Diclofenac Sodium 4% Spray Gel - cyathus.cz

PAR Diclofenac Sodium 4% Spray Gel
UK/H/0562-3/001/E01
In a local tolerance study in rabbits, pharmacokinetic parameters for diclofenac were
estimated following topical application of DSG 4% and Voltaren ® Emulgel.
Table 1. Pharmacokinetic parameters estimated following topical application of
different diclofenac formulations to NZW rabbits.
Group 1 Group 2 Group 3 Group 4 Group 5
AUC (ng.h)/ml 2370 4113 1319 891 1399
C max (ng/ml) 595 1059 233 102 536
t max (h) 0.5 0.8 1.5 3 0.5
Values are mean of six animals
Group 1: 1.6g Voltaren ® Emulgel on 160cm 2 equivalent to 18.6mg diclofenac diethylamine salt
Group 2: 0.4ml DSG 4% on 160cm 2 equivalent to 16mg diclofenac sodium
Group 3: 0.4ml DSG 4% on 40cm 2 equivalent to 16mg diclofenac sodium
Group 4: 0.2ml DSG 4% on 80cm 2 equivalent to 8mg diclofenac sodium
Group 5: 0.1ml DSG 4% on 40cm 2 equivalent to 4mg diclofenac sodium
Peak plasma concentrations were attained within 30 minutes post-dose and thereafter slowly
decreased over a 24h period. After topical application of equivalent doses of Voltaren ®
Emulgel and DSG 4% (groups 1 and 2), plasma C max and AUC attained with DSG 4% were
two-fold higher than those attained with Voltaren ® Emulgel.When identical doses of DSG 4%
were applied to rabbit skin, the extent of systemic absorption was proportional to application
site surface area (comparison of PK data of groups 2 and 3).
In healthy volunteers, however, plasma C max and AUC attained after topical administration of
DSG 4% were considerably lower than those attained after an equivalent oral dose of
Voltaren 50mg tablets (see Medical Assessment). Therefore, given the low systemic exposure
anticipated with DSG 4% in humans, it is unlikely that topical administration of DSG 4%
would be of safety concern.
In a tissue distribution study in mice (iv dose), the highest levels of radioactivity were
detected in blood and highly perfused tissues including liver, kidneys, heart and lungs.
Radioactive levels in liver, bile and kidneys exceeded blood levels. The percutaneous
absorption of Voltaren ® Emulgel (1.16% diclofenac diethylammonium) and Voltaren Cream
(1% diclofenac sodium in a cream formulation) in guinea pigs, rabbit and man was
investigated. In guinea pigs, between 3-6% of the dose of Voltaren Cream (40, 100 or 320mg,
applied to 10cm 2 of occluded skin) was absorbed through the skin. Diclofenac applied
topically on the knee joint of rabbits penetrated the patellar ligament, the adipose corpus and
the synovial fluid. In man, 6% of Voltaren ® Emulgel (5mg/cm 2 applied to non-occluded skin)
was absorbed through the skin. Diclofenac steady state plasma concentrations after repeat
topical administration of Voltaren Cream (2.5g three times daily, equivalent to daily dose of
75mg diclofenac sodium) were 20-40nmol/l. After topical application of Voltaren ® Emulgel
(2.5g four times daily for 3-4 days equivalent to a daily dose of 93mg diclofenac) to arthritic
patients, diclofenac concentrations in plasma (≥20nmol/l) were considerably lower than that
in synovial fluid (≥370nmol/l) and synovial tissues (≥410nmol/l).
Diclofenac is highly bound to serum proteins (>99% in rats, dogs, baboons, monkeys and
man), crosses the placenta and the blood-brain barrier and is secreted in breast milk. Within
24h of oral administration of diclofenac (5mg/kg) to pregnant rats, the milk to plasma
exposure ratio for unchanged diclofenac was 0.14, whilst fetal concentrations were the same
as maternal blood levels.
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