·         Inflammatory and degenerative forms of rhumatism: rhumatoid arthritis, juvenile rheumatoid  arthritis, ankylosing spondylitis, osteaarthritis including spondyloarthritis,

·         Painful syndromes of the vertebral column.

·         Non-articular rheumatism.

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

·         Painful and/or inflammatory gynaecological conditions, e.g. primary dysmenorrhoea or adnexitis.

 

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. 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).

 

The tablets should be swallowed whole with liquid, preferably with meals and must not be divided or chewed.

 

For oral administration

 

General Target population - Adults:

 

The usual daily dose of Voltaren Retard is 100-150 mg, i.e. one 100 mg prolonged-release coated tablet, or two 75 mg prolonged-release coated tablets. In milder cases and for long-term therapy, one 75 mg or 100 mg prolonged-release coated tablet per day is normally sufficient. If symptoms are most pronounced at night or in the morning, Voltaren Retard should preferably be taken in the evening.

 

The prolonged-release coated tablets should be swallowed whole with liquid, preferably with meals.

 

Special populations

 

Paediatric population (below 18 years of age)

Voltaren 75 mg and 100 mg prolonged release tablets are not suitable for children and adolescents.

 

Elderly (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 sSection 4.4 “Special warnings and 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 sSection 4.4 “Special warnings and precautions for use").

 

Renal impairment

Voltaren is contraindicated in patients with renal impairment (GFR <15 ml/min/1.73 m² ) (see section 4.3 contraindication). 

No specific studies have been carried out in patients with renal impairment, thereforeno specific dose adjustment recommendations can be made. Caution is advised when administering diclofenac to patients with renal impairment (see section 4.4 Special Warnings and precautions for use").

 

Hepatic impairment

Voltaren is contraindicated in patients with hepatic impairment (see section 4.3 contraindication). 

No specific studies have been carried out in patients with hepatic impairment, therefor, no specific dose adjustment recommendations can be made. Caution is advised when administering diclofenac to patients with mild to moderate hepatic impairment (see section 4.4 Special Warnings and precautions for use).

• Hypersensitivity to the active substance or any of the excipients. indicated under section 6.1 • A history of bronchospasm, angioedema, urticaria, acute rhinitis, nasal polyps or allergy-like symptoms after taking acetylsalicylic acid or other non-steroidal anti-inflammatory drugs. • Active, gastric or duodenal ulcer, gastrointestinal bleeding or perforation. • Inflammatory bowel disease (such as Crohn’s disease or ulcerative colitis). • Third trimester of pregnancy (see section 4.6 Pregnancy and lactation). • Hepatic failure (Child-Pugh class C) (cirrhosis of the liver and ascites). • Renal failure (GFR <15 ml/min/1.73 m2). • Severe heart failure (NYHA III-IV), • Treatment of post-operative pain after coronary bypass surgery (or use of a heart-lung machine).

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 apperance sign of rash, mucosal lesions or any other signs of hypersensitivity.

 

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

 

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 with systemic NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided due to the potential for additive undesirable effects (see section 4.5 Interactions with other medicaments and other forms of interaction).

 

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

 

Voltaren Retard/SR tablets contain sucrose and therefore are not recommended for patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency.

 

This medicine contains less than 1 mmol (23 mg) of sodium per dosage unit (coated tablet, prolonged-release tablet and drops), making it practically “sodium-free”.

 

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 (intolerance to analgesics / analgesics-induced asthma), Quincke’s oedema or urticaria are more frequent than in other patients. Therefore, special precaution is recommended in such patients (readiness for emergency). This is applicable as well to patients with allergic reaction to other substances, e.g. rash, pruritus or urticaria.

 

Gastrointestinal effects:

 

As with all NSAIDs, including diclofenac close medical surveillance is imperative and particular caution should be excised when prescribing diclofenac in patients with symptoms indicative of gastrointestinal 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 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 ulcers (particularly if complicated by bleeding or perforation) and in elderly patients.

 

Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) 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 patient, should report any unusual abdominal symptoms (especially GI bleeding).

Caution is recommended in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants, selective serotonin-reuptake inhibitors (SSRIs) or anti-platelet agents (see section 4.5 Interaction with other medicaments 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 prescribing Voltaren to patients with impairment of hepatic function as their condition may be exacerbated. (see section 4.8 Undesirable effects).

 

As with other 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 Diclofenac, calls for regular monitoring of liver enzyme levels.

 

Voltaren 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 for when using diclofenac 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, history of hypertension, the elderly, patients receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function, and those 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 diclofenac in such cases. Discontinuation of therapy is usually followed by recovery to the pre-treatment state.

 

Cardiovascular and cerebrovascular 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 warning. Patients should be instructed to see a physician immediately in case of such an event.

 

Haematological effects:

As with other NSAIDs, complete blood counts are recommended during long-term treatment with Voltaren Retard/SR.

 

Voltaren may temporarily inhibit platelet aggregation Patients with coagulation disorders should be carefully monitored.

The following interactions include those observed with Voltaren Retard/SR tablets and/or other pharmaceutical forms of diclofenac.

