Chemical formula: C₁₄H₁₁Cl₂NO₂ Molecular mass: 296.149 g/mol PubChem compound: 3033
Diclofenac is a non-steroidal anti-inflammatory drug. The mechanism of action of diclofenac in AK may be related to the inhibition of the cycloxygenase pathway leading to reduced prostaglandin E2 (PGE2) synthesis. In addition, immunohistochemistry (IHC) from skin biopsies ac revealed that the clinical effects of diclofenac in AK are primarily due to anti-inflammatory, anti-angiogenic and possibly anti-proliferative effects and apoptosis-inducing mechanisms.
When administered systemically, diclofenac has analgesic, antipyretic and anti-inflammatory properties. When used topically this active substance possesses analgesic and anti-inflammatory properties.
Diclofenac has been shown to clear AK lesions with maximum therapeutic effect seen 30 days after cessation of drug therapy.
Data from 3 company-sponsored, randomised, double-blind clinical trials in which diclofenac was used as a comparator arm (Studies 0908, 1004 and 0702) provide further evidence on the efficacy of diclofenac in the treatment of AK lesions (including hyperkeratotic lesions) across a number of endpoints. Specifically the diclofenac arm showed histological clearance rates between 47.6% and 54.1% while these were between 33,9% and 42.7% for vehicle. Complete clinical clearance of AK lesions was achieved in 37.9% and 23.4% of patients at 30 (n=11/29) and 60 days post-treatment (n=76/380).
In a three arm study comparing 0.5% 5-FU, diclofenac and vehicle, both active arms were superior to vehicle in histological and complete cure rates, whereas 0.5% 5-FU was not inferior to diclofenac and showed higher histological clearance compared to it (70.1% vs 54.1%).
Moderate-to-significant improvements were reported using investigator and patient Global Improvement Index following diclofenac treatment.
Observational 1-year follow-up data indicate that following treatment with diclofenac, complete clearance was achieved by 28.8% and 36.8% at 6 and 12 months post treatment respectively (18.9% and 25.0% with placebo at similar time points).
The efficacy of diclofenac has been investigated in 32 patients (24 on diclofenac, 8 on placebo) who had previously undergone organ transplantation, and now had a currently stable graft. diclofenac was superior to vehicle in both complete clearance of AK lesions (41% vs 0%) and lesion count reduction (53% vs 17%).
There is a limited clinical trial experience of the use of diclofenac in JRA/JIA paediatric patients. In a randomised, double-blind, 2-week, parallel group study in children aged 3-15 years with JRA/JIA, the efficacy and safety of daily 2-3 mg/kg BW diclofenac was compared with acetylsalicylic acid (ASS, 50-100 mg/kg BW/d) and placebo – 15 patients in each group. In the global evaluation, 11 of 15 diclofenac patients, 6 of 12 aspirin and 4 of 15 placebo patients showed improvement with the difference being statistically significant (p<0.05). The number of tender joints decreased with diclofenac and ASS but increased with placebo. In a second randomised, double-blind, 6 week, parallel group study in children aged 4-15 years with JRA/JIA, the efficacy of diclofenac (daily dose 2-3 mg/kg BW, n=22) was comparable with that of indomethacin (daily dose 2-3 mg/kg BW, (n=23).
Diclofenac eye drops contain diclofenac sodium, a non-steroidal compound with pronounced anti-inflammatory and analgesic properties. Inhibition of prostaglandin biosynthesis, which has been demonstrated experimentally, is regarded as having an important bearing on its mechanism of action. Prostaglandins play a major role in the causation of inflammation and pain.
In clinical trials, diclofenac eye drops have been found to:
The effective daily dose after ocular application of diclofenac (approximately 0.25-0.5 mg diclofenac sodium) corresponds to less than 1% of the daily dose recommended for Voltarol in rheumatic indications.
Diclofenac Eye Drops contain a cyclodextrin, hydroxypropyl γ-cyclodextrin (HPγ-CD). Cyclodextrins (CDs) increase the aqueous solubility of some lipophilic water-insoluble drugs. It is believed that CDs act as true carriers by keeping hydrophobic drug molecules in solution and delivering them to the surface of biological membranes.
Diclofenac is rapidly and completely absorbed from sugar-coated tablets. Food intake does not affect absorption.
Peak plasma concentration after one 50 mg sugar-coated tablet was 3.9 µmol/l after 20-60 minutes. The plasma concentrations show a linear relationship to the size of the dose.
