Diclofenac Subject

Pharmacokinetics The pharmacokinetics following oral administration of a single dose or multiple doses of diclofenac/misoprostol to healthy subjects under fasted conditions are similar to the pharmacokinetics of the 2 individual components. Food decreases the multiple-dose bioavailability profile of both formulations. 

A 19-year-old man was admitted to hospital following the ingestion of 1.5 g of diclofenac sodium and 4 g of chlormezanone. Plasma-diclofenac concentrations of 60.1 pg/ml and 0.19 jig/ml were reported at 7 and 15 hours, respectively chlormezanone could not be determined. The subject recovered after about 2 days (P. Netter et al., Eur. J. din. Pharmac., 1984, 26, 535-536). 

In a randomized comparison of celecoxib and diclofenac plus omeprazole, renal adverse events, including hypertension, peripheral edema, and renal insufficiency, were common and similar in the two groups (105). They occurred in the 24% of the patients who took celecoxib and in 31% of those who took diclofenac plus omeprazole. Among patients with renal impairment at baseline, 51% of those who took celecoxib and 41% of those who took diclofenac plus omeprazole had renal adverse events. Careful monitoring of renal function in patients taking COX-2 inhibitors or traditional NSAIDs is mandatory, especially in high-risk subjects (for example those with pre-existing renal disease, diabetes, or heart failure). 

To test whether omeprazole accelerates healing of standardized gastroduodenal lesions in the presence of diclofenac, 12 healthy volunteers took consecutive 2-week courses of omeprazole 40 mg/day or placebo, with diclofenac given in the second week of each course, in a double-blind, crossover study (3). Omeprazole did not accelerate the healing of pre-existing mucosal lesions or prevent the development of small diclofenac-induced mucosal lesions. Omeprazole increased serum gastrin in all subjects. 

Rodriguez, Varas-Lorenzo etat.[188]2004 Nested case- Ml associated with 404183 subjects 50- control cohort NSAIDuse 84years old. 20000 Controls were randomly sampled and frequency was matched to cases by age, sex, and calendaryear. Multivariate Adjusted Odds ratio Current NSAID use vs nonuse 1.07 (0.95-1.20) Previous CHD History 1.12 (0.91-1.38) Incidence rate of Ml was slightly higher among people with history of CHD. Estimates for Naproxen, ibuprofen, and diclofenac were comparable with no major effects on the risk of Ml. 

Dilger K, Herriinger C, Peters J et al. Effects of celecoxib and diclofenac on blood pressure, renal function, and vasoactive prostanoids in young and elderly subjects. Journal of Clinical Pharmacology 2002 42 985-994. 

The description and quantification of between-subject variability become very important in a population of patients. For example, the double-peak phenomenon observed on median PK profiles of sustained-release diclofenac is due to large differences in individual values (39). 

COX-2 inhibitors demonstrate similar analgesic benefits when compared to traditional NSAIDs. For example, 748 subjects randomized to rofecoxib (12.5 or 25 mg daily) or diclofenac (50 mg three times daily) showed similar improvements in pain, stiffness, physical function, and other measures of efficacy. In a 12-week trial of 1003 subjects with knee OA, celecoxib at 100 or 200 mg twice daily was more effective than placebo and comparable to naproxen 500 mg twice daily for relief of pain, stiffness, and limitation of physical function. ... 

To study effects on clinically important GI complications with celecoxib, the CLASS study used celecoxib (400 mg twice daily, or twice the highest FDA-approved dose) compared to diclofenac and ibuprofen at standard dose. Celecoxib use was reported to be associated with a reduced incidence for the combined end point of symptomatic ulcers and ulcer complications (perforations, gastric outlet obstruction, or bleeding). Some subjects also used aspirin for car-dioprotection, but there is concern that GI safety of COX-2 inhibitors is blunted with use of concomitant aspirin (even 30 mg of aspirin can suppress gastric prostaglandin prodnction)." For patients taking aspirin and celecoxib, nicer complications were higher than with celecoxib only, but lower than with traditional NSAIDs. 

Meloxicam demonstrates some COX-2 selectivity, but a clinical advantage or hazjard has yet to be established. There is significantly less gastric injury compared to piroxicam (20 mg/day) in subjects treated with 7.5 mg/day of meloxicam, but the advantage is lost with 15 mg/day. Like diclofenac, meloxicam does not offer a desirable cdterrmtive to prescribing celecoxib to patients at increased risk of myocardial infarction or stroke. 

O-Methylation of xenobiotic catechols occurs preferentially at the meta position, L-dopa and isoproterenol being classical examples. Frequently 0-methylation is a late event in the metabolism of aryl groups, after they have been oxidized to catechols. Thus the anti-inflammatory drug diclofenac yields in humans 3 -hydroxy-4 -methoxy-diclo-fenac as the major metabolite with a very long plasmatic half-life. Noncatechol diphenols are not subject to methylation, e.g. terbutaUne. A few monophenols can also undergo methylation to a limited extent. 

The manufacturer of spirapril briefly noted in a review that there was no relevant pharmacokinetic interaction between spirapril and diclofenac. Oxaprozin 1.2 g daily for 3 weeks did not affect the pharmacokinetics of enalapril 10 to 40 mg daily in 29 patients with hypertension. A brief mention is made in a review that, in healthy subjects, the pharmacokinetics of ramipril were unaffected by indometacin [dosage not stated] given for 3 days. ... 

