Diltiazem,nicardipine and verapamil markedly raise serumciclosporin levels but also appear to possess kidney protective effects. A single case describes elevated ciclosporin levels caused bynisoldipine. Nifedipine normally appears not to interact,but risesand falls in ciclosporin levels have been seen in a few patients. Felodipine,isradipine, lacidipine and nitrendipine normally appearnot to raise serum ciclosporin levels. Amlodipine has modestlyincreased ciclosporin levels in some studies,but not in others, andit may also have kidney-protective properties.
Ten hypertensive patients with kidney transplants taking ciclosporin (3 of them also taking azathioprine) were also given amlodipine 5 to 10mg daily for 4 weeks. The hypertension was well controlled, drug well tolerated, and pharmacokinetics of ciclosporin remained unaltered (See reference number 1). However, another study in 11 hypertensive kidney transplant patients found that amlodipine, given for 7 weeks, raised ciclosporin levels by an average of 40%, without affecting creatinine levels (See reference number 2). A review identified two other studies that have found increases in ciclosporin levels of 23 % and 43 % with amlodipine,whereas four studies have found no change (See reference number 3). Amlodipine is reported to reduce ciclosporin-associated nephrotoxicity in a study in patients with psoriasis,(See reference number 4)and in a review of kidney-transplant recipients (See reference number 3).
A pharmacokinetic study in 9 patients taking ciclosporin found that addition of diltiazem 180mg daily increased trough blood level, maximum blood level and half-life of ciclosporin by 112%, 37%, and 43%, respectively (See reference number 5). Sixty-five kidney transplant patients taking ciclosporin and diltiazem were found to need less ciclosporin when compared with 63 control patients not given diltiazem (7.3 mg/kg daily compared with 9 mg/kg daily). There were considerable individual differences in dose requirements (See reference number 6). Other studies clearly confirm that diltiazem can raise ciclosporin blood levels (See reference number 7-32). In some cases ciclosporin blood levels were not only controlled by reducing ciclosporin dosage by 30 to 60%, but it appeared that diltiazem had a kidney protective role (reduced nephrotoxicity, fewer rejection episodes and haemodialysis sessions) (See reference number 11,22,33-37). Another study found that a reduction in ciclosporin dose of about 21 % was required for both men and women during chronic administration of diltiazem 90mg twice daily, despite reports of higher activity of cytochrome P450 isoenzyme CYP3A4 in women than in men (See reference number 38).
Thirteen kidney transplant patients had no significant changes in their serum ciclosporin levels when they took felodipine 2.5 to 10mg daily and serum creatinine levels were also unchanged. Mean blood pressures fell from 161/100 to 152/90 mmHg (See reference number 39). Another study found no significant changes in ciclosporin levels in patients also given felodipine (See reference number 40). A single 10mg dose of felodipine was found to have beneficial effects on blood pressure,renal haemodynamics, renal tubular sodium and water handling in ciclosporin-treated kidney transplant patients. The effects of long-term use were not studied (See reference number 41). A single-dose study in 12 healthy subjects found that maximum serum levels of ciclosporin 5 mg/kg were slightly raised by 16 % by felodipine 10 mg, while AUC and maximum plasma level of felodipine were raised by 58 % and 151%, respectively, but blood pressures were unchanged (See reference number 42). The same group of workers also briefly described acute and short-term studies in groups of kidney transplant and dermatological patients,which found that felodipine 5 to 10mg reduced blood pressure and opposed ciclosporin nephrotoxicity (See reference number 43). A study in heart transplant patients taking ciclosporin found that felodipine attenuated hypertrophic effects of ciclosporin on transplanted hearts (See reference number 44).
Ten kidney transplant patients taking ciclosporin,prednisone and azathioprine started taking lacidipine 4mg daily. A very small increase in trough blood levels (6%) and AUC (14%) of ciclosporin occurred. The blood pressures fell from 142/93 to 125/79 mmHg, and 14-hour urinary output rose from 1401 to 2050 mL (See reference number 49).
The manufacturers of lercanidipine contraindicate concurrent use of ciclosporin as plasma levels of lercanidipine were raised threefold by ciclosporin, and ciclosporin AUC was raised by 21 % by lercanidipine (See reference number 50).
