Introduction:
Macdicol is a brand name of diclofenac sodium, is a non-steroidal anti-inflammatory agent. Its chemical name is Sodium [o-[ (2,6-dichloropheny) amino] phenyl] acetate and its structural formula is as shown below.

Clinical Pharmacology:
In pharmacologic studies, diclofenac sodium has shown anti-inflammatory, analgesic and antipyretic activity. As with other nonsteroidal anti-inflammatory agents its mode of action is not known; however, its ability to inhibit prostaglandin synthesis may be involved in the anti-inflammatory effect.

Pharmacokinetics:
Macdicol is completely absorbed from the gastrointestinal tract after fasting oral administration with peak plasma levels occurring in 2-3 hours. However, due to first-pass metabolism only about 50% of the absorbed dose is systemically available. The mean terminal half-life in plasma is approximately 2 hours, but early elimination is much more rapid. Area under the
plasma concentration curve (AUC) is dose-proportional within the range of 25 mg to 150 mg. Peak plasma levels are less than dose-proportional and are approximately 1.0, 1.5 and 2 ug/ml for 25 mg, 50 mg and 75 mg doses respectively. Clearance and volume of distribution were about 350 ml/min and 550 ml/kg respectively. After repeated oral administration of 50 mg
b.i.d. Macdicol did not accumulate in plasma. The degree of accumulation of diclofenac metabolites is unknown. Some of the metabolites may have activity, more than 99% of diclofenac is reversibly bound to human plasma albumin.

Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Approximately 65% of the dose is excreted in the urine, and approximately 35% in the bile Conjugates of the principal metabolite, 4’-hydroxy-diclofenac account for 20-30% of the dose excreted in the urine and for 10-20% of the dose excreted in the bile. Conjugates of three other metabolites (5-hydroxy-3’-hydroxy and 4’, 5- dihydroxy-diclofenac) together account for 10-20% of the dose excreted in the urine and for small amount excreted in the bile. Conjugates of unchanged diclofenac account for 5-10% of the dose excreted in the urine and for less than 5% excreted in the bile. Little or no unchanged unconjugated drug is excreted. It is not known whether there is genetic
polymorphism in the enzymes responsible for metabolism of diclofenac.

The extent of absorption of Macdicol is not significantly affected when the drug is taken with food, however there is usually a delay in the onset of absorption of 1 to 4.5 hours, with delays as long as 10 hours in some patients. There is also a reduction in peak plasma levels.

A 4 week study comparing plasma level profiles of diclofenac (50 mg b.i.d.) in younger (26-46) versus older (66-81) adults did not show differences between age groups (10 patients per age group).

Single dose studies of the effects of renal function impariment (50 mg intravenously) or hepatic impairment (100 mg oral
solution) have been performed in small numbers of patients. To date no differences in the pharmadcokinetics of diclofenac have been detected in patients with renal or hepatic impariment. In patients with renal impairment (N-5, creatinine clearance 3 to 42 ml/min.) AUC values and elimination rates were comparable to those in healthy subjects. In patients with biopsy confirmed cirrhosis or chronic active hepatitis (variably elevated transaminases and mildly elevated bilirubins, N=10), diclofenac concentrations and urinary elimination values were comparable to those in healthy subjects.

Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs during the first 4 hours following a dose, while plasma levels are higher than those in synovial fluid, after which the process reverses and synovial fluid levels are slightly higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac sodium.

In healthy subject, the daily administration of 150 mg of diclofenac sodium for 3 weeks resulted in a mean fecal blood loss less than that observed with 3.0 g of aspirin daily. In repeated dose studies, mean fecal blood loss with 150 mg of
diclofenac sodium was also less than that observed with 750 mg of naproxen or 150 mg of indomethacin. Repeated dose endoscopic studies in normal volunteers showed that daily doses of 75 mg or 100 mg of diclofenac sodium for 1 week caused fewer gastric lesions, and those that did occur had lower scores that these which occured following 500 mg daily doses of naproxen. The clinical significance of these findings is unknown since there is no evidence available to indicate that diclofenac is less likely than other drugs of its class to cause serious gastrointestinal lesions when used in chronic
therapy.

In patients with rheumatoid arthritis, Macdicol has been adiministered safely in combination with gold or corticosteroids.

