For the use of a Registered Medical Practitioner only
(Diclofenac Sodium Sustained Release Tablets 100
NSAIDs may cause an increased risk of serious cardiovascular thrombotic
events, myocardial infarction, and stroke, which can be fatal. This risk
may increase with duration of use. Patients
with cardiovascular disease or risk factors for cardiovascular disease
may be at greater risk.
Diclofenac sodium is contraindicated for the treatment of perioperative
pain in the setting of coronary artery bypass graft (CABG) surgery.
RISK OF GI ULCERATION, BLEEDING AND PERFORATION WITH NSAID
Serious GI toxicity such as bleeding, ulceration and perforation can
occur at any time, with or without warning symptoms, in patients treated
with NSAID therapy. Although minor upper GI
problems (e.g. dyspepsia) are common, usually developing early in
therapy, prescribers should remain alert for ulceration and bleeding in
patients treated with NSAIDs even in the absence
of previous GI tract symptoms.
Studies to date have not identified any subset of patients not at risk
of developing peptic ulceration and bleeding. Patients with prior
history of serious GI events and other risk factors
associated with peptic ulcer disease (e.g. alcoholism, smoking, and
corticosteroid therapy) are at increased risk. Elderly or debilitated
patients seem to tolerate ulceration or bleeding less
than other individuals and account for most spontaneous reports for
fatal GI events.
Each film-coated sustained release tablet contains
Diclofenac sodium 100 mg
Excipients: Lactose, Hydroxypropyl Methylcellulose (Methocel-K
100MCR), Hydroxypropyl Cellulose (HPC-L), Sodium Lauryl Sulphate, Colloidal
Silicon Dioxide, Purified Talc, Magnesium stearate,
Hydroxypropyl Methylcellulose, Titanium Dioxide, Ponceau 4R Lake, Polyethlene Glycol-400, Purified Water
Pink coloured, round biconvex, film coated tablets.
DIFNAL OD contains diclofenac sodium which is a benzene-acetic acid
derivative. Diclofenac sustained release tablets have prolonged release
profile. The chemical name is 2-[(2,6-dichlorophenyl)amino] benzeneacetic
acid, monosodium salt. The molecular weight is 318.14. Its molecular formula
is C14H10CI2NNaO2, and it has the following structural formula:
PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES
Mechanism of action
Diclofenac sodium is a non-steroldal compound with pronounced antlrheumatic,
anti-inflammatory, analgesic and antipyretic properties. Inhibition of
prostaglandin biosynthesis, which has been
demonstrated in experiments, is considered fundamental to its mechanism of
action. Prostaglandins play a major role in causing inflammation, pain and
fever. Diclofenac sodium in vitro does not
suppress proteoglycan biosynthesis in cartilage at concentrations equivalent
to those reached in humans.
In rheumatic diseases, the anti-inflammatory and analgesic properties of
diclofenac sodium elicit a clinical response characterised by marked relief
from signs and symptoms such as pain at rest, pain on
movement, morning stiffness, and swelling of the joints, as well as by an
improvement in function.
In post-traumatic and post-operative inflammatory conditions, diclofenac
sodium relieves both spontaneous pain and pain on movement and reduces
inflammatory swelling and wound edema. The possibility of prescribing the
medicinal product in a single daily dose considerably simplifies long-tern
treatment and helps to avoid the possibility of dosage errors.
Judged by urinary recovery of unchanged diclofenac and its hydroxylated
metabolites, the same amount of diclofenac is released and absorbed from Diclofenac sodium SR tablets as from enteric-coated
tablets. However, the systemic availability of diclofenac from Diclofenac
sodium SR tablets is on average about 82% of that achieved with the same
dose of diclofenac sodium enteric-coated tablets
(possibly due to release-rate dependent "first-pass" metabolism). As a
result of a slower release of the active substance from Diclofenac sodium SR
tablets, peak concentrations attained are lower than
those observed following the administration of gastro-resistant tablets.
Mean peak concentrations of 0.5 micrograms/mL or 0.4 micrograms/mL (1.6 or
1.25 micro mol/L) are reached on average 4 hours after ingestion of a
prolonged-release tablet of 100 mg or 75 mg. Food
has no clinically relevant influence on the absorption and systemic
availability of Diclofenac sodium SR tablets.
On the other hand, mean plasma concentrations of 13 ng/mL (40 nmol/L) can be
recorded at 24 hours (16 hours) after administration of prolonged-release
tablet of 100 mg (75 mg). The amount absorbed
is linearly related to the dose strength.
Since about half of diclofenac is metabolised during its first passage
through the liver ("first pass" effect), the area under the concentration
curve (AUC) following oral or rectal administration is about half
that following en equivalent parenteral dose.
Pharmacokinetic behaviour does not change after repeated administration. No
accumulation occurs provided the recommended dosage intervals are observed.
Trough concentrations are around 22 ng/mL or 25 ng/mL (70 nmol/L or 80 nmol/L)
during treatment with Diclofenac sodium prolonged-release tablets 100 mg
once dally or 75 mg twice daily.
99.7% of diclofenac is bound to serum proteins, mainly to albumin (99.4%).
The apparent volume of distribution calculated is 0.12 to 0.17 L/kg. Diclofenac enters the synovial fluid, where maximum
concentrations are measured 2 to 4 hours after peak plasma values have been
attained. The apparent half-life for elimination from the synovial fluid is
3 to 6 hours. Two hours after reaching peak plasma
values, concentrations of the active substance are already higher in the synovial fluid than in the plasma, and they remain higher for up to 12
Biotransformation of diclofenac takes place partly by glucuronidation of the
intact molecule, but mainly by single and multiple hydroxylation and
methoxylation, resulting in several phenolic metabolites
most of which are converted to glucuronide conjugates. Two of these phenolic
metabolites are biologically
active, but to a much smaller extent Than diclofenac.
Total systemic clearance of diclofenac from plasma is 263 ±56 mL/min (mean
value ±SD). The terminal half-life in plasma is 1 to 2 hours. Four of the
metabolites, including the two active ones, also have
short plasma half-lives of 1 to 3 hours. One metabolite,
3'-hydroxy-4'-methoxy-diclofenac has a much longer plasma half-life.
However, this metabolite is virtually inactive.
About 60% of the administered dose is excreted in the urine as the
glucuronide conjugate of the intact molecule and as metabolites, most of
which are also converted to glucuronide conjugates. Less than
1% is excreted as unchanged substance. The rest of the dose is eliminated
as metabolites through the bile in the feces.
No relevant age-dependent differences in the drug's absorption, metabolism
or excretion have been observed.
In patients suffering from renal impairment, no accumulation of the
unchanged active substance can be inferred from the single-dose kinetics
when applying the usual dosage schedule. At a creatinine
clearance of <10 mL/min, the calculated steady-state plasma levels of the hydroxy metabolites are about 4 times higher than in normal subjects.
However, the metabolites are ultimately cleared
through the bile.
In patients with chronic hepatitis or non-decompensated cirrhosis, the
kinetics and metabolism of diclofenac are the same as in patients without
Inflammatory and degenerative forms of rheumatism: rheumatoid arthritis,
ankylosing spondylitis, osteoarthritis and spondylarthritis, painful
syndromes of the vertebral column, non-articular rheumatism.
Painful post-traumatic and post-operative inflammation and swelling.