ase or risk factors had a higher absolute incidence of excess serious cv thrombotic events, due to their increased baseline rate. some observational studies found that this increased risk of serious cv thrombotic events began as early as the first weeks of treatment. the increase in cv thrombotic risk has been observed most consistently at higher doses. to minimize the potential risk for an adverse cv event in nsaid-treated patients, use the lowest effective dose for the shortest duration possible. physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous cv symptoms. patients should be informed about the symptoms of serious cv events and the steps to take if they occur. there is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious cv thrombotic events associated with nsaid use. the concurrent use of aspirin and an nsaid, such as diclofenac, increases the risk of serious gastrointestinal (gi) events. status post coronary artery bypass graft (cabg) surgery two large, controlled clinical trials of a cox-2 selective nsaid for the treatment of pain in the first 10 to 14 days following cabg surgery found an increased incidence of myocardial infarction and stroke. nsaids are contraindicated in the setting of cabg. post-mi patients observational studies conducted in the danish national registry have demonstrated that patients treated with nsaids in the post-mi period were at increased risk of reinfarction, cv-related death, and all-cause mortality beginning in the first week of treatment. in this same cohort, the incidence of death in the first year post mi was 20 per 100 person years in nsaid-treated patients compared to 12 per 100 person years in non-nsaid exposed patients. although the absolute rate of death declined somewhat after the first year post-mi, the increased relative risk of death in nsaid users persisted over at least the next four years of follow-up. avoid the use of diclofenac sodium in patients with a recent mi unless the benefits are expected to outweigh the risk of recurrent cv thrombotic events. if diclofenac sodium is used in patients with a recent mi, monitor patients for signs of cardiac ischemia. heart failure and edema the coxib and traditional nsaid trialists’ collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in cox-2 selective-treated patients and nonselective nsaid-treated patients compared to placebo-treated patients. in a danish national registry study of patients with heart failure, nsaid use increased the risk of mi, hospitalization for heart failure, and death. additionally, fluid retention and edema have been observed in some patients treated with nsaids. use of diclofenac may blunt the cv effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ace inhibitors, or angiotensin receptor blockers (arbs)]. avoid the use of diclofenac sodium in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. if diclofenac sodium is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

