Pharmacy Blog – Dr Vibore

Clinical evidence,mechanism, importance and management

Ten heart transplant patients taking ciclosporin,azathioprine and diltiazem were also given clodronate 800mg daily for one week. No statistically significant differences were seen in their ciclosporin blood levels or AUCs while they were taking clodronate. Three of them were also taking simvastatin,two were taking ranitidine and one was taking propafenone, furosemide and cyclophosphamide. There would seem to be no reason for avoiding concurrent use, but authors of report suggest that longer-term use of clodronate should be well monitored (See reference number 1). There seems to be no information about other bisphosphonates.

1. Baraldo M,Furlanut M, Puricelli C. No effect of clodronate on cyclosporin A blood levels inheart transplant patients simultaneously treated with diltiazem and azathioprine. Ther DrugMonit (1994) 16, 435.

Ciclosporin serum levels are markedly reduced by rifampicin andtransplant rejection can rapidly develop. Rifamycin seems to interact similarly,but limited evidence suggests that rifabutin interacts to a lesser extent. Ethambutol and isoniazid do not generallyappear to interact with ciclosporin although case reports have described alterations in ciclosporin levels.

The clearance of ciclosporin in a patient with a kidney transplant doubled when isoniazid,ethambutol, pyridoxine and rifampicin 600mg daily were given. When these drugs were replaced by rifabutin 150mg and clofazimine 100mg daily ciclosporin clearance fell to about its former levels, but after about 3 weeks clearance was about 20 % greater than before antimycobacterial drugs were given (See reference number 1).

A study in 39 kidney transplant patients taking ciclosporin at a mean dose of 158mg daily found that ciclosporin dose needed to be increased by between 150 to 525mg daily (an average dose of 469mg daily) when rifampicin 450 to 600mg daily was taken as part of a regimen for tuberculosis

A heart transplant patient taking ciclosporin started taking rifampicin 600mg daily with amphotericin B for treatment of an Aspergillus fumigatus infection. The dosage of ciclosporin was increased stepwise and levels climbed to a plateau before suddenly falling again. The dosage had to be increased to more than 30 mg/kg daily to achieve serum levels in range 100 to 300 nanograms/mL (See reference number 3)

A considerable number of other reports about individual patients, both adult and paediatric, confirm that a very marked fall in serum ciclosporin levels occurs, often to undetectable levels, accompanied by transplantation rejection in many instances, if rifampicin is given either intravenously or orally without raising ciclosporin dosage (See reference number 1,4-28). Ciclosporin levels become toxic within 2 weeks of stopping rifampicin unless previously adjusted ciclosporin dosage is reduced (See reference number 4,6).

Three patients needed increases in dosage of ciclosporin when given rifampicin and erythromycin, although latter normally reduces ciclosporin requirements (See reference number 19,29,30). Another patient whose ciclosporin levels had been raised by clarithromycin,, had a fall in their levels when rifampicin was added (See reference number 31).

Rifamycin sodium used to irrigate a wound has been reported to reduce serum levels of ciclosporin in a kidney transplant patient (See reference number 32)

Isoniazid(See reference number 12,22,23) and ethambutol(See reference number 22,23) do not normally interact with ciclosporin. However, there is one case report describing a patient who had a gradual rise in serum ciclosporin levels when isoniazid and ethambutol were stopped,(See reference number 14) and another which attributed a marked rise in ciclosporin levels to use of isoniazid (See reference number 33). There have been several other case reports of successful treatment of tuberculosis in heart and kidney transplant patients using isoniazid,ethambutol, pyrazinamide with ofloxacin, or streptomycin (See reference number 34,35). Consider also pyrazinamide,, and quinolones, .

Rifampicin stimulates metabolism of ciclosporin by cytochrome P450 isoenzyme CYP3A(See reference number 36) resulting in a marked increase in ciclosporin clearance. In addition, rifampicin decreases ciclosporin absorption by inducing its metabolism by gut wall,(See reference number 37) thus producing a significant fall in ciclosporin levels. If rifampicin is given with erythromycin or clarithromycin, enzyme inhibitory effects of macrolides are swamped by more potent enzyme-inducing effects of rifampicin. Rifabutin has some enzyme-inducing properties but extent is quite small compared with rifampicin, and onset may be delayed (See reference number 38).

The interaction between ciclosporin and rifampicin is very well documented, well established and clinically important, as transplant rejection may occur unless ciclosporin dosage is markedly increased. In one study 27 % of patients taking rifampicin lost grafts due to rejection, and this was directly attributed to interaction (See reference number 22). The interaction develops within a few days (within a single day in one case(See reference number 20)). Monitor effects of concurrent use and increase ciclosporin dosage appropriately. Three- to fivefold dosage increases (sometimes frequency-increases from two to three times daily) have proved to be effective,with daily monitoring. Remember also to reduce ciclosporin dosage when rifampicin is stopped to reduce risk of ciclosporin toxicity.

