Data Sheet

DICLAX

Diclofenac sodium 25mg and 50mg enteric film-coated tablets

Presentation

25mg Tablets: round, yellowish tan coloured, biconvex, enteric film coated tablets, printed N over 25 on one face the other face plain.

50mg Tablets: tan coloured, round, biconvex, enteric film coated tablets, printed N over 50 on one face the other face plain.

Uses

Actions

Diclofenac sodium is a non-steroidal anti-inflammatory agent possessing both analgesic and antipyretic properties. Diclofenac sodium does not act through the pituitary-adrenal axis, however, the specific mode of action is not fully known. It inhibits prostaglandin synthesis by interfering with the action of prostaglandin synthetase, which may explain, in part, its actions.

Clinically, a daily dose of 75-150mg diclofenac is comparable in efficacy to 3-5g daily of aspirin.

Diclofenac sodium is similar in activity to equivalent dosages of indomethacin (75-150mg daily), and causes less side effects at these doses.

The use of diclofenac in arthritic patients does not affect the progressive course of the disease but it has been shown to be effective with respect to pain relief, decreased joint tenderness and swelling and increased mobility.

Anti-Inflammatory Activity in Rats: The anti-inflammatory potency of diclofenac sodium was assessed by testing inhibition of paw oedema (carrageen solution and kaolin suspension) and reduction of adjuvant arthritis (Freund's adjuvant). 

* Determined by graphic interpolation from 3 or more doses.

Analgesic Activity in Mice and Rats: The antinociceptive effect of diclofenac sodium was assessed by a number of established tests with results as tabulated.

Antipyretic Activity in Rats: Doses of 0.5mg/kg p.o. diclofenac lowered body temperature by 1.5^oC in rats given an i.m. injection of a 15% yeast suspension (10mL/kg).

Inhibition of Prostaglandin: The inhibition of prostaglandin synthesis in-vitro (IC₅₀) is 1.6 mM/L. There exists a close correlation between certain febrile reactions and increased prostaglandin levels in the brain. Prostaglandin E₂ formation, which parallels antipyresis but does not induce hypothermia in the afebrile animal, was reduced by diclofenac (0.5mcg/mL).

Platelet Adhesiveness: At 15mcg/mL, diclofenac reduces collagen-induced agglutination in rabbit platelets by 50%. ADP-induced adhesiveness at the same dosage is similarly affected. At 10mg/kg p.o., diclofenac protected rabbits against the lethal effects of thrombokinase without untoward effects.

Gastrointestinal Tolerability: In rats, oral doses of 17mg/kg diclofenac sodium caused blood loss of 150uL in 72 hours, as measured by the administration of ⁵¹Cr-labelled erythrocytes.

Pharmacokinetics

Diclofenac sodium is rapidly and almost completely absorbed and distributed to blood, liver, and kidneys when given orally in man. Peak plasma concentrations are reached within 1.5-2.5 hours after oral administration of the tablets. The pharmacokinetic behaviour of diclofenac is not altered under repeated administration.

Administration of diclofenac sodium after food results in a delayed absorption and lower peak plasma concentration but does not affect the total amount of medicine reaching the systemic circulation. Hence, the area under the plasma concentration time curve (AUC) is not significantly reduced.

Diclofenac sodium is highly bound to serum proteins, mostly (over 99%) to albumin.

Studies of the pharmacokinetics of diclofenac and its major metabolites in patients with rheumatoid arthritis show that following oral administration the medicine rapidly penetrates into synovial fluid. Concentrations of diclofenac in synovial fluid were found to be higher than those in plasma.

Diclofenac sodium is eliminated primarily by hepatic metabolism with only about 5-10% of an oral dose being excreted unchanged in the urine. About 90% of an oral dose is excreted in the first 96 hours. When labelled diclofenac sodium is administered to subjects with normal renal function, approximately 50% of the radioactivity is excreted in the urine while 30-35% is eliminated via the bile.

Hepatic impairment does not appear to have any significant effect on plasma levels of unchanged diclofenac.

The principal metabolites are hydroxylated derivatives of diclofenac, which are subsequently excreted as the glucuronide and sulphate conjugates. Conjugates of diclofenac itself account for 5-10% of the dose recovered in the urine and less than 5% of that excreted in the bile.

Studies comparing the pharmacokinetics of diclofenac in elderly patients with that of younger patients have revealed no significant differences with respect to mean maximum plasma concentrations or urinary excretion pattern.

