Aceclofenac

1. Aceclofenac

2. Specifics of action
• 1 trial studied the in • Although all tested • Considering the
vitro effects of NSAIDs caused a above results, it is
several (NSAIDs) on statistically reasonable to
pro-inflammatory significant propose that the
cytokines and PGE2 decrease on IL-6 prophylactic
production by and TNF-α levels, treatment with
synovial membrane aceclofenac & aceclofenac could
from loose tenoxicam were delay the process
endoprosthesis of seen to be more of the aseptic
hip / knee effective loosening of
arthroplasty tissue.

3. Specifics of action

4. Benefits of action
Aceclofenac and its metabolite penetrate the
inflammatory cells like
neutrophils, monocytes and synovial cells
Get hydrolyzed to the
active diclofenac &
4`-hydroxydiclofenac
Inhibits cytokine Suppress
release by production of
inflammatory PGE 2 at the site
cells of inflammation

5. Benefits of action
Suppression of cytokine
mediated proteases & Stimulates the synthesis of the
increases production/ cytokine receptor antagonists in
release of proteoglycan the articular chondrocytes
Chondro-
Stimulatory effects on cartilage
protective
matrix synthesis.
properties
Synthesis of
glycosaminoglycan in
Inhibition of
osteoarthritic cartilage.
cytokine release
by inflammatory Net result is decrease in
cells disease progression & repair

6. Translation of Benefits of action
↓ joint Better outcome
Decreases pain
inflammation
intensity
Visibility
Reduces disease
Improves of benefits
of action severity / progression
mobility
↓ duration of Improves functional
morning stiffness capacity of the joints
like knee

7. Pharmacokinetics
• Rapidly and completely absorbed after oral
administration [Bioavailability = nearly 100%],
• Peak plasma concentrations are reached 1-3 hours
after an oral dose.
• Highly protein bound (approx. 99%).
• Presence of food does not alter the extent of
absorption but absorption rate is reduced [↑ Tmax].
• After multiple dosing, aceclofenac penetrates into
the synovial fluid
– Concentration = approximately 60% of plasma level

8. Metabolism
• Metabolized to
1. Major metabolite = 4'-hydroxyaceclofenac; &
2. Other metabolites = Diclofenac, 4'-
hydroxydiclofenac & 5-hydroxydiclofenac.
• Main route of elimination
– Renal, with 70 to 80% of an administered dose
found in the urine, mainly as the glucuronides of
aceclofenac and its metabolites
• Plasma elimination half-life
– Approximately 4 hours.

9. Observation of Selectivity
• Inhibition of cox-2 by both aceclofenac and
4'-hydroxyaceclofenac but with minimal
effects on cox-1. How can we say so?
• IC50 values of cox-1 and cox-2 respectively
have been observed as follows:
Cox-1 Cox-2
Aceclofenac > 100 0.8
4-Hydroxy-aceclofenac > 100 36
Further evidence of cox-2 selectivity of aceclofenac has been
shown by an IC50 ratio (cox-2: cox-1) of 0.26

10. Aceclofenac
Efficacy
&
Indications

11. Aceclofenac – clinical efficacy
• In large trials of 2 to 6 months duration in
various diseases, aceclofenac significantly
reduced pain and improves functional
capacity and mobility relative to baseline in
patients with
– osteoarthritis,
– rheumatoid arthritis or
– ankylosing spondylitis
• In addition, reduced inflammation in patients
with rheumatoid arthritis. [Disease progression?]

12. Use in OA
• One trial was a controlled, comparative, randomized, and
double-blind study that included 247 patients suffering from
osteoarthritis.
• Patients were randomized to receive either aceclofenac
(100 mg twice daily) or diclofenac (75 mg twice daily).
• Clinical assessment was done at screening, randomization,
and at 2 weeks, 4 weeks and 8 weeks of treatment by
calculating
– Western Ontario MacMaster (WOMAC) scores,
– time taken to walk 100 feet,
– visual analogue scores for pain,
– investigator's assessment on a Likert scale and
– joint tenderness.
• Tolerability assessment was based on adverse events.
• Patient compliance was also assessed.
Curr Med Res Opin. 2006; 22(5):977-88

13. Use in OA
• Aceclofenac was found to be statistically superior to
diclofenac in efficacy parameters of
– WOMAC scores,
– investigator's assessment and
– joint tenderness.
• Aceclofenac was found to be statistically superior to
diclofenac in terms of GI tolerance.
• Patient compliance was also better with better
acceptance.
• The overall response of patients' osteoarthritis to
aceclofenac was found to be statistically superior to
diclofenac by both physician and patient.
Curr Med Res Opin. 2006; 22(5):977-88