They found that use of three antitubercular drugs (not including rifampicin) for at least 9 months reduced mortality. Other reports similarly found that regimens without rifampicin were suitable for treatment of tuberculosis in transplant patients (See reference number 23,34,35)

Another suggested alternative is to replace ciclosporin with another non-interacting immunosuppressant, such as azathioprine and low-dose prednisolone for immunosuppression, if rifampicin is needed (See reference number 13).

Other rifamycins may also be an option; limited evidence suggests that rifabutin interacts minimally. However, manufacturer(See reference number 39) and CSM in UK(See reference number 40)caution about possibility of an interaction, and close monitoring of ciclosporin levels would still be advisable. Topical rifamycin interacted like rifampicin in one patient when it was applied to a wound (See reference number 32).

Vandevelde C,Chang A, Andrews D, Riggs W, Jewesson P. Rifampin and ansamycin interactions with cyclosporine after renal transplantation. Pharmacotherapy (1991) 11, 88–9.

El-Agroudy AE,Refaie AF, Moussa OM, Ghoneim MA. Tuberculosis in Egyptian kidneytransplant recipients: study of clinical course and outcome. J Nephrol (2003) 16, 404–11.

Modry DL,Stinson EB, Oyer PE, Jamieson SW, Baldwin JC, Shumway NE. Acute rejectionand massive cyclosporine requirements in heart transplant recipients treated with rifampin.Transplantation (1985) 39, 313–14.

Langhoff E,Madsen S. Rapid metabolism of cyclosporin and prednisone in kidney transplantpatients on tuberculostatic treatment. Lancet (1983) ii, 1303.

Cassidy MJD,Van Zyl-Smit R, Pascoe MD, Swanepoel CR, Jacobson JE. Effect of rifampicin on cyclosporin A blood levels in a renal transplant recipient. Nephron (1985) 41, 207–8.

Coward RA,Raferty AT, Brown CB. Cyclosporin and antituberculous therapy. Lancet (1985) i, 1342–3.

Howard P,Bixler TJ, Gill B. Cyclosporine-rifampin drug interaction. Drug Intell Clin Pharm (1985) 19, 763–4.

Van Buren D,Wideman CA, Ried M, Gibbons S, Van Buren CT, Jarowenko M, Flechner SM, Frazier OH, Cooley DA, Kahan BD. The antagonistic effect of rifampin upon cyclosporine bioavailability. Transplant Proc (1984) 16, 1642–5.

Allen RDM,Hunnisett AG, Morris PJ. Cyclosporin and rifampicin in renal transplantation.Lancet (1985) i, 980.

Langhoff E,Madsen S. Rapid metabolism of cyclosporin and prednisone in kidney transplantpatient receiving tuberculostatic treatment. Lancet (1983) ii, 1031.

Offermann G,Keller F, Molzahn M. Low cyclosporin A blood levels and acute graft rejectionin a renal transplant recipient during rifampin treatment. Am J Nephrol (1985) 5, 385–7.

Jurewicz WA,Gunson BK, Ismail T, Angrisani L, McMaster P. Cyclosporin and antituberculous therapy. Lancet (1985) i, 1343.

Daniels NJ,Dover JS, Schachter RK. Interaction between cyclosporin and rifampicin. Lancet (1984) ii, 639.

Leimenstoll G,Schlegelberger T, Fulde R, Niedermayer W. Interaktion von Ciclosporin undEthambutol-Isoniazid. Dtsch Med Wochenschr (1988) 113, 514–15.

Prado A,Ramirez M, Aguirre EC, Martin RS, Zucchini A. Interaccion entre ciclosporina yrifampicina en un caso de transplante renal. Medicina (B Aires) (1987) 47, 521–4.

Al-Sulaiman MH,Dhar JM, Al-Khader AA. Successful use of rifampicin in the treatment oftuberculosis in renal transplant patients immunosuppressed with cyclosporine. Transplantation (1990) 50, 597–8.

Sánchez DM,Rincón LC, Asensio JM, Serna AB. Interacción entre ciclosporina y rifampicina. Rev Clin Esp (1988) 183, 217.

Peschke B,Ernst W, Gossmann J, Kachel HG, Schoeppe W, Scheuermann EH. Antituberculous drugs in kidney transplant recipients treated with cyclosporine. Transplantation (1993)56, 236–8.

Zylber-Katz E. Multiple drug interactions with cyclosporine in a heart transplant patient. Ann Pharmacother (1995) 29,127–31. Correction. ibid. 790.

Wandel C,Böhrer H, Böcker R. Rifampicin and cyclosporine dosing in heart transplant patients. J Cardiothorac Vasc Anesth (1995) 9, 621–2.

Capone D,Aiello C, Santoro GA, Gentile A, Stanziale P, D’Alessandro R, Imperatore P, Basile V. Drug interaction between cyclosporine and two antimicrobial agents, josamycin andrifampicin, in organ-transplanted patients. Int J Clin Pharmacol Res (1996) 16, 73–6.