 

Observed interactions to be considered

 

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

 

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 increase plasma concentrations of co-administered lithium. Monitoring of the serum lithium level is recommended.

 

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

 

Diuretics and antihypertensive agents:  As other NSAIDs, co-administeration of Voltaren may reduce the antihypertensive effects of diuretics and antihypertensive agents (e.g. beta-blockers, angiotensin converting enzyme (ACE) inhibitors

 

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. (see section 4.4 Special warnings and 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. Therefore, it should be given at doses lower than those that would be used in patients not receiving ciclosporin or Tacrolimus. 

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

 

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

 

Anticipated interactions to be considered

 

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

 

Anticoagulants 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).  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 anticoagulant concomitantly, close monitoring of such patients is recommended.

 

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).

 

Antidiabetics:  Clinical studies have shown that Voltaren can be given together with oral antidiabetic agents without influencing their clinical effect.  However there have been isolated reports of hypoglycaemic and hyperglycaemic 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 recommended when NSAIDs, including diclofenac, are administered less than 24 hours before or after treatment with methotrexate, since blood levels of methotrexate may rise and the toxicity of this substance be increase.

 

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

fertility

the use of diclofenac may impair female fertility and is not recommended in women attempting to conceive. Consideration should be given to stopping diclofenac in women who may have difficulties 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 safety data"). The relevance of this finding for humans is unclear.

 

Pregnancy

Inhibition of prostaglandin synthesis may have negative impact on 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 synthetase inhibitor in early pregnancy. The risk is believed to increase with dose and duration of therapy.

 

In animals, administration of a prostaglandin synthetase 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 malformation, have been reported in animals given a prostaglandin synthetase inhibitor during organogenesis (see section 5.3 preclinical safety data)

 

First/second trimester

During the first and second trimesters of pregnancy, diclofenac should not be given unless absolutely necessary. If Voltaren is used by a woman attempting to conceive, or during the 1st or 2nd trimester of pregnancy, the dose should be kept as low and 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 foetus to:

-           cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension) (see section 5.3 preclinical safety data)

-           renal dysfunction, which may progress to renal failure with oligohydroamniosis

 

·         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

 

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

 

Lactation

As with other NSAIDs, diclofenac passes into breast milk in small amounts. As a precaution, Therefore Voltaren Retard/SR tablets should not be administered during breast feeding in order to avoid undesirable effects in the infant. If treatment is essential, the infant should be switched to bottle feeding

Patients who experience visual disturbances, light-headedness, dizziness, , drowsiness, or other central nervous system disturbances while taking Voltaren retard or SR  should refrain from driving or using machinery.

 

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 short-term or long-term use.

 

Table 1

 

 

Blood and lymphatic system disorders
Very rare	Thrombocytopenia, leucopoenia, anaemia (including haemolytic and aplastic anaemia), agranulocytosis.
Immune system disorders
Rare   Very rare	Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock). Angiooedema (including face oedema). Psychiatric disorders Very rare       Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder.     Nervous system disorders Common Rare Very rare         Headache, light-headedness. Somnolence, Paraesthesia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis, taste disturbances, cerebrovascular accident. Eye disorders Very rare Unknown Visual disturbance, visual impairment , diplopia.   Ear and labyrinth disorders Common Very rare Vertigo. Tinnitus, hearing impaired.   Cardiac disorders Uncommon*     Frequency not known: Myocardial infarction, cardiac failure, palpitations, chest pain.   Kounis syndrome Vascular disorders Common Very rare Hypertension vasculitis. Respiratory, thoracic and mediastinal disorders Rare Very rare Asthma (including dyspnoea). Pneumonitis. Gastrointestinal disorders Common   Rare         Very rare                     Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia. Gastritis, gastrointestinal haemorrhage, haematemesis, haemorrhagic diarrhoea, melaena, gastrointestinal ulcer (with or without bleeding, gastrointestinal stenosis  or perforation, which may lead to peritonitis) Colitis (including haemorrhagic colitis, ischaemic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis,glossitis, oesophageal disorder, intestinal diaphragm diease, pancreatitis.   Voltaren Retard/SR may provoke chronic inflammatory conditions with pseudomembranes and strictures in the lower intestines (small and large intestines)     Hepatobiliary disorders Common Rare Very rare Transaminases increased. Hepatitis, jaundice, hepatic dysfunction Fulminant hepatitis, hepatic necrosis, hepatic failure. Skin and subcutaneous tissue disorders Common Rare Very rare       Not known:     Rash. Urticaria. Bullous dermatitis, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), dermatitis exfoliative, loss of hair, photosensitivity reaction, purpura, Henoch-Schoenlein  purpura, pruritus.     Drug rash with eosinophilia and systemic symptoms (DRESS) Renal and urinary disorders Common   Very rare Fluid retention, oedema.   Acute renal failure, haematuria, proteinuria, nephrotic syndrome, tubulointerstitial nephritis, renal papillary necrosis. General disorders and administration site conditions Rare Oedema

 

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

 

Meta-analyses of controlled Clinical trial and pharmaepidemiological data point towards an increased risk of arterial thromboembolic events (for example myocardial infarction or stroke) associated with the use of diclofenac, particularly at high doses (150mg daily) and in 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

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

 

 

To report any side effect(s):

·         Saudi Arabia

 

-          Saudi Food and Drug Authority National Pharmacovigilance Center (NPC):

 

o Fax: +966112057662

o Call NPC at +966-11-2038222, Exts: 2317-2356-2340.

o Toll free phone: 8002490000

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: +996112658100

o Fax: +966112658107

o Email: adverse.events@novartis.com

 

•    Other GCC States:

-  Please contact the relevant competent authority.

