Apo-Diclo

Diclofenac sodium.

25 mg: Each tablet contains: diclofenac sodium 25 mg. Energy: 1 kJ (0.2 kcal), Sodium: 1 mmol.
50 mg: Each tablet contains: diclofenac sodium 50 mg. Energy: 2 kJ (0.4 kcal), Sodium: 1 mmol.

Pharmacology: Diclofenac has demonstrated anti-inflammatory, analgesic and antipyretic properties in classical animal test systems. Its exact mode of action is not known. However, since it exhibits an anti-inflammatory effect even in adrenalectomized animals, its action is not mediated through the pituitary adrenal axis.
Diclofenac inhibits prostaglandin biosynthesis in vitro and in vivo. This inhibitory effect may be involved in its anti-inflammatory actions.
Diclofenac has been found to relieve pain, reduce fever, swelling and tenderness and increase mobility in patients with rheumatic disorders of the types listed. Although diclofenac affords relief of symptoms, it does not alter the course of underlying disease.
Clinical trials in rheumatoid arthritis indicate that 150mg daily of diclofenac is more effective than placebo, and as effective as 2.4 g daily of ibuprofen or 3.6g daily of ASA.
Diclofenac is similar in activity to equivalent dosages of indomethacin (75 to 150 mg daily), and causes less CNS side effects at these doses.
Diclofenac 150 mg daily induces minimal gastrointestinal blood loss, significantly less so than ASA 3g or naproxen 750mg daily.
In man, orally administered diclofenac is rapidly and almost completely absorbed and distributed to blood, liver and kidneys. The plasma concentrations show a linear relationship to the amount of drug administered.
The mean terminal drug half-life in plasma was 18 hours after oral doses. Diclofenac is extensively bound (99%) to serum albumin. In single dose studies (oral or IM) in patients with active rheumatoid disease and joint effusions, diclofenac concentrations were found to be higher in synovial fluid at least 3 times greater than that from plasma.
The ability of elderly subjects to absorb, metabolize and excrete diclofenac does not appear to differ significantly from those of young subjects.
In man about 40% to 60% of the drug and its metabolites and eliminated in the urine and the balance in the feces.
More than 90% of an oral dose is accounted for in elimination products within 72 hours. The chief metabolites are conjugates of the 3', 4' and 5-hydroxy- derivatives of diclofenac. Free diclofenac accounts for less than 1% of the does excreted in the urine. Conjugates of diclofenac itself account for 5 to 10% of the dose recovered in the urine.
A single dose pharmacokinetic study in patients with varying degrees of renal dysfunction (creatinine clearance rate ranging from 3ml/min to 42ml/min), suggests that moderate renal impairment does not affect the elimination rate of unchanged diclofenac from plasma but that it may reduce the elimination rate of the metabolites (i.e. pharmacologically less active metabolites) of the drug. Although no accumulation of pharmacologically active substance seems to occur, caution is advised while administering diclofenac to patients with impaired kidney function.

For the symptomatic treatment of rheumatoid arthritis and osteoarthritis, including degenerative joint disease of the hip.

Rheumatoid arthritis: Treatment should be initiated with 75 mg to 150 mg per day in 3 or 4 doses, depending on the severity of the condition. For maintenance, the dose should be reduced to the minimum amount that will provide control of symptoms, usually 75 mg to 100 mg daily in 3 divided doses.
Osteoarthritis: The starting and maintenance dose is usually 75 mg/day in 3 divided doses. The dose should be adjusted individually to the minimum dose that will provide control of symptoms.
The maximum recommended daily dose is 150 mg.
Diclofenac should be taken with food and the tablets should be swallowed whole.

Symptoms and Treatment: Worldwide reports on overdosage with diclofenac cover 27 cases. In 10 of these 27 cases, diclofenac was the only drug taken, all of these patients recovered. The highest dose of diclofenac was 2.5 g in a 20 year old male who suffered acute renal failure as a consequence, and who was treated with three dialysis sessions and recovered in 2 days. The next highest dose was 2.35 g in a 17 year old girl who experienced vomiting and drowsiness. A dose of 2 g of diclofenac was taken by a woman of unspecified age who remained asymptomatic.
There is no specific antidote for diclofenac. Supportive and symptomatic treatment is recommended and may include emptying of the stomach by induction of vomiting or gastric lavage. Also, measures to reduce absorption (activated charcoal) and to accelerate elimination (dialysis) may be considered.