Aguado JM,Herrero JA, Gavaldá J, Torre-Cisneros J, Blanes M, Rufí G, Moreno A, GurguíA, Hayek M, Lumbreras C and the Spanish Transplantation Infection Study Group, GESITRA. Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplantrecipients in Spain. Transplantation (1997) 63, 1276–86.

Muñoz P,Palomo J, Muños R, Rodríguez-Creixéms M, Pelaez T, Bouza E. Tuberculosis inheart transplant recipients. Clin Infect Dis (1995) 21, 398–402.

Freitag VL,Skifton RD, Lake KD. Effect of short-term rifampin on stable cyclosporine concentration. Ann Pharmacother (1999) 33, 871–2.

Almeida RV,Carvalho JGR, Mulinari A, Hauck P. Tuberculosis in renal transplant recipients. J Am Soc Nephrol (1997) 8, 709A.

Kim YH,Yoon YR, Kim YW, Shin JG, Cha IJ. Effects of rifampin on cyclosporine disposition in kidney recipients with tuberculosis. Transplant Proc (1998) 30, 3570–2.

Zelunka EJ. Intravenous cyclosporine-rifampin interaction in a pediatric bone marrow transplant recipient. Pharmacotherapy (2002) 22,387–90.

Koselj M,Bren A, Kandus A, Kovac D. Drug interactions between cyclosporine and rifampicin, erythromycin, and azoles in kidney recipients with opportunistic infections. Transplant Proc (1994) 26, 2823–4.

Hooper TL,Gould FK, Swinburne CR, Featherstone G, Odom NJ, Corris PA, Freeman R,McGregor CGA. Ciprofloxacin: a preferred treatment for legionella infections in patients receiving cyclosporin A. J Antimicrob Chemother (1988) 22, 952–3.

Soto J,Sacristan JA, Alsar MJ. Effect of the simultaneous administration of rifampicin anderythromycin on the metabolism of cyclosporine. Clin Transplant (1992) 6, 312–14.

Plemmons RM,McAllister CK, Garces MC, Ward RL. Osteomyelitis due to Mycobacterium haemophilum in a cardiac transplant patient: case report and analysis of interactions amongclarithromycin, rifampin and cyclosporine. Clin Infect Dis (1997) 24, 995–7.

Renoult E,Hubert J, Trechot Ph, Hestin D, Kessler M, L’Hermite J. Effect of topical rifamycin SV treatment on cyclosporin A blood levels in a renal transplant patient. Eur J Clin Pharmacol (1991) 40, 433–4.

Diaz Couselo FA,Porato F, Turin M, Etchegoyen FP, Diez RA. Interacciones de la ciclosporina en transplantados renales. Medicina (B Aires) (1992) 52, 296–302.

Jastrzębski D,Zaklicyński M, Kozielski J, Siola M, Dworniczak S, Wojdyla A, Zembala M.Possibility to treat lung tuberculosis without using rifampicin in heart transplant recipients-two case reports. Ann Transplant (2003) 8, 42–4.

Vachharajani TJ,Oza UG, Phadke AG, Kirpalani AL. Tuberculosis in renal transplant recipients: rifampicin sparing treatment protocol. Int Urol Nephrol (2002) 34, 551–3.

Pichard L,Fabre JM, Domergue J, Fabre G, Saint-Aubert B, Mourad G, Maurel P. Molecularmechanism of cyclosporine A drug interactions: inducers and inhibitors of cytochrome P450screening in primary cultures of human hepatocytes. Transplant Proc (1991) 23, 978–9.

Hebert MF,Roberts JP, Prueksaritanont T, Benet LZ. Bioavailability of cyclosporine withconcomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin Pharmacol Ther (1992) 52, 453–7.

Perucca E,Grimaldi R, Frigo GM, Sardi A, Möning H, Ohnhaus EE. Comparative effects ofrifabutin and rifampicin on hepatic microsomal enzyme activity in normal subjects. Eur J Clin Pharmacol (1988) 34, 595–9.

Mycobutin (Rifabutin). Pharmacia Ltd. UK Summary of product characteristics,October2006.

Committee on the Safety of Medicines/Medicines Control Agency. Revised indication anddrug interactions of rifabutin. Current Problems (1997) 23,14.

Bosentan modestly decreases ciclosporin levels,and ciclosporinincreases bosentan levels. The manufacturer of bosentan contraindicates combination, because of possible increasedrisk of liver toxicity.

Clinical evidence,mechanism, importance and management

In a study designed to assess effects of bosentan on ciclosporin renal toxicity, 7 healthy subjects were given bosentan 500mg and ciclosporin 300 mg, both twice daily, for 7 days. Bosentan did maintain renal plasma flow,which is markedly decreased by ciclosporin. However, bosentan was calculated to have reduced AUC of ciclosporin by about 50%. In addition, bosentan had no effect on ciclosporin-induced rise in blood pressure, and headache, nausea, and vomiting were a problem with combination. Moreover, steady-state AUC of bosentan was raised 1.7-fold when compared with AUC of a single dose of bosentan (See reference number 1). It should be noted that bosentan induces its own metabolism,and after 7 days, plasma levels are about 50 to