Indications:
Macdicol is indicated for the treatment of the signs and symptoms of rheumatoid arthritis, osteoarthrosis, low back pain, active musculo-skeletal disorders, such as peri-arthritis (especially frozen shoulder), tendinitis, tenosynovitis, bursitis, sprains, strains and dislocations, relief of pain in fractures, ankylosing spondylitis, acute gout, control of pain and inflammation in
orthopaedic, dental and other minor surgery. Painful and/or inflammatory conditions in gynecologic e.g. primary dysmenorrhoea or adnexitis. It is also indicated as an adjuvant in severe painful inflammatory infections of the ear, nose or throat e.g. pharyngotonsillitis otitis.

Contraindications:
Macdicol is contra-indicated in patients with hypersensitivity to it. Acute and suspected peptic ulcer or gastro-intestinal bleeding diclofenac sodium should not be given to patients in whom aspirin or other non steroidal anti-inflammatory drugs induce asthma, urticaria or other allergic-type reactions.

Precautions:
Patients with history of gastrointestinal ulceration, heamatemesis or melaena, ulcerative colitis, crohn’s diseases, bleeding diathesis or haematological abnormalities, and patients suffering with severe hepatic, cardiac or renal insufficiency or elderly should be kept under close surveillance.

During prolonged treatment with Macdicol as with other highly active nonsteroidal antiinflammatory agents blood counts and monitoring of hepatic and renal function are indicated as precautionary measures.

Effects on ability to drive or use machines patients experiencing dizziness or other central nervous disturbances should refrain from driving a vehicle or operating machine.

During pregnancy Macdicol should be employed only for compelling reasons and only in the lowest effective dose. As in the case of other prostaglandin-synthetase inhibitors, this applies particularly to the last 3 months of pregnancy (owing to the possibility of uterine inertia and/or premature closure of the ductus arteriosus). Following oral doses of 50 mg administered every 8 hours, the active substance passes into the breast milk, but in quantities so small that no undersirable effects on the infant are to be expected.

Side Effects:
There have been reported of gastro-intestinal ulceration haematemesis and mealena. Initially some patients may complain of epigastric pain, eructation, nausea and diarrhoea, headach or slight dizziness. These side effects are usually of mild nature. Liver function disorders including hepatitis with or without jaundice. In isolated cases, acute renal insufficiency urinary
abnormalities, intestinal nephritis or nephrotic syndrome may rarely occur. Central nervous side effects such as tiredness, insomnia or irritability, have occured in rare instances.Occasionally skin reactions, fluid retention and abnormalities of serum transaminases have been reported. In the course
of extensive clinical usage, very rarely leucopenia, thrombocytopenia or aplastic anemia have been reported. There have been isolated reports of anaphylactoid/anaphylactic reactions, bronchospasm and erythema multiforma.

Drug Interactions:
Aspirin
Concomitant administration Macdicol and aspirin is not recommended because Macdicol is displaced from its binding sites during the concomitant administration of aspirin, resulting in lower plasma concentrations, peak plasma levels and ACU values.

Anticoagulants:
While studies have not shown Macdicol to interact with anticoagulants of the warfarin type, caution be exercised. Nonetheless, since interactions have been seen with other NSAIDs. Because prostaglandins play an important role in
hemostasis and NSAIDs affect platelet function as well, concurrent therapy with all NSAIDs, including Macdicol and warfarin requires close monitoring of patients to be certain that no change in their anticoagulant dosage is required.

Digoxin, Methotrexate,. Cyclosporine:
Macdicol like other NSAIDs, through effects on renal prostaglandins, may cause increases toxicity of certain drugs. Digoxin and methotrexate serum levels may be elevated as well as cyclosporine’s nephrotoxicity. Patients receiving these drugs who are started on, or are given increased doses of Macdicol or any other NSAID, and particularly those patients with altered renal function, should be observed for the development of the specific toxicities of these drugs. In the case of digoxin, serum levels should be monitored.

Lithium:
Macdicol decreases lithium renal clearance and increases lithium plasma levels. In patients taking Macdicol and lithium concomitantly, lithium toxicity may develop.

Oral Hypoglycemics:
Macdicol does not alter glucose metabolism in normal subjects nor are the effects of oral hypoglycemic agents altered by the concomitant administration of Macdicol. There are rare reports however, from postmarketing experiences of changes in effects in insulin or oral hypoglycemic agents in the presence of diclofenac which necessitated changes in the doses of such agents. Both hypo and hyperglycemic effects have been reported. A direct casual relationship has not been established, but physicians should be consider the possibility that diclofenac may alter a diabetic patient’s response to insulin or oral hypoglyemic agents.