Nicardipine 20mg three times daily raised ciclosporin blood levels in 9 patients by 110 % (from 226 to 430 nanograms/mL, range 24 to 341%). Their serum creatinine concentrations rose from 136 to 147 micromol/L (See reference number 51).
Other studies have found increases in serum ciclosporin levels,in some cases as much as two to threefold, when nicardipine was given (See reference number 52-58).
Five of 9 patients who had an interaction with nicardipine (see above) had no interaction when they were given nifedipine (See reference number 51). No changes in ciclosporin levels were seen in other studies,(See reference number 36,59-63) but raised(See reference number 17,20) and reduced levels(See reference number 64)have been reported in others. Two studies found that nifedipine appeared to protect patients against nephrotoxicity of ciclosporin (See reference number 65,66). However, there is some evidence that adverse effects of nifedipine such as flushing, rash(See reference number 67) and gingival overgrowth may be increased (See reference number 68-71). However, another study in 121 renal transplant patients found prevalence of gingival overgrowth in patients taking ciclosporin was increased (but not to a statistically significant extent) by concurrent use of calcium-channel blockers (not specified) (See reference number 72).
A 46-year-old man taking azathioprine,prednisolone and ciclosporin after a kidney transplant 18 months previously was given nisoldipine 5mg twice daily. During following month his ciclosporin levels rose from a range of 100 to 150 micrograms/L up to 200 micrograms/L and an increase in serum creatinine levels occurred. His ciclosporin dose was gradually reduced from 325 to 250mg daily, and his ciclosporin and creatinine levels returned to acceptable range (See reference number 73).
Nitrendipine 20mg daily for 3 weeks had no significant effect on ciclosporin blood levels in 16 kidney transplant patients (See reference number 74)
Twenty-two kidney transplant patients given ciclosporin and verapamil had ciclosporin blood levels that were 50 to 70 % higher than in 18 other patients not given verapamil,despite similar ciclosporin doses in both groups. Serum creatinine levels were lower in those taking verapamil. Moreover, only 3 of 22 had rejection episodes within 4 weeks compared with 10 out of 18 not given verapamil (See reference number 75).
Other studies have found that verapamil 120 to 320mg daily can increase,double or even triple ciclosporin blood levels in individual patients with kidney or heart transplants (See reference number 24,40,62,64,76-80). Combined use does not apparently increase severity or prevalence of gingival overgrowth caused by ciclosporin (See reference number 81).
The increased ciclosporin levels are largely due to calcium-channel blockers inhibiting ciclosporin metabolism by cytochrome P450 isoenzyme CYP3A4 in liver. Note that, of calcium-channel blockers, diltiazem and verapamil are strongest CYP3A4 inhibitors (see Calcium-channel blockers, ). Diltiazem also appears to reduce ischaemia-induced renal tubular necrosis (See reference number 82). Other calcium-channel blockers also seem to have a kidney-protective effect. The raised felodipine levels are possibly due to competitive inhibition by ciclosporin of intestinal and liver metabolism,or changes in P-glycoprotein activity.
The interactions of ciclosporin with diltiazem,nicardipine and verapamil are established and relatively well documented. Concurrent use need not be avoided,but ciclosporin levels should be well monitored and dosage reductions made as necessary. Even though ciclosporin blood levels are increased,these calcium-channel blockers appear to have a kidney-protective effect. One study(See reference number 83) noted that, although calcium-channel blockers increase ciclosporin blood levels, this is of no harm to patient, since no changes in renal function were observed. With diltiazem and verapamil ciclosporin dosage can apparently be reduced by about 25 to 50 % and possibly more with nicardipine. One case suggests that this is also true with nisoldipine. Several studies suggest that substantial cost savings can be made by combining either diltiazem(See reference number 13,84,85) or verapamil(See reference number 24) with ciclosporin. Take care not to substitute one diltiazem product for another after patient has been stabilised because there is evidence that their bioequivalence differences may alter extent of interaction (See reference number 27,86). Concurrent use with lercanidipine is contraindicated by manufacturers (See reference number 50).
The situation with amlodipine is also uncertain,but isradipine, lacidipine and nitrendipine appear to be non-interacting alternatives. Many of calcium channel blockers have a kidney-protective effect.
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