14. Use in RA
• In randomized, double blind comparative trial in 170
patients in each group, aceclofenac (100 mg twice
daily for 3 or 6 months) was compared wioth
diclofenac 50 mg. tid
– Although both treatment groups showed significant
improvement in all evaluations of pain and inflammation
& a progressive reduction in morning stiffness, there
were no significant differences between the groups.
– But, greater improvement in hand grip strength was seen
with aceclofenac (22% improvement) than diclofenac
(17% improvement). Adverse GI events were less with
aceclofenac (13%) than with diclofenac (17%).
Curr Med Res Opin. 1995;13(6):305-15

15. Use in ankylosing spondylitis
• In randomized, double blind trials involving
104 to 308 patients after aceclofenac 100 mg
twice daily for 3 months, Improvements were
observed similar to those observed with
indomethacin, naproxen or tenoxicam.
1. Reduced duration of morning stiffness and pain
intensity and
2. Improved spinal mobility.
J Rheumatol. 1996 Jul;23(7):1194-9.

16. Use in acute lumbago
• In a comparative study, Aceclofenac (100 mg
orally, twice daily) was superior to diclofenac
in alleviating functional impairment in a 7
days study in 100 patients with acute
lumbago.
• In a non-comparative study in 67 patients,
aceclofenac 100 mg twice daily was
associated with symptomatic relief of acute
low back pain.

17. Use in dental pain
• The analgesic efficacy as single doses of
aceclofenac 100 mg has been assessed in
patients with moderate to severe tooth pain
and in extraction of impacted third molars
and found to be greater than that of placebo.
• Aceclofenac was more efficient in controlling
pain when administered before the surgery
as maximum impact of activity for this
condition was evident at 6h after surgery,
which is the time of maximum pain for this
surgical procedure.
Int J Oral Maxillofac Surg. 2006 Jun;35(6):518-21

18. Other uses
Post Operative Dysmenorrhoea Musculoskeletal trauma
In various studies, In a more recent Aceclofenac 100 mg
aceclofenac 100 mg has noncomparative study in twice daily has also been
been superior to 1338 women with assessed in patients with
paracetamol 650 mg in dysmenorrohea treated musculoskeletal trauma,
providing relief from for first 3 days of 2 although only non-
postepisiotomy pain, consecutive cycles, comparative studies are
particularly 3 to 5 hours aceclofenac appeared to available.
after ingestion. be effective as other
NSAIDs with lesser side
effects.

19. Drug interactions
• Concomitant administration of aceclofenac
and antidiabetic drugs = hypo or
hyperglycaemia
• Co-administration with other NSAIDS of
corticosteroids may result in increased
frequency of adverse event.
• ↓ the activity of diuretics, but ↑ the activity of
anticoagulants and also ↑ cyclosporin
nephrotoxicity
• May ↑ plasma concentrations of lithium,
digoxin and methotrexate.

20. ADRs
• Most adverse events affect mainly the GI system;
are minor, reversible and include
– dyspepsia (7.5%), nausea (1.5%), diarrhea (1.5%),
flatulence (0.8%), gastritis (0.6%), constipation (0.5%),
vomiting (0.5%), ulcerative stomatitis (0.1%), pancreatitis
(0.1%).
• Rare adverse effect
– dizziness (1%), vertigo (0.3%), paraesthesia and tremor.
• Withdrawal rates significantly lower than other
NSAIDS in relation to incidence of GI adverse
events.

21. Dosage
• 100 mg given twice daily by mouth, one
tablet in the morning and one in the evening.
• In patients with mild renal impairment, there
is no evidence to suggest dosage
modification but caution should be exercised
as with other NSAIDS.

22. Summary
Faster, safer onset of
action
Pain control +
More potent effect with
2. Repair, and selectivity for Cox-2
3. ↓ in disease
progression
Protection of
chondrocytes against Aceclofenac Well tolerated and
ROS and breakdown better GI tolerability
Classical inhibition of
Stimulatory effects on
prostaglandins E2
matrix component
synthesis Decrease in the
expression of cytokines
like IL-1 & TNF-α

23. Summary
Osteoarthritis
Ankylosing
RA Spondylitis
Dental pain
Dysmenorrhoea