In a single dose pharmacokinetic study performed in order to evaluate the effect on clearance of diclofenac in the presence of varying degrees of renal impairment (creatinine clearance rates ranging from 3mL/min to 42mL/min), renal impairment did not affect plasma concentration of unchanged diclofenac.

The plasma concentrations of total diclofenac metabolites tended to be higher than in normal subjects. Although these metabolites are predominantly present in conjugated form and hence pharmacologically inactive, caution is advised when administering diclofenac to patients with impaired renal function.

Diclofenac sodium readily crosses the placenta. A level of 100ng/mL was measured in the breast milk of a patient on long-term treatment with a daily dosage of 150mg diclofenac sodium. Extrapolation suggests that an infant of 4-5kg, consuming one litre of breast milk per day would receive less than 0.03mg/kg/day of diclofenac sodium.

Indications

DICLAX tablets are indicated for the treatment of symptoms related to rheumatoid arthritis and severe osteoarthritis.

Dosage and Administration

DICLAX tablets are to be taken orally. Initially 100-150mg daily in 2-3 divided doses before food reducing to 75-100mg daily in divided doses.

Diclofenac sodium is not recommended for use in children.

Contraindications

Peptic ulcer or active inflammatory disease of the gastrointestinal system.

Known or suspected hypersensitivity to the medicine. Diclofenac sodium should not be used in patients in whom acute asthmatic attacks, urticaria, rhinitis or other allergic manifestations are precipitated by aspirin or other non-steroidal anti-inflammatory agents. Fatal anaphylactoid reactions have occurred in such individuals.

Warnings and Precautions

Peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal have been reported during therapy with non-steroidal anti-inflammatory agents including diclofenac sodium. If peptic ulceration is suspected or confirmed, or if gastrointestinal bleeding or perforation occurs, diclofenac sodium should be discontinued, an appropriate treatment instituted, and the patient closely monitored.

Diclofenac sodium should not be prescribed to patients vulnerable to gastrointestinal ulceration and bleeding.

Patients taking diclofenac sodium 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.

There is no definitive evidence that the concomitant administration of histamine H₂ receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow continuation of therapy when and if these adverse reactions appear.

Elderly, frail and debilitated patients appear to be at higher risk from a variety of adverse reactions from non-steroidal anti-inflammatory medicines. For such patients, consideration should be given to a starting dose lower than usual, with individual adjustment when necessary and under close supervision.

Because abnormalities of bone marrow function have occurred, patients being treated with diclofenac sodium should have blood chemistry checked regularly. Anaemia secondary to gastrointestinal tract toxicity can occur; therefore periodic haemoglobin estimations are advised.

Renal Function: Caution is required with dosage where renal dysfunction exists. As with other non-steroidal anti-inflammatory medicines, long-term administration of diclofenac sodium to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with haematuria, proteinuria, and occasionally nephrotic syndrome.

A second form of renal toxicity has been seen in patients with prerenal conditions leading to the reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory medicine may cause a dose-dependent reduction in prostaglandin formation and may precipitate loss of renal function. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, and the elderly. Discontinuation of non-steroidal anti-inflammatory therapy is usually followed by recovery to the pretreatment state.

During long-term therapy, kidney function should be monitored periodically.

Hepatic Function: As with other non-steroidal anti-inflammatory agents, borderline elevations of one or more liver tests may occur. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with this medicine. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with this medicine as with other non-steroidal anti-inflammatory agents. Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg. eosinophilia, rash, etc.), diclofenac sodium should be discontinued.

During long-term therapy, liver function tests should be monitored periodically. Diclofenac sodium should be used in the presence of impaired liver function, only in case of necessity and under strict observation.

Fluid and Electrolyte Balance: Fluid retention and oedema have been observed in patients treated with diclofenac sodium. Therefore, as with many other non-steroidal anti-inflammatory agents, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. Diclofenac sodium should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention.

Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients at risk.

Haematology: Medicines inhibiting prostaglandin biosynthesis do interfere with platelet function to some degree, therefore, patients who may be adversely affected by such an action should be carefully observed when diclofenac sodium is administered.

Blood dyscrasias associated with the use of non-steroidal anti-inflammatory agents are rare, but could have severe consequences.

Infection: In common with other anti-inflammatory agents, diclofenac sodium may mask the usual signs of infection.