Diclofenac undergoes first-pass metabolism and is extensively metabolised.
After administration of diclofenac 75 mg/ml solution for injection by the i.m. route, absorption is rapid and the mean peak plasma concentration of 2.603 ± 0.959 µg/ml (2.5 ug/ml equals approximately 8 µmol/L) is reached after 34 minutes. The area under the concentration curve AUCo-t is 250.07 ± 46.89 µg/ml.min. In comparative clinical studies the mean peak plasma concentration for intramuscular Voltarol (75mg/3ml) is 2.242 ± 0.566 µg/ml which is reached after 27 minutes and the AUCo-t is 246.70± 39.74 µg/ml.min. The AUC after i.m. administration is about twice as large as it is following oral or rectal administration as this route avoids “first-pass” metabolism.
After administration of diclofenac 75 mg/ml solution for injection by the s.c. route, absorption is rapid and the mean peak plasma concentrations of 2.138 ± 0.646 µg/ml (2.5 µg/ml equals approximately 8 µmol/l) is reached in 40 minutes. The AUCo-t is 261.94 ± 53.29 µg/ml.min. In comparative clinical studies the mean peak plasma concentration for intramuscular Voltarol is 2.242 ± 0.566 µg/ml at 27 minutes and the AUCo-t is 246.70 ± 39.74 µg/ml.min. A subcutaneous dose of 75 mg of diclofenac was bioequivalent to an intramuscularly administered dose of Voltarol 75 mg/3 ml in terms of AUC and Cmax. The AUC after subcutaneous administration is about twice as large as it is following oral or rectal administration as this route avoids “first-pass” metabolism.
Dose linearity in terms of AUC has been demonstrated for diclofenac absorbed after subcutaneous administration. Cmax was found to be not proportional to dose, with mean Cmax values of 1090 ng/ml, 1648.9 ng/ml and 1851.1 ng/ml with the 25 mg, 50 mg and 75 mg dose of diclofenac respectively.
After administration of diclofenac 75mg/mL solution for injection by intravenous bolus, absorption sets in immediately, and mean peak plasma concentration of about 16.505 ± 2.829 µg/mL are reached in 3 minutes. In comparative pharmacokinetic studies, were diclofenac was measured in plasma up to 8 hours post-dose, diclofenac 75 mg/mL i.v. bolus was found to be bioequivalent to Voltarol 75 mg/3mL ampoule administered as a 30-min i.v. infusion (100 mL) in terms of systemic exposure (AUC0-t: 5193.46 ± 1285 ng/mL.h and 4584.13 ± 1014.20 ng/mL.h, for diclofenac and Voltarol, respectively), but with a substantially higher rate of absorption (Cmax for Voltarol 75 mg/3mL infusion was 6.117 ± 1.051 µg/mL). Also, diclofenac peak plasma concentration (Cmax) following diclofenac i.v. bolus injection was found to be comparable to that reported in the literature for a similar diclofenac sodium and hydroxyl-propyl-ß-cyclodextrin-containing solution for injection (Dyloject 75mg/2mL, Javelin Pharm. Ltd., UK) given by the same route (Cmax: 15.147 ± 2.829 µg/mL). The diclofenac AUC after bolus intravenous administration is about twice as large as it is following oral or rectal administration as this route avoids “first-pass” metabolism.
Mean absorption through the skin varies between <1-12% with large inter-individual variability. Absorption is dependent on the amount of the topical dose applied and the site of application.
Diclofenac is highly bound to plasma proteins (99.7%), chiefly albumin (99.4%).
Diclofenac was detected in a low concentration (100 ng/mL) in breast milk in one nursing mother. The estimated amount ingested by an infant consuming breast milk is equivalent to a 0.03 mg/kg/day dose.
Diclofenac binds highly to serum albumin.
Biotransformation of diclofenac involves partly conjugation of the intact molecule, but mainly single and multiple hydroxylations resulting in several phenolic metabolites, most of which are converted to glucuronide conjuguates. Two of these phenolic metabolites are biologically active, however to a much lesser extent than diclofenac. Metabolism of diclofenac following percutaneous and oral administration is similar.
Diclofenac and its metabolites are excreted mainly in the urine. Systemic clearance of diclofenac from plasma is 263 ± 56 ml/min (mean value ± standard deviation) following oral administration. Terminal plasma half-life is short (1-2 hours). For the metabolites also have short terminal half-lives of 1-3 hours.