Symptoms

There is no typical clinical picture resulting from diclofenac over dosage. Over dosage may cause symptoms such as vomiting, gastrointestinal bleeding, diarrhoea, light-headedness, tinnitus, convulsions.  Acute renal failure and liver damage are possible in the event of severe 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 haemo-perfusion are unlikely to be helpful in eliminating NSAIDs, including diclofenac, due to their 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.

Pharmacotherapeutic group

Nonsteroidal anti-inflammatory drugs (NSAIDs).

 

Mechanism of action

Voltaren contains the sodium salt of diclofenac, a nonsteroidal agent with pronounced antirheumatic analgesic, anti- inflammatory  and antipyretic activity. 

 

Inhibition of prostaglandin biosynthesis 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 the concentrations reached in human beings. 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

 

Judged on the basis of the urinary recovery of unchanged diclofenac and its hydroxylated metabolites, the same amount of diclofenac is released and absorbed from Voltaren Retard/SR as from the gastro-resistant tablets. However, on average the systemic bioavailability of diclofenac from Voltaren Retard/SR is approximately 82% of that attained with the same dose of Voltaren administered in the form of gastro-resistant tablets (possibly due to release-rate-dependent first-pass metabolism). Owing to the slower release of the active substance from Voltaren Retard/SR, peak plasma concentrations are lower than with the gastro-resistant tablets.

 

Mean peak plasma concentrations of 0.5 µg/ml and 0.4 µg/ml are attained on average 4 hours after administration, respectively, of 100 mg or 75 mg prolonged release tablets. Ingestion with food has no notable effect on the absorption and systemic bioavailability of Voltaren Retard/SR.

 

On the other hand, mean plasma concentrations of 13 ng/ml are recorded 24 hours (16 hours) after ingestion of 100 mg (75 mg).

 

Ingestion of 100 mg once daily or 75 mg twice daily produces trough plasma levels of approximately 22 ng/ml and 25 ng/ml, respectively.

 

Pharmacokinetic behaviour does not change on repeated administration.  Accumulation does not occur, provided the recommended dosage intervals are observed. Plasma concentrations attained in children after equivalent doses (mg/kg body weight) are similar to those attained in adults.

 

Distribution

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

 

The apparent volume of distribution has been calculated at 0.12 to 0.17 L/kg.

 

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

 

Metabolism

Biotransformation of diclofenac is partly by glucuronidation of the intact molecule, but mainly by single and multiple hydroxylation and methoxylation. This results 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 pharmacologically active, but to a much lesser extent than diclofenac itself.

 

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. The virtually inactive metabolite, 3'-hydroxy-4'-methoxy-diclofenac, has a much longer half-life.

 

About 60% of the administered dose is excreted in the urine in the form of metabolites. compared with less than 1% as unchanged substance. The rest of the dose is eliminated as metabolites through the bile in the faeces.

 

Linearity/non-linearity

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

Characteristics in patients

Elderly:  No relevant age-dependent differences in the drug's absorption, metabolism, or excretion have been observed,

 

Patients with renal impairment:  In patients with renal impairment, no accumulation of the unchanged active substance with usual dosage schedule. In patients with  a creatinine clearance of <10 mL/min, the theoritical 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.

 

Patients with hepatic disease:  In patients with 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.

 

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 section "4.3 Contraindications" and "4.6 Pregnancy/Breast-feeding").

 

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).

The tablets also contain the following inactive ingredients:

 

Tablet core

Sucrose (90.8 mg sucrose/75 mg coated tablet and 119 mg sucrose/100 mg coated tablet)

Cetyl alcohol

Polyvinylpyrrolidone

Silica

Magnesium stearate

 

Tablet coat

Hydroxypropyl methylcellulose

Polysorbate 80

Talc

Titanium Dioxide (E171)

Iron Oxide (E172)

 

Tablet polish

Polyethylene glycol

Sucrose

 

Tablet printing ink

Shellac

Propylene glycol

Aluminium hydroxide

Iron oxide (E172)

None known.

Three years.

Do not store above 30℃.

Protect from moisture

Store in the original package                            

Medicines should be kept out of the reach of children.

100 mg Retard tablet:

The tablets are packed in PVC/PE/PVDC blister packs of 10 and 30.

75 mg SR tablet:

The tablets are packed in PVC/PE/PVDC blister packs of 20.

The tablets should be swallowed whole with liquid, preferably with meals.