Ophthalmology: Blurred and/or diminished vision has been reported with the use of diclofenac sodium and other non-steroidal anti-inflammatory agents. If such symptoms develop, diclofenac sodium should be discontinued and an ophthalmologic examination performed; ophthalmic examination should be carried out at periodic intervals in any patient receiving diclofenac sodium for an extended period of time.

Central Nervous System: Headache, dizziness, lightheadedness and mental confusion have been reported by patients following therapy with diclofenac sodium. Patients should be cautioned against operating machinery or motor vehicles if they are experiencing these symptoms (see ADVERSE EFFECTS).

Hypersensitivity Reactions: As with other non-steroidal anti-inflammatory agents, hypersensitivity reactions have been reported with diclofenac sodium. Patients should be told to immediately report occurrence of symptoms such as skin rash, swelling, hives or itching as well as shortness of breath, wheezing, troubled breathing or tightness in the chest.

Use in Children: DICLAX is not recommended for use in children under 16 years of age because safety and dosage ranges have not been established for paediatric patients.

Use in Pregnant or Lactating Women: The safety of diclofenac sodium has not been established in these conditions and therefore its use is not recommended during pregnancy or lactation. When diclofenac sodium was administered before or after the delivery process had begun in rats, rabbits and mice, a prolonged pregnancy and protracted labour was observed. Other non-steroidal anti-inflammatory agents have shown similar results, and the evidence suggests that this may be due to decreased uterine contractility resulting from the inhibition of prostaglandin synthesis.

The propensity of diclofenac sodium to interact with other medicines may influence the treatment of other conditions.

Acute Toxicity:

General clinical symptoms for mice and rats at low dose levels were apathy, diarrhoea and emaciation. At higher dose levels, rats and mice exhibited ataxia, rapid shallow respiration, ptosis, flaccidity and diarrhoea. Severe growth suppression was noted in animals at all dose levels. Gross necropsy findings in the mice and rats that died were slight haemorrhaging of the GI tract, gastritis, enteritis and congestion of the lungs and of the adrenals.

Long-Term Toxicity Studies: Long-term toxicity studies are reported for a number of species and the results are given below:

Diclofenac sodium was orally administered to male and female rats in doses of 0.25, 1.0 and 2.0mg/kg/day from 59 weeks (high dose groups) to 98 weeks (low and intermediate dose groups). High dose related mortality rates resulted in termination of the high dose administration after 59 weeks; the high mortality rate was caused by severe dose-dependent ulceration of the gastrointestinal tract, with perforated ulcers leading to peritonitis and sequelae. Body weight gains and feed consumption of the treated groups were close to the controls. Haematologic patterns showing neutrophilic leucocytosis and anaemia were seen in the high and intermediate dose groups, particularly females at weeks 52 and 98, respectively. Female animals tended to develop enlarged adrenals and eventually experienced depressed glucose and elevated alkaline phosphatase levels. Histology studies carried out on the tissues of the control, low and intermediate dose groups showed medicine related changes including mucosal ulceration of the small intestine, lymphangiectasis, lymphoid hypoplasia, and plasma cell hypoplasia of the mesenteric lymph nodes, foci of hepatocytic hyperplasia, adrenal cortical atrophy and prostatitis. No increase in tumour incidence was observed in the medicine treated groups as compared to the control group.

Diclofenac sodium was administered orally in gelatin capsules once daily to baboons (Papio spp.) at dose levels of 0, 5, 15 (reduced to 10 on day 254) and 50 (reduced to 30 on day 38) mg/kg/day for up to 52 weeks. At all dose levels studied, diclofenac caused ulceration of the gastrointestinal tract. Ulceration was confined to the colon in the low dose group but was present in the stomach and small intestine also in the other two groups. Body weights were below controls. Constipation, with occasional episodes of diarrhoea, was a marked feature. In all treated groups, there was a dose related fall in serum albumin levels. Anaemia and an increased ESR were observed in the high dose group. In the recovery groups (control, low and intermediate), no intestinal lesions were present. Food consumption and body weight gains were within normal limits. Haematology parameters were comparable to controls and serum albumin levels returned toward normal values.

Reproduction Studies:

Rats: Doses of 2 and 4mg/kg/day were given orally to male and female rats with no noticeable effect on fertility. Dosing was carried out during premating, mating, gestation, and lactation periods. At the higher dose, prolonged gestation and dystocia were observed. Embryotoxicity (low birth weight, failure to survive) was observed at both doses but it was minimal at 2mg/kg/day. Postnatal survival and growth of pups from medicine treated animals were comparable to those of controls except for slightly retarded growth at the higher dose.