ighteen percent of diclofenac sodium gel treated patients and 4% of vehicle-treated patients discontinued from the clinical trials due to adverse events (whether considered related to treatment or not). these discontinuations were mainly due to skin irritation or related cutaneous adverse reactions. table 1 below presents the aes reported at an incidence of >1% for patients treated with either diclofenac sodium gel or vehicle (60- and 90-day treatment groups) during the phase 3 studies. table 1. adverse events reported (>1% in any treatment group) during diclofenac sodium gel phase 3 clinical trials incidences for 60-day and 90-day treatments 60-day treatment 90-day treatment diclofenac sodium gel (%) gel vehicle (%) diclofenac sodium gel (%) gel vehicle (%) n=48 n=49 n=114 n=114 body as a whole 21 20 20 18 abdominal pain 2 0 1 0 accidental injury 0 0 4 2 allergic reaction 0 0 1 3 asthenia 0 0 2 0 back pain 4 0 2 2 chest pain 2 0 1 0 chills 0 2 0 0 flu syndrome 10 6 1 4 headache 0 6 7 6 infection 4 6 4 5 neck pain 0 0 2 0 pain 2 0 2 2 cardiovascular system 2 4 3 1 hypertension 2 0 1 0 migraine 0 2 1 0 phlebitis 0 2 0 0 digestive system 4 0 6 8 constipation 0 0 0 2 diarrhea 2 0 2 3 dyspepsia 2 0 3 4 metabolic and nutritional disorders 2 8 7 2 creatine phosphokinase increased 0 0 4 1 creatinine increased 2 2 0 1 edema 0 2 0 0 hypercholesteremia 0 2 1 0 hyperglycemia 0 2 1 0 sgot increased 0 0 3 0 sgpt increased 0 0 2 0 musculoskeletal system 4 0 3 4 arthralgia 2 0 0 2 arthrosis 2 0 0 0 myalgia 2 0 3 1 nervous system 2 2 2 5 anxiety 0 2 0 1 dizziness 0 0 0 4 hypokinesia 2 0 0 0 respiratory system 8 8 7 6 asthma 2 0 0 0 dyspnea 2 0 2 0 pharyngitis 2 8 2 4 pneumonia 2 0 0 1 rhinitis 2 2 2 2 sinusitis 0 0 2 0 skin and appendages 75 86 86 71 acne 0 2 0 1 application site reaction 75 71 84 70 acne 0 4 1 0 alopecia 2 0 1 1 contact dermatitis 19 4 33 4 dry skin 27 12 25 17 edema 4 0 3 0 exfoliation 6 4 24 13 hyperesthesia 0 0 3 1 pain 15 22 26 30 paresthesia 8 4 20 20 photosensitivity reaction 0 2 3 0 pruritus 31 59 52 45 rash 35 20 46 17 vesiculobullous rash 0 0 4 1 contact dermatitis 2 0 0 0 dry skin 0 4 3 0 herpes simplex 0 2 0 0 maculopapular rash 0 2 0 0 pain 2 2 1 0 pruritus 4 6 4 1 rash 2 10 4 0 skin carcinoma 0 6 2 2 skin nodule 0 2 0 0 skin ulcer 2 0 1 0 special senses 2 0 4 2 conjunctivitis 2 0 4 1 eye pain 0 2 2 0 urogenital system 0 0 4 5 hematuria 0 0 2 1 other 0 0 0 3 procedure 0 0 0 3 skin and appendages adverse events reported for diclofenac sodium gel at less than 1% incidence in the phase 3 studies: skin hypertrophy, paresthesia, seborrhea, urticaria, application site reactions (skin carcinoma, hypertonia, skin hypertrophy lacrimation disorder, maculopapular rash, purpuric rash, vasodilation). adverse reactions reported for oral diclofenac dosage form (not topical diclofenac sodium gel, 3%): *incidence greater than 1% marked with asterisk. body as a whole: abdominal pain or cramps*, headache*, fluid retention*, abdominal distention*, malaise, swelling of lips and tongue, photosensitivity, anaphylaxis, anaphylactoid reactions, chest pain. cardiovascular: hypertension, congestive heart failure, palpitations, flushing, tachycardia, premature ventricular contractions, myocardial infarction, hypotension. digestive: diarrhea*, indigestion*, nausea*, constipation*, flatulence*, liver test abnormalities*, pub*, i.e., peptic ulcer, with or without bleeding and/or perforation, or bleeding without ulcer, vomiting, jaundice, melena, esophageal lesions, aphthous stomatitis, dry mouth and mucous membranes, bloody diarrhea, hepatitis, hepatic necrosis, cirrhosis, hepatorenal syndrome, appetite change, pancreatitis with or without concomitant hepatitis, colitis, intestinal perforation. hemic and lymphatic: hemoglobin decrease, leukopenia, thrombocytopenia, eosinophilia, hemolytic anemia, aplastic anemia, agranulocytosis, purpura, allergic purpura, bruising. metabolic and nutritional disorders: azotemia, hypoglycemia, weight loss. nervous system: dizziness*, insomnia, drowsiness, depression, diplopia, anxiety, irritability, aseptic meningitis, convulsions, paresthesia, memory disturbance, nightmares, tremor, tic, abnormal coordination, disorientation, psychotic reaction. respiratory: epistaxis, asthma, laryngeal edema, dyspnea, hyperventilation, edema of pharynx. skin and appendages: rash*, pruritus*, alopecia, urticaria, eczema, dermatitis, bullous eruption, erythema multiforme major, angioedema, stevens-johnson syndrome, excess perspiration, exfoliative dermatitis. special senses: tinnitus*, blurred vision, taste disorder, reversible and irreversible hearing loss, scotoma, vitreous floaters, night blindness, amblyopia. urogenital: nephrotic syndrome, proteinuria, oliguria, interstitial nephritis, papillary necrosis, acute renal failure, urinary frequency, nocturia, hematuria, impotence, vaginal bleeding.

l reproduction studies are not always predictive of human response, this drug should not be used during pregnancy unless the benefits to the mother justify the potential risk to the fetus. because of the risk to the fetus resulting in premature closure of the ductus arteriosus, diclofenac should be avoided in late pregnancy.

