DESCRIPTION:
Diclofenac sodium is a white or slightly yellowish crystalline powder. The chemical name is 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt. The molecular weight is 318.14 g/mol. Its molecular formula is C₁₄H₁₀Cl₂NNaO₂.

COMPOSITION:
Each Capsule contains: Diclofenac Sodium U.S.P…… 50mg (As Enteric Coated Pellets)
(Product Specs.: M.S.)

CLINICAL PHARMACOLOGY:
Pharmacodynamic Properties: Pharmacotherapeutic group: Acetic acid derivatives and related substances, ATC code: M01AB05

Mechanism of Action:
Diclofenac sodium is a non-steroidal agent with marked analgesic/anti-inflammatory properties. It is an inhibitor of prostaglandin synthetase, (cyclo-oxygenase). Diclofenac sodium in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in human beings.

THERAPEUTIC INDICATIONS:
Adults and elderly
Relief of all grades of pain and inflammation in a wide range of conditions, including:
(i) arthritic conditions: rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gout, (ii) acute musculo-skeletal disorders such as periarthritis (for example frozen shoulder), tendinitis, tenosynovitis, bursitis, (iii) other painful conditions resulting from trauma, including
fracture, low back pain, sprains, strains, dislocations, orthopaedic, dental and other minor surgery.

Children

Diclofenac Sodium 50 mg tablets are not suitable for children.

DOSAGE AND ADMINISTRATION:
To be taken whole with liquid, preferably with or after food.

Adults
75 mg to 150 mg daily in two or three divided doses. The recommended maximum daily dose of diclofenac sodium is 150mg.

Elderly
it is recommended that the lowest effective dosage be used in frail elderly patients or those with a low body weight and the patient should be monitored for GI bleeding during NSAID therapy.

Patients with Renal Impairment
Diclofenac is contraindicated in patients with renal failure. Caution is advised when administering diclofenac to patients with mild to moderate renal impairment.

Patients with Hepatic Impairment
Diclofenac is contraindicated in patients with hepatic failure.

CONTRAINDICATIONS:

• Hypersensitivity to the active substance or to any of the
• Active, gastric or intestinal ulcer, bleeding or perforation.
• History of gastrointestinal bleeding or perforation, relating to previous NSAIDs therapy.
• Active, or history of recurrent peptic ulcer / hemorrhage.
• Last trimester of pregnancy
• Hepatic failure
• Renal failure
• Established congestive heart failure (NYHA-II-IV), ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease.
• Like other non-steroidal anti-inflammatory drugs (NSAIDs), diclofenac is also contraindicated in patients in whom attacks of asthma, angiodema, urticaria or acute rhinitis are precipitated by ibuprofen, acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.

WARNINGS AND PRECAUTIONS:

Lactose
This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

General
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms. The concomitant use of diclofenac with systemic NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided due to the absence of any evidence demonstrating synergistic benefits and the potential for additive undesirable effects. As with other nonsteroidal anti-inflammatory drugs including diclofenac, allergic reactions, including anaphylac-tic/anaphylactoid reactions, can also occur without earlier exposure to the drug.

Gastrointestinal effects
Gastrointestinal bleeding (haematemesis, melaena), ulceration or perforation, which can be fatal has been reported with all NSAIDs including diclofenac, and may occur at any time during treatment, with or without warning symptoms or a previous history of serious gastrointestinal (GI) events. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the medicinal product should be withdrawn.

Caution is recommended in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors (SSRIs) or anti-platelet agents such as acetylsalicylic acid.

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

Hepatic impairment
Close medical surveillance is required when prescribing diclofenac to patients with impairment of hepatic function, as their condition may be exacerbated.

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

Renal impairment
As fluid retention and oedema have been reported in association with NSAID therapy, including diclofenac, particular caution is called for in patients with impaired cardiac or renal function. 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.

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 diclofenac. Diclofenac sodium tablets should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.

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.

Cardiovascular and cerebrovascular effects
Patients with congestive heart failure (NYHA-I) or patients with significant risk factors for cardiovascular events should only be treated with diclofenac after careful consideration. Patients should remain alert for the signs and symptoms of serious arteriothrombotic 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
During prolonged treatment with diclofenac, as with other NSAIDs, monitoring of the blood count is recommended. Diclofenac may reversibly inhibit platelet aggregation (see anticoagulants in section 4.5). Patients with defects of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.

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, reactions on NSAIDs like asthma exacerbations, Quincke’s oedema or urticaria are more frequent than in other patients. Therefore, special precaution is recommended in such patients. This is applicable as well for patients who are allergic to other substances, e.g. with skin reactions, pruritus or urticaria.

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

Female fertility
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.

DRUG INTERACTIONS:

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

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

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

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.

Other NSAIDS including cyclo-oxygenase-2 selective inhibitors and corticosteroids
Co-administration of diclofenac and other systemic NSAIDs or corticosteroids may increase the risk of gastrointestinal bleeding or ulceration. Avoid concomitant use of two or more NSAIDs. Selective serotonin reuptake inhibitors (SSRIs)
Concomitant administration of SSRIs may increase the risk of gastrointestinal bleeding.

Antidiabetics
Reports of hypoglycaemic and hyperglycaemic effects necessitating changes in the dosage of the antidiabetic agents during treatment with diclofenac. For this reason, monitoring of the blood glucose level is recommended as a precautionary measure during concomitant therapy.

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 increased.

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

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

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

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.

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

ADVERSE EFFECTS:

Common:
Headache, dizziness, Vertigo, Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia, Transaminases increased, Rash.

Uncommon:
Myocardial infarction, cardiac failure, palpitations, chest pain.

Rare:
Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock), Somnolence, tiredness, Asthma (including dyspnoea), Gastritis, gastrointestinal haemorrhage, haematemesis, diarrhoea haemorrhagic, melaena, gastrointestinal ulcer with or without bleeding or perforation, Hepatitis, jaundice, liver disorder, Urticaria, Oedema.

Very Rare:
Thrombocytopenia, leucopoenia, anaemia (including haemolytic and aplastic anaemia), agranulocytosis, Angioneurotic oedema (including face oedema), Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder, Paraesthesia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis, taste disturbances, cerebrovascular accident, Visual disturbance, vision blurred, diplopia, Tinnitus, hearing impaired, Hypertension, hypotension, vasculitis, Pneumonitis, Colitis, constipation, stomatitis (including ulcerative stomatitis), glossitis, oesophageal disorder, diaphragm-like intestinal strictures, pancreatitis, Fulminant hepatitis, hepatic necrosis, hepatic failure, 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, Acute renal failure, haematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis, Impotence.

Not Known:
Confusion, hallucinations, disturbances of sensation, malaise, Optic neuritis, Kounis syndrome, Ischaemic colitis

USE IN PREGNANCY AND LACTATION:

Pregnancy:
If diclofenac is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible. Diclofenac sodium tablets are contraindicated during the third trimester of pregnancy.

Lactation:
Like other NSAIDs, diclofenac passes into the breast milk in small amounts. Therefore, diclofenac should not be administered during breast feeding in order to avoid undesirable effects in the infant.

OVERDOSE:
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 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

SHELF LIFE:
3 years.

STORAGE:
Protect from heat, sunlight & moisture, store below 30°C. The expiration date refer to the product correctly stored at the required condition. Keep out of the reach of children.

Patients and healthcare professionals can also report suspected adverse drug reaction at ade@bosch-pharma.com.
To be sold on prescription of a registered medical practitioner only.

PRESENTATION:
Aaram capsule 50mg in blister pack of 2 x 10’s