Diuretics:
Macdicol and other NSAIDs can inhibit the activity of diuretics. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium levels.

Other Drugs:
In small groups of patients (7-10/interaction study), the concomitant administration of azathioprine, gold chloroquine, D-penicillamine, prednisolone, doxycyline, or digitoxin did not significantly alter the levels and ACU values of Macdicol.

Protein Binding:
In vitro, Macdicol interferes minimally or not all with the protein binding of salicylic acid (20% decrease in binding), tolbutamide, prednisolone (10% decrease in binding), or warfarin. Benzylpencillin, ampicillin, oxacillin, chlortetracycline, doxycycline cephalothin, erythromycin and sulfamethoxazole have no influence in vitro on the protein binding of Macdicol in human
serum.

Drug/Laboratory Test Interactions Effect on Blood Coagulation:
Macdicol increase platelet aggregation time but does not affect bleeding time, plasma thrombin clotting time plasma fibrinogen, of factors V and VII to XII. Statistically significant changes in prothrombin and partial thromboplastin times have been reported in normal volunteers. The mean changes were observed to be less than 1 second in both instances, however, and unlikely to be clinically important. Macdicol is a prostaglandin synthetics inhibitor, however, and all drugs that inhibit prostagiandin synthesis interfere with platelet function to some degree; therefore, patients who may be adversely affected by such an
action should be carefully observed.

Carcinogenesis, Mutagenesis, Impairment of Fertility:
Long-term carcinogenicity studies in rats given Macdicol up to 2 mg/kg/day (approximately the human dose) have revealed no significant increases in tumor incidence.

There was a slight increase in benign mammary fibroadenomas in mid-dose females (high dose females had excessive mortality), but the increase was not significant for this common rat tumon. Macdicol did not show mutagenic potential in various mutagenicity studies including the Ames test. Macdicol administered to male and female rats at 4 mg/kg/day did not affect fertility.

Over Dosage:
There is no specific antidote to Macdicol and the treatment is symptomatic. Worldwide report on over dosage with diclofenac
(upto 2.5 g) cover 27 cases. In 10 of these 27 cases, diclofenac was only the drug taken, all of these patients recovered.

In case of acute overdosage it is recommended that the stomach be emptied by vomiting or lavage. Forced diuresis may
be beneficial because the drug is excreted in the urine. The elimination of diclofenac remains unproven, because of its
light protein binding rate and extensive metabolism, supportive and symptomatic treatment should be given for complications
such as hypotension, renal failure, convulsion, gastrointestinal irritation and respiratory depression. In addition to supportive
measures, the use of oral activated charcoal may help to reduce the absorption of Macdicol.

Dosage and Administration:
Tablets (Adults)
The initial general daily dosage is 100 to 150 mg/day b.i.d. or t.i.d. For long term therapy, patients should be generally maintained on the lowest dosage consistent with achieving a satisfactory therapeutic response.

In osteoarthritis, the recommended dosage is 100 to 150 mg/day in divided doses 50 mg b.i.d. or t.i.d.

In rheumatoid arthritis, the recommended dosage is 150 to 200 mg/day in divided doses 50 mg b.i.d. or t.i.d.

In ankylosing spondylitis, the recommended dosage is 100 to 125 mg/day administered as 25 mg q.i.d. with an extra 25
mg dose at bed time if necessary.
The tablets should be swallowed whole with liquid preferably before meals.

Capsules:
The recommended initial daily dose is 100 mg, administered as 1 Capsule of Macdicol SR 100 In milder cases, as well as for long - term therapy, 1 capsule of Macdicol SR 100 daily is usually sufficient.
Where the symptoms are most pronounced during the night or in the morning, Macdicol SR 100 should preferably be taken in the evening.
The capsules should be taken whole with liquid, preferably with meals.

Injections:
Usually, administer 1 ampoule (3ml) for one time daily. For systemic therapy, injection should be given deeply into the gluteal muscle to ensure delivery. Use alternate sites for subsquent injections.
To be used by the physician.

Children:
The dosage strengths in tablets, capsules SR and injection form are not recommended for use in children.

Elderly Patients:
The Pharmacokinetics of Macdicol are not impaired in elderly patients and the standard elder dose may be used. Non steroidal antiinflammatory drugs should be used with particular caution in older patients who generally are more prone
adverse reactions.