The age of the patient has no influence on the absorption, metabolism, or excretion of diclofenac.
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 theoretical steady-state plasma levels of metabolites are about four times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.
In the presence of impaired hepatic function (chronic hepatitis, non-decompensated cirrhosis) the kinetics and metabolism are the same as for patients without liver disease.
After topical application, the absorption of diclofenac in normal and compromised epidermis are comparable although there is a large inter-individual variation. Systemic absorption of diclofenac is approximately 12% of the administered dose for compromised skin and 9% for intact skin.
Spectrofluoroscopy has shown that diclofenac concentrates in the oral mucosa and then is gradually absorbed, thus producing haematic concentrations that are very low, and insufficient to express pharmacological effects.
Diclofenac is eliminated primarily in the urine, in the form of metabolite, and the remaining part is excreted in the bile and faeces.
Oral diclofenac is rapidly and almost completely absorbed from the gastrointestinal (GI) tract: however, the drug undergoes extensive first-pass metabolism in the liver, with only about 50-60% of a dose as enteric-coated tablets reaching the systemic circulation as unchanged drug.
Following oral administration of a single 25, 50, 75, or 150 mg dose as enteric-coated tablets in healthy adults, average peak plasma diclofenac concentrations of 0.5-1, 1-1.5, 2, and 2.5 mg/mL, respectively within about 1.5-3 hours. The area under the plasma concentration-time curve (AUC) increases linearly with single diclofenac doses of 25-150 mg.
The systemic absorption of mouthwash doses of diclofenac is relatively low compared to oral doses. The systemic bioavailability of diclofenac after 7 days of mouth rinsing b.i.d. with 25 ml of is about 1/10th in terms of AUC and 1/20th to 1/50th in terms of Cmax of that obtained with the oral administration of 25 mg diclofenac tablets.
This low absorption should greatly diminish the potential for any systemic drug side-effects when diclofenac is administered by this route.
In rabbits, peak concentrations of 14C-labelled diclofenac could be demonstrated in the cornea and conjunctiva 30 minutes after application. The highest amounts are found in these two tissues and in the choroid and retina. Elimination was fast and almost complete after 6 hours.
Penetration of diclofenac into the anterior chamber has been confirmed in humans. No measurable levels of diclofenac could be found in humans after ocular application of diclofenac sodium eye drops.
Non-clinical data based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential reveal no special hazards for humans beyond those already outlined. In animal studies, chronic toxicity of diclofenac following systemic administration mainly manifested as gastrointestinal lesions and ulcers. In a 2-year toxicity study, rats treated with diclofenac showed a dose-related increase in thrombotic occlusion of the cardiac vessels.
In animal studies on reproductive toxicity, systemically administered diclofenac caused inhibition of ovulation in rabbits and impairment of implantation and early embryonic development in rats. The gestational period and duration of parturition were prolonged by diclofenac. The embryotoxic potential of diclofenac was studied in three animal species (rat, mouse, rabbit). Foetal death and growth retardation occurred at maternotoxic dose levels. Based on the available non-clinical data, diclofenac is regarded as non-teratogenic. Doses below the maternotoxic threshold had no impact on the postnatal development of the offspring.
Conventional studies on local tolerability reveal no special hazards for humans.
Preclinical data of systemically applied diclofenac from acute and repeated dose toxicity studies, as well as from genotoxicity and carcinogenicity studies revealed no specific hazard for humans at the intended therapeutic doses.
In reproductive and developmental toxicity studies systemic diclofenac has been shown to cross the placental barrier in mice and rats. Whilst no teratogenic effects have been demonstrated, maternally toxic doses were associated with dystocia, prolonged gestation, decreased foetal survival, and intrauterine growth retardation. The effects of diclofenac on fertility and delivery as well as the constriction of the ductus arteriosus in utero are pharmacological consequences of this class of prostaglandin synthesis inhibitors
Local ocular tolerance and toxicity of diclofenac 0.1% eye drops (containing hydroxypropyl-gamma cyclodextrin) were investigated and no evidence of toxicity and local adverse effects was found.
Concentrations of HP-gamma-CD in plasma and aqueous humor were below detection limits (1 nMol/mL) in rabbits after single or four times daily (q.i.d.) ocular administration of diclofenac 0.1% eye drops.
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