In patients with active or recent history of inflammatory disease of the gastrointestinal tract such as peptic, ulcer, gastritis, regional enteritis or ulcerative colitis.
Diclofenac is contraindicated in patients with known or suspected hypersensitivity to the drug. Since cross-sensitivity has been demonstrated diclofenac should not be given to patients in whom ASA or other non-steroidal anti-inflammatory NSAIDs have induced asthma, rhinitis, urticaria, or other allergic-type reactions because severe, rarely fatal, anaphylactic like reactions to diclofenac have been reported in such patients.
Special Populations: Established cardiovascular disease or significant cardiovascular risk factors: The use of high dose diclofenac (150mg/day) for more than 4 weeks is contraindicated in patients with established cardiovascular disease (congestive heart failure, established ischemic heart disease, peripheral arterial disease) or uncontrolled hypertension.
If diclofenac treatment is needed, patients with established cardiovascular disease, uncontrolled hypertension or significant cardiovascular risk factors (e.g. hypertension, hyperlipidaemia, diabetes mellitus and smoking) should be treated only after careful consideration and at doses ≤ 100 mg daily if the treatment is for more than 4 weeks. As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, diclofenac should always be prescribed at the lowest effective daily dose and for the shortest duration possible.

Peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal have been reported during therapy with NSAIDs including diclofenac.
Diclofenac should be given under close medical supervision to patients prone to gastrointestinal tract irritation particularly those with a history of peptic ulcer, diverticulosis or other inflammatory disease of the gastrointestinal tract. In these cases the physicians must weigh the benefits of treatment against the possible hazards.
Patients taking any NSAID including this drug should be instructed to contact a physician immediately if they experience symptoms or signs suggestive of peptic ulceration or gastrointestinal bleeding. These reactions can occur without warning symptoms or signs and at any time during the treatment.
Elderly, frail and debilitated patients appear to be at higher risk from a variety of adverse reactions from NSAIDs. For such patients, consideration should be given to a starting dose lower than usual, with individual adjustment when necessary and under close supervision (See Precautions).
Cardiovascular effects: Treatment with NSAIDs, including diclofenac, particularly at high dose and in long term, may be associated with a small increased risk of serious cardiovascular thrombotic events (including myocardial infarction and stroke).
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 be advised to 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.
Renal Function: As a class, non-steroidal anti-inflammatory drugs have been associated with renal papillary necrosis and other abnormal renal pathology in long-term administration to animals. In humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria and occasionally nephrotic syndrome.
The second form of renal toxicity generally associated with non-steroidal anti-inflammatory drugs is seen in patients with conditions leading to a reduction in renal blood flow or blood volume, where renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug results in a dose-dependent decrease in prostaglandin synthesis and secondarily, in a reduction of renal blood flow, which may precipitate overt renal failure. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuresis and the elderly. Discontinuation of NSAID therapy is typically followed by recovery to the pre-treatment state.
Since APO-DICLO metabolites are eliminated primarily by the kidneys, patients with significantly impaired renal function should be more closely monitored than subjects with normal renal function. In these cases, lower doses of APO-DICLO should be anticipated and patients carefully monitored. During long-term therapy, kidney function should be monitored periodically.

Pregnancy: Diclofenac should be used during pregnancy only if the benefits to the mother justify the potential risk to the fetus. Because of the known effects of prosta glandin-inhibiting drugs on the fetal cardiovascular system (closure of ductus arteriosus), use of diclofenac during late pregnancy should be avoided.
Labor and Delivery: The effects of diclofenac on labor and delivery in pregnant women are unknown. However, as with uterine contraction, reproduction studies perfor med in rats, rabbits and mice showed prolonged pregnancy and protracted labor when diclofenac was administered before or after the delivery process. Diclofenac readily crosses the placental barrier.
Lactation: Diclofenac has been found in the milk of nursing mothers. As with other drugs that are excreted in milk, diclofenac is not recommended for use in nursing women.
In one patient on long-term treatment with diclofenac 150 mg daily, a level of 100 mg/ml was measured in breast milk. By extrapolation, an infant of 4 to 5 kg, consuming 1L/day of breast milk, would receive less than 0.03mg/kg/day of diclofenac.
When administering diclofenac to the elderly, special care is indicated. The dosage should be reduced to the lowest level that will provide control of symptoms.

