity studies carried out in rats, hypertrophy of mesenteric lymph nodes or lymphadenitis with reactive hyperplasia were observed. These changes were accompanied by neutrophilia that was also observed in studies in monkeys. These are presumably secondary reactions to the ulcers observed in the gastrointestinal tract. In a two-year study, a dose-dependent increase in thrombotic vascular occlusions in the heart was observed in rats treated with diclofenac.

Reproductive toxicity

Additional studies indicate that, with repeated oral doses in rats (> 1 mg/kg body weight), diclofenac causes effects that influence fertility (lower testosterone level, and decreased epididymal and testicular weight in association with histopathological changes). Similar effects were also observed in the F1 generation following doses of ≥ 1.25 mg/kg in a two-generation study. In dogs, daily subcutaneous doses of 2 mg/kg diclofenac sodium led to an increased spermatid count. Further studies describe a decreased mating frequency in female rats following a repeated dose of ≥ 0.5 mg/kg diclofenac. For this reason, an influence on both male and female fertility cannot be ruled out.

Diclofenac crosses the placental barrier in rodents. Administration of NSAIDs (including diclofenac) inhibited ovulation in rabbits and implantation and placentation in rats, and led to premature closure of the ductus arteriosus in pregnant rats. Maternally toxic doses of diclofenac were associated with dystocia, prolonged gestation, decreased fetal survival, and intrauterine growth retardation in rats. The slight effects of diclofenac on reproduction parameters and delivery as well as closure of the ductus arteriosus in utero are pharmacological effects of this class of prostaglandin synthetase inhibitors (see sections "4.3 Contraindications" and " 4.6 Fertility, Pregnancy and lactation").

In a study in mice, teratogenicity (cleft palate) was observed at the maternally toxic dose of 4 mg/kg. In rats and rabbits, doses up to the maternally toxic level did not lead to teratogenic effects. Delayed ossification and reduced fetal weight in a study in rabbits were the only changes observed in these investigations.

At maternally toxic doses, the perinatal and post-natal development of the offspring were impaired (fertility, see above, also birth weight and delayed post-natal growth).

Core for 50 mg: Cellulose microcrystalline; lactose monohydrate; magnesium stearate; maize starch; povidone; silica, colloidal anhydrous; sodium starch glycolate (type A);

Coating for 50 mg: hypromellose; iron oxide red (E172); iron oxide yellow (E172); macrogoglycerol hydroxystearate; Methacrylic acid – ethyl acrylate copolymer; macrogol 8000; talc; titanium dioxide (E171); Simeticone; alpha-octadecyl-omega-hydroxy-polyglykolether; sorbic acid.

Gastro-resistant coated tablets: Maize starch, lactose monohydrate (16 mg lactose/25 mg coated tablet and 25 mg lactose/50 mg coated tablet), sodium starch glycolate type A, microcrystalline cellulose, colloidal anhydrous silica, povidone K30, magnesium stearate, hypromellose, talc, iron oxide red, titanium dioxide, macrogoglycerol hydroxystearate (130 mcg/25 mg coated tablet and 220 mcg/50 mg coated tablet), iron oxide yellow, methacrylic acid – ethyl acrylate copolymer (1:1) dispersion 30 per cent/methacrylic acid copolymer, macrogol 8000, silicone antifoam emulsion SE 2.

Not applicable.

-           Do not store above 30°C.

-           Store in the original package

-           Must be kept out of the reach and sight of children.

-           Protect from moisture.

50        mg gastro-resistant tablets x 20

Not all pack sizes may be marketed

No special requirement.