Mice and Rats: Teratology studies at oral doses of 2, 3, 10 and 20mg/kg/day showed no teratogenic effects on foetuses. At the higher doses, pronounced gastrointestinal effects were observed in the dams and a marked toxic effect noted in foetuses (reduced birth weights and increased foetal deaths).

Rabbits: Pregnant females treated with oral doses of 5 or 10mg/animal/day throughout the gestation period showed a dose-dependent increase in resorption rates, diminished foetus weights, and abnormal skeletal findings. Definite embryotoxicity was observed at the highest dose although there was no evidence to suggest teratology.

Mutagenicity Studies: Mutagenicity studies were carried out in-vitro using bacteria with, and without microsomal activation, and in mammalian cells. Studies in-vitro were also performed. Diclofenac sodium was not mutagenic in any of these test systems.

Additional bacterial DNA-repair assay studies showed that the mutagenicity of diclofenac sodium was significant in one of two strains. However, the mutagenicity was shown to be much weaker than that of a positive control test substance. Although indomethacin exhibited similar positive results, several other non-steroidal anti-inflammatory medicines were not shown to be mutagenic. Therefore, the mutagenicity of indomethacin and diclofenac sodium was considered questionable.

Carcinogenicity Studies: In a survey of the literature to date, there have been no reports published which indicate that diclofenac is carcinogenic. Interestingly, prostaglandin synthesis inhibitors have been found to reduce the growth rate of both experimental and human malignant neoplasms.

Rats: In one study the growth rate and vascularisation of transplantable rat tumours were markedly inhibited by diclofenac sodium and also by indomethacin. In other experiments, where two transplantable rat tumours were studied, it was shown that prolonged administration of diclofenac sodium to rats significantly changed the tumour blood flow towards higher values. Taken together, these studies would appear to be inconsistent.

In a two-year carcinogenicity study, both male and female rats were exposed to diclofenac sodium (medicine mixed in feed) at doses of 0.25, 0.5, 1.0 and 2.0mg/kg/day. A positive dose related trend in tumours of the subcutaneous tissue, mammary gland and adrenal medulla was found in females while males showed a similar trend in C-cell adenomas of the thyroid.

Mice: The ability of natural killer (NK) cells to lyse tumour cells was increased following i.p. injection of diclofenac into mice. Data from experiments employing in-vitro cultures of bone marrow-derived macrophages showed that diclofenac induced cytotoxic activity in macrophages against P815 mastoma and YAC-1 lymphoma tumour cells. At an equimolar concentration (5 x 10^-6M) indo-methacin was shown to have about 3 times more cytolytic capacity than diclofenac. Untreated macrophages (controls) were not able to kill YAC-1 or P815 tumour cells.

Adverse Effects

The most common adverse effects encountered with non-steroidal anti-inflammatory medicines are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred on occasion, particularly in the elderly. The following adverse effects with approximate incidences have been reported:

Gastrointestinal System: The approximate incidence of gastrointestinal side effects is 15.2%. Epigastric or abdominal discomfort, pressure, heaviness or distension was the most frequently seen gastrointestinal adverse reaction (6%). Additional gastrointestinal adverse effects with approximate incidence include: epigastric, gastric or abdominal pain (5%), nausea (2%), anorexia (1%), diarrhoea, vomiting, flatulence, constipation or eructation (1%) and gastric and duodenal ulcerations and bleeding (0.2%).

Allergic: The total incidence of allergic reactions in patients treated with diclofenac has been estimated to be 0.4%. These reactions consisted of hypersensitivity, and rare idiosyncratic reactions with pruritus, rash, fever and eosinophilia.

Central Nervous System: The total incidence of CNS adverse effects is approximately 9%. Dizziness (5%) was the most common central nervous system adverse effect followed by headache (3%). Other CNS adverse effects with an approximate incidence of 1% included malaise, insomnia, drowsiness, impaired concentration, impaired vision and tiredness.

Cardiovascular System: Cardiovascular system adverse effects had an approximate incidence of 4.5% consisting of palpitations (2.5%), angina and arrhythmias (2.0%).

Dermatologic System: The approximate incidence of dermatologic side effects was 4% including rash (2%) and pruritus (1.5%). Skin eruption, eczema and urticaria, erythema occurred less frequently than 0.5%.

Oedema and Water Retention: Facial oedema had an approximate incidence of 2% and general oedema was reported less frequently (0.5%).