Gastrointestinal, dermatological and CNS adverse reactions are the most common seen. The most severe adverse reactions observed were gastric ul cer and gastrointestinal bleeding while the most severe dermatological reactions observed were erythema multiforme (Stevens-Johnson Syndrome and Lyell Syndrome). Fatalities have occurred on occasion, particularly in the elderly.
Adverse reactions reported in clinical trials and spontaneous reports are summarized as follows.
Gastrointestinal (15.2%): epigastric or abdominal di scomfort, pressure, heaviness, or distention (6%); nausea (2%); anorexia (1%); diarrhea, vomiting, flat ulence, constipation or eructation (1%); gastric and duodenal ulcerations and bleeding (0.2%); hyperacidity, stomatitis, coated tongue; peptic ulcer with perforation; lower gut disorders (e.g. nonspecific he morrhagic colitis and exacerbation of ulcerative colitis).
Allergic: hypersensitivity reactions (e.g. bronchos pasm anaphylactic/anaphylactoid systemic reactions including hypotension).
CNS (9%): dizziness (5%); headache (3%); malaise, insomnia, drowsiness, impaired concentration, impaired vision, tiredness (1%); irritability, sweating; vertigo, disturbances of sensation, tinnitus, convulsions.
Dermatologic (4%): rash (2%); pruritus (1.5%); skin eruption, eczema, urticaria, erythema (less than 0.5%). In isolated cases: Photosensitivity reactions: loss of hair, erythema multiforme and variants (Stevens-Johnson Syndrome, Lyell Syndrome).
Cardiovascular (4.5%): palpitation (2.5%): angina, arrhythmias (2.0%); exacerbation of cardiac failure.
Opthalmological: disturbances of vision (blurred vision, diplopia).
Hematologic: some patients manifested anemia secondary to gastrointestinal bleeding, leukopenia, thrombocytopenia, aplastic anemia, agranulocytosis, hemolytic anemia.
Edema and Water Retention (2.5%): facial edema (2%); general edema, (0.5%); peripheral edema, renal failure, nephrotic syndrome; urinary abnormalities (e.g. hematuria), interstitial nephritis.
Hepatic: liver function disorders including hepatitis with or without jaundice, in isolated cases fulminant.
Respiratory: asthma in patient sensitive to ASA.
Cardiac disorders: Uncommon*: Myocardial infarction, cardiac failure, palpitations, chest pain.
*The frequency reflects data from long-term treatment with high dose (150mg/day).
Description of selected adverse drug reaction: Arteriothrombotic events: Meta-analysis and pharmacoepidemiological data point towards a small increased risk of arteriothrombotic events (for example myocardial infarction) associated with the use of diclofenac, particularly at a high dose (150 mg daily) and during long-term treatment.

In man, ASA reduces the serum levels of diclofen ac when the 2 drugs are taken simultaneously; the bioavailability of ASA is reduced by the presence of diclofenac.
Digoxin and methotrexate serum levels may be elevated as well as cyclosporine nephrotoxicity. Patients receiving these drugs who are started on, or are given increased doses of diclofenac or any other NSAID, and particularly those patients with altered renal fu nction, should be observed for the development of the specific toxicities of these drugs. In the case of digoxin, serum levels should be monitored.
Pharmacodynamic studies have shown no potentiation of oral anticoagulation drugs due to concurrent administration with diclofenac. Nevertheless, when anticoagulants are given concurrently with diclofenac, special caution is advised since interactions have been seen with other NSAIDs.
Diclofenac does not alter glucose metabolism in normal subjects nor are the effects of oral hypoglycemic agents altered by the concomitant administration. There are rare reports, however, 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 causal relationship has not been established, but physicians should consider the possibility that diclofenac may alter a diabetic patient’s response to insulin or oral hypoglycemic agents.
NSAIDS have been reported to inhibit the activity of diuretics. Concomitant treatment with potassium sparing diuretics may be associated with increased serum potassium levels.
Concomitant administration of glucocorticoids, though sometimes necessary for therapeutic reasons, may aggravate gastrointestinal side effects. Concurrent oral treatment with 2 or more nonsteroidal antirheumatic drugs may promote the occurrence of side effects.
In vitro, diclofenac interferes minimally or not at all with the protein binding of salicylic acid (20% decrease in binding), tolbutamide, prednisolone (10% decrease in binding), or warfarin, Benzylpenicillin, ampicillin, oxacillin, chlortetracycline, cephalothin, erythromycin and sulfamethoxazole have no influence in vitro on the protein binding of diclofenac in human serum.
Diclofenac, when administered concomitantly with lithium will increase the lithium plasma concentration through an effect on lithium renal clearance: dosage adjustment of lithium may be required.

Incompatibility: None known.

Store at room temperature and protect from humidity.

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.

POM

Tab 25 mg (yellow, round, biconvex, enteric coated, engraved 25 on one side) x 100's. 50 mg (light brown, round, biconvex, enteric coated, engraved 50 on one side) x 500's.