A study in healthy subjects found that diclofenac increased the clearance of amoxicillin. An isolated report describes acute interstitial nephritis with nephrotic syndrome associated with the use of naproxen and amoxicillin. 

In a study in 20 healthy subjects diclofenac 100 mg caused a slight reduction in the AUC and a slight increase in the mean renal clearance of a single 2-g dose of amoxicillin. It should be noted that there was considerable individual variation and overlapping between the two groups, and the clinical significance of this finding is unclear. 

A single-dose, crossover study in 6 healthy, fasting subjects found that the simultaneous use of colestyramine 8 g markedly reduced the AUC of a single 100-mg oral dose of enteric-coated diclofenac by 62% and reduced its maximum plasma levels by 75%. Colestipol 10 g reduced the diclofenac AUC by 33% and its maximum plasma levels by 58%. ... 

A study in 12 healthy subjects who were given diclofenac 50 mg twice daily for 14 days, with Ginkgo biloba extract (Ginkgold) 120 mg twice daily on days 8 to 15, found no alteration in the AUC or oral clearance of diclofenac. ... 

In 14 healthy subjects famotidine 40 mg raised the peak plasma levels of enteric-coated diclofenac 100 mg from 5.84 to 7.04 mg/L. Peak plasma diclofenac levels also occurred more rapidly (2 versus 2.75 hours). The extent of the absorption was unchanged. Diclofenac did not affect the pharmacokinetics of ranitidine nor its ability to suppress gastric pH. Another study also found that the pharmacokinetics of diclofenac were unaffected by ranitidine. ... 

No change in tree diclofenac levels was seen when 6 healthy subjects were given floctafenine 400 mg with diclofenac 75 mg daily for a week. ... 

Diclofenac Diclofenac 25 mg given with paracetamol 500 mg, both three times daily for 14 days, had no effect on the pharmacokinetics of diclofenac in 6 healthy subjects. ... 

In another study a single 40-mg oral dose of pantoprazole and diclofenac 100 mg (as enteric-coated Voltarol) were given to 24 healthy subjects together and separately. Neither drug affected the pharmacokinetics of the other. ... 

A study in 6 healthy subjects found that after taking rifampicin 450 mg daily for 6 days, the maximum serum level of diclofenac, measured 8 hours after a single 100-mg dose of an enteric-coated tablet, was reduced by 43% and the AUC was reduced by 67% ... 

Ketoprofen reduced morphine-associated respiratory depression, and did not alter morphine pharmacokinetics. Similarly, diclofenac did not alter morphine pharmacokinetics in one study. Improved pain relief and reduced adverse effects have been found when morphine was given with lomoxicam, ketoprofen, or ketorolac. However, in another, diclofenac slightly increased respiratory depression despite reducing morphine use, possibly because of persistent levels of an active metabolite of morphine. Diclofenac did not affect the pharmacokinetics or analgesic effects of codeine in healthy subjects. Intramuscular diclofenac did not affect the pharmacokinetics of methadone solution in cancer patients. Ibuprofen did not appear to interact... 

A single 50-mg dose of diclofenac sodium did not have an important effect on the pharmacokinetics of a single 100-mg dose of codeine phosphate in a placebo-controlled crossover study in 12 healthy subjects. There was no effect on the metabolic clearance of morphine, and only a slight (about 5% to 10%) increase in the levels of glucuronide metabolites. In addition, diclofenac did not alter the analgesic effects of codeine as assessed in a cold pressor test (a test in which opioids, but not NSAIDs, are effective). ... 

Although this interaction perhaps requires confirmation in a multiple-dose study in a clinical setting, the findings in healthy subjects suggest that no special precautions are required during the concurrent use of diclofenac and codeine. 

One patient taking fenbufen 800 mg had involuntary movements of the neck and upper extremities after taking ofloxacin 600 mg. The pharmacokinetics of ofloxacin 200 mg twice daily were unchanged by ketopro-fen 100 mg daily for 3 days in 10 healthy subjects. The incidence of psychotic adverse effects (euphoria, hysteria, psychosis) in 151 patients on ofloxacin were not increased by the concurrent use of NSAIDs (aspirin, diclofenac, indometacin, dipyrone)."... 

In a single-dose study in 24 healthy subjects, simultaneous administration of ximelagatran 24 mg and enteric-coated diclofenac 50 mg caused no change in the pharmacokinetics of either drug. In this study, there was also no additional effect of the combination on activated partial thromboplastin time or capillary bleeding time, suggesting that no pharmacodynamic interaction occurs. ... 

In a randomised crossover study, 18 healthy subjects were given modi-fied-release diclofenac 75 mg on the same day as two 120-mg doses of nateglinide, given 4 hours apart. The pharmacokinetics of both drugs were unaltered by concurrent use. ... 

Diclofenac. In a study in 8 healthy subjects, diazepam increased the AUC of diclofenac by 60% while the clearance was reduced by 36%. The effects of diazepam on diclofenac appeared to depend on the time of administration and may reflect time-dependent effects of diazepam on gastrointestinal function. More study is needed. 

A clinical study found that diclofenac 75 mg given intravenously to 10 patients reduced the dose of intravenous midazolam needed to produce sedation and hypnosis by 35%, when compared with 10 control subjects not given diclofenac. The clinical importance of this is uncertain. 

Mahender VN, RambhauD, RaoBR,Rao VVS, VenkateshwarluG. Time-dependent influence of diazepam on the pharmacokinetics of orally administered diclofenac sodium in human subjects. Clin Drug Invest (1995) 10, 296-301. 

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