Special Senses: Occurring with an incidence of approximately 1% are taste disorder and visual and hearing disturbances including blurred vision, scotoma, diplopia and tinnitus.

Other reactions listed below have been reported in patients receiving diclofenac sodium for which the true incidence has not been determined.

• Gastroinestinal: Hyperacidity, stomatitis, coated tongue.
• Nervous System: Impaired concentration, sweating.
• Cardiovascular: Exacerbation of cardiac failure.
• Haematologic: Anaemia secondary to gastrointestinal bleeding, leukopenia, thrombocytopenia, aplastic anaemia.
• Dermatologic: Erythema multiforme and Stevens-Johnson syndrome.
• Hepatic Jaundice, transaminase elevations, hepatitis.
• Respiratory System: Asthma in patients sensitive to aspirin.
• Renal: Peripheral oedema, acute renal failure, interstitial nephritis, nephrotic syndrome, papillary necrosis, extramembranous glomerulonephritis.

Interactions

In man, the plasma levels and bioavailability of diclofenac are reduced when taken simultaneously with aspirin.

Concurrent use of lithium and diclofenac sodium has been reported to impair lithium clearance and to increase steady state plasma lithium concentration. Monitoring of plasma lithium levels is therefore advised and reduction of lithium dosage may be required in order to prevent lithium intoxication.

Digoxin plasma concentrations may be increased by simultaneous administration of diclofenac and hence, adjustment of digoxin dosage may be required.

Although pharmacodynamic studies have not shown potentiation of oral hypoglycaemic or anticoagulant medicines during concomitant diclofenac sodium administration, caution with concurrent use is recommended.

Non-steroidal anti-inflammatory agents have been reported to inhibit the activity of diuretics. The diuretic effect of chlorthalidone was progressively impaired by increasing doses of diclofenac sodium when administered to rats.

The antihypertensive effect of hydrochlorothiazide may be decreased by diclofenac in patients with essential hypertension.

Although concurrent administration of glucocorticoids may increase the risk of side effects such as ulceration or haemorrhage, concurrent use in the treatment of arthritis may provide additional therapeutic benefit and permit reduction of glucocorticoid dosage. Simultaneous oral therapy with 2 or more non-steroidal anti-inflammatory agents may increase the risk of side effects.

Methotrexate plasma concentrations may be increased due to the effects of diclofenac on renal prostaglandins. Patients should not receive this combination since severe and sometimes fatal toxicity has been reported.

The concomitant administration of aluminium hydroxide or magnesium hydroxide antacids may delay the absorption of diclofenac but does not affect the total amount absorbed.

Clinical Laboratory Tests: Changes in laboratory test values may occur during diclofenac therapy. Persistently abnormal or worsening renal, hepatic or haematological test values should be followed up carefully, as with any medicine, since they may in rare cases be related to therapy.

Overdosage

The following signs and symptoms may be encountered in the event of overdosage:

Headache, motor restlessness, muscular twitching, ataxia, convulsion, hyperexcitability, dizziness, epigastric pain, nausea, vomiting, diarrhoea, haematemesis, acute gastric or duodenal ulceration, hepatic disorder and oliguria.

Experience with diclofenac sodium overdosage is limited and there is no specific antidote. In the event of overdosage, supportive and symptomatic treatment is recommended which may include emptying of the stomach by induction of vomiting, gastric aspiration and lavage or treatment with a saline cathartic. Activated charcoal to reduce absorption and dialysis to accelerate elimination may also be considered.

Pharmaceutical Precautions

DICLAX tablets should be stored below 30 °C, protected from light and moisture and kept out of the reach of children.

Medicine Classification

Prescription Medicine.

Package Quantities

DICLAX tablets: 100 tablets

Further Information

Diclofenac sodium is (2-(2,6-dichloroanilino) phenyl)-acetate. It has a molecular formula and weight of C₁₄H₁₀Cl₂NNaO₂ and 318.1 respectively.

Other ingredients of the tablets are: Talc, Ethylcellulose, Magnesium stearate, Povidone, Hydroxypropylmethylcellulose, Diethylphthalate, Titanium dioxide, Synthetic iron oxide (E172), Polyethylene glycol 400, and Stearic acid.

Name and Address

Douglas Pharmaceuticals Ltd
P.O. Box 45-027
AUCKLAND 8

Ph: (09) 835-0660
Fax: (09) 835-0665

Date of Preparation

31 December 1998