TGP Diclofenac Sodium

White to off white bi-convex film coated tablet engraved with "ACME" on one face and other face being plain.
Each film-coated tablet contains: Diclofenac Sodium BP 100 mg.

Non-selective COX inhibitor.
Pharmacology: Pharmacodynamics: 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.
Pharmacokinetics: Absorption: Diclofenac is 100% absorbed after oral administration compared to IV administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available. Food has no significant effect on the extent of diclofenac absorption. There is usually a delay in the onset of absorption of 1 to 4.5 hours and a reduction in peak plasma levels of <20%.
Distribution: The apparent volume of distribution of Diclofenac sodium is 1.4 L/kg.
Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15-105 μg/mL) achieved with recommended doses.
Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of Diclofenac.
Metabolism: Five Diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5-hydroxy-,3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy-Diclofenac. The major Diclofenac metabolite, 4'-hydroxy-Diclofenac, has very weak pharmacologic activity. The formation of 4'-hydroxy-Diclofenac is primarily mediated by CPY2C9. Both Diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8 may also play a role in Diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy- and 3'-hydroxy-Diclofenac. In patients with renal dysfunction, peak concentrations of metabolites 4'-hydroxy- and 5-hydroxy-Diclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects.
Excretion: Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged Diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged Diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged Diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged Diclofenac is approximately 2 hours.

For the relief of painful and inflammatory conditions due to rheumatoid arthritis, tendinitis, osteoarthritis, bursitis, and other articular or periarthritic disorders.

Adult: One tablet once a day after meals. Diclofenac sodium SR should not be fragmented, nor should they be chewed. If necessary, the daily dose can be increased to 150 mg by taking in addition, either of 2 Diclofenac sodium 25 mg tablet/capsule or 1 Diclofenac sodium 50 mg tablet/capsule, or suppositories.
To be dispensed on physician's prescription.

There is no typical clinical picture resulting from Diclofenac over dosage. Over dosage can cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal hemorrhage, diarrhea, dizziness, disorientation, excitation, coma, drowsiness, tinnitus, fainting or convulsions. In the case of significant poisoning acute renal failure and liver damage are possible. 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 hemo-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.

Diclofenac sodium is contraindicated in peptic ulcer, previous sensitivity to Diclofenac Sodium and in asthmatic patients in whom attacks of asthma, urticaria or acute rhinitis are precipitated by Aspirin or other nonsteroidal anti-inflammatory agents with prostaglandin synthesis inhibiting activity.

Precaution should be taken in patients with symptoms/history of gastro-intestinal disease, impaired hepatic, cardiac or renal function, pregnancy, porphyria and patients who are taking diuretics, anticoagulant, or anti-diabetics. During prolonged treatment, periodical monitoring of liver function should be carried out and blood counts are recommended. Possibility of hypersensitivity reactions to sodium disulphite particularly in patients with asthma.

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/fetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of 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 been shown to result in increased pre- and post-implantation loss and embryo-fetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. 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. During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the fetus 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 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 labor.
Consequently, Diclofenac sodium tablets are contraindicated during the third trimester of pregnancy.
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.
As with other NSAIDs, the use of Diclofenac 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 should be considered.

Occasional gastrointestinal disorders, headache, dizziness or vertigo, rash, elevation of SGOT/SGPT, rare peptic ulcer, gastro-intestinal bleeding, hepatitis, hypersensitivity reactions. In isolated cases, disturbances of sensation, erythema multiforme, purpura, abnormalities of renal function, blood dyscrasias may occur.

The following interactions include those observed with Diclofenac gastro-resistant tablets and/or other pharmaceutical forms of Diclofenac.
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 antihypertensive 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. 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 and periodically thereafter, particularly for diuretics and ACE inhibitors due to the increased risk of nephrotoxicity.
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.
Anticoagulants and anti-platelet agents: Caution is recommended since concomitant administration could increase the risk of bleeding. Although clinical investigations do not appear to indicate that Diclofenac affects the action of anticoagulants, there are reports of an increased risk of hemorrhage in patients receiving Diclofenac and anticoagulants concomitantly. Therefore, to be certain that no change in anticoagulant dosage is required, close monitoring of such patients is required. As with other nonsteroidal anti-inflammatory agents, Diclofenac in high dose can reversibly inhibit platelet aggregation.
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: 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 hypoglycemic and hyperglycemic 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.
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: 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 Voriconazole), which could result in a significant increase in peak plasma concentration and exposure to Diclofenac due to inhibition of Diclofenac metabolism.

Store at temperatures not exceeding 30°C.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

M01AB05 - diclofenac ; Belongs to the class of acetic acid derivatives and related substances of non-steroidal antiinflammatory and antirheumatic products.

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