ingle oral 75 mg dose of diclofenac (voltaren ® ) † produced an auc of 1600 ng/hr/ml. therefore, the systemic bioavailability after topical application of diclofenac sodium gel is lower than after oral dosing. comparative bioavailability studies have not been conducted between available diclofenac topical products (gels containing 1 to 3% diclofenac) which have different dosing regimens. a cross-study evaluation of the data indicates that diclofenac is more bioavailable when applied to diseased skin and less bioavailable when applied to intact skin. blood drawn at the end of treatment from 60 patients with ak lesions treated with diclofenac sodium gel in three adequate and well-controlled clinical trials was assayed for diclofenac levels. each patient was administered 0.5 g of diclofenac sodium gel twice a day for up to 105 days. there were up to three 5 cm x 5 cm treatment sites per patient on the face, forehead, hands, forearm, and scalp. serum concentrations of diclofenac were, on average, at or below 20 ng/ml. these data indicate that systemic absorption of diclofenac in patients treated topically with diclofenac sodium gel is much lower than that occurring after oral daily dosing of diclofenac sodium. no information is available on the absorption of diclofenac when diclofenac sodium gel is used under occlusion. distribution diclofenac binds tightly to serum albumin. the volume of distribution of diclofenac following oral administration is approximately 550 ml/kg. metabolism biotransformation of diclofenac following oral administration involves conjugation at the carboxyl group of the side chain or single or multiple hydroxylations resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. two of these phenolic metabolites are biologically active, however to a much smaller extent than diclofenac. metabolism of diclofenac following topical administration is thought to be similar to that after oral administration. the small amounts of diclofenac and its metabolites appearing in the plasma following topical administration makes the quantification of specific metabolites imprecise. elimination diclofenac and its metabolites are excreted mainly in the urine after oral dosing. systemic clearance of diclofenac from plasma is 263±56 ml/min (mean±sd). the terminal plasma half-life is 1 to 2 hours. four of the metabolites also have short terminal half-lives of 1 to 3 hours.

genotoxic in in vitro point mutation assays in mammalian mouse lymphoma cells and ames microbial test systems, or when tested in mammalian in vivo assays including dominant lethal and male germinal epithelial chromosomal studies in mice, and nucleus anomaly and chromosomal aberration studies in chinese hamsters. it was also negative in the transformation assay utilizing balb/3t3 mouse embryo cells. fertility studies have not been conducted with diclofenac sodium gel. diclofenac sodium showed no evidence of impairment of fertility after oral treatment with 4 mg/kg/day (7 times the estimated systemic human exposure) in male or female rats. * based on body surface area and assuming 10% bioavailability following topical application of 2 g diclofenac sodium gel per day (1 mg/kg diclofenac sodium).

affect the absorption of the study medication. application of dermatologic products such as sunscreens, cosmetics, and other drug products was not permitted. patients were instructed to apply a small amount of diclofenac sodium gel (approximately 0.5 g) onto the affected skin, using their fingers, and gently smoothing the gel over the lesion. in addition, all patients were instructed to avoid sun exposure. complete clearing of the ak lesions 30 days after completion of treatment was the primary efficacy variable. no long-term patient follow-ups, after the 30-day assessments, were performed for the detection of recurrence. complete clearance of actinic keratosis lesions 30 days post-treatment (all locations) diclofenac sodium gel vehicle p-value study 1 90 days treatment 27/58 (47%) 11/59 (19%) <0.001 study 2 90 days treatment 18/53 (34%) 10/55 (18%) 0.061 study 3 60 days treatment 15/48 (31%) 5/49 (10%) 0.021 30 days treatment 7/49 (14%) 2/49 ( 4%) 0.221 complete clearance of actinic keratosis lesions 30 days post-treatment (by location) scalp forehead face arm/forearm back of hand study 1 90 days treatment diclofenac sodium gel 1/4 (25%) 17/30 (57%) 9/17 (53%) 4/12 (33%) 6/16 (38%) vehicle 3/9 (33%) 8/24 (33%) 5/17 (29%) 4/12 (33%) 0/14 (0) p-value 0.7646 0.0908 0.1682 1.000 0.0650 study 2 90 days treatment diclofenac sodium gel 2/6 (33%) 9/19 (47%) 4/5 (80%) 5/8 (63%) 1/17 (6%) vehicle 0/4 (0) 6/22 (27%) 2/8 (25%) 0/5 (0) 3/16 (19%) p-value 0.4235 0.1870 0.0727 0.0888 0.2818 study 3 60 days treatment diclofenac sodium gel 3/7 (43%) 13/31 (42%) 10/19 (53%) 0/1 (0) 2/8 (25%) vehicle 0/6 (0) 5/36 (14%) 2/13 (15%) 0/2 (0) 1/9 (11%) p-value 0.2271 0.0153 0.0433 - 0.4637 30 days treatment diclofenac sodium gel 2/5 (40%) 4/29 (14%) 3/14 (21%) 0/0 (0) 0/9 (0) vehicle 0/5 (0) 2/29 (7%) 2/18 (11%) 0/1 (0) 1/9 (11%) p-value 0.2299 0.3748 0.4322 - 0.6521 all data combined diclofenac sodium gel 8/22 (36%) 43/109 (39%) 26/55 (47%) 9/21 (43%) 9/50 (18%) vehicle 3/24 (13%) 21/111 (19%) 11/56 (20%) 4/20 (20%) 5/48 (10%) p-value 0.0903 0.0013 0.0016 0.2043 0.3662

r slurring of speech, and to report any of these symptoms to their health care provider immediately. heart failure and edema advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur.