Interaction between cyclosporin A and nonsteroidal antiinflammatory drugs.
OBJECTIVE
Although cyclosporin A (CyA) has been shown in a series of controlled trials to be of benefit to patients with rheumatoid arthritis (RA), the majority of patients continue to require nonsteroidal antiinflammatory drugs (NSAID) for relief of joint pain and stiffness. Our aim was to determine whether there is a clinically important difference in calculated creatinine clearance when CyA is given concurrently with NSAID with high cyclooxygenase activity (indomethacin and ketoprofen) compared with sulindac, which has been claimed to have fewer renal effects than other NSAID, and compared with a simple analgesic, paracetamol.


METHODS
Patients with RA started 2.5 mg/kg CyA/day and dosage was increased cautiously to 5 mg/kg/day or less if the serum creatinine rose by > or = 30% above baseline. The mean stabilized dose was 171.43 +/- 48.94 mg/day. Once CyA dose was stabilized, patients were allocated in random order to possible sequences of 4 week periods of acetaminophen, indomethacin, ketoprofen, and sulindac. Monitoring of cyclosporine levels, nephrotoxicity, and hepatoxicity, and adjustment of doses were by an "unblinded" clinician not in direct contact with study patients. All other assessments were made by a "blinded" clinician. Patients were instructed to take the identical appearing gelatin capsules qid. The multiple crossover design was analyzed using analysis of variance procedures for repeated measures.


RESULTS
35 patients were enrolled, of whom 32 patients completed the acetaminophen and at least one course of NSAID. The calculated creatinine clearance was increased by 2.79 ml/min (3.5%) on average for acetaminophen versus all 3 NSAID (6% for indomethacin, 2.3% for ketoprofen, 2.6% for sulindac). The study had adequate power to detect a true difference of more than 10% in mean creatinine clearance for each major comparison.


CONCLUSIONS
NSAID studied did not produce a clinically important difference in the calculated creatinine clearance in these patients-the difference with acetaminophen was modest and not of clinical significance. There is no evidence that any of the 3 NSAID studied have an advantage or disadvantage. It seems reasonable to allow patients to continue an NSAID of their or their clinician's choice.
Tugwell
P
P
Department of Medicine, University of Ottawa, Canada.
Ludwin
D
D
Gent
M
M
Roberts
R
R
Bensen
W
W
Grace
E
E
Baker
P
P
D000082:Acetaminophen / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D018712:Analgesics, Non-Narcotic / Q000627:therapeutic use; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D003131:Combined Modality Therapy; D003404:Creatinine / Q000378:metabolism; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000627:therapeutic use*; D004347:Drug Interactions; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007213:Indomethacin / Q000627:therapeutic use; D007660:Ketoprofen / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D000082:Acetaminophen; D016572:Cyclosporine; D007660:Ketoprofen; D003404:Creatinine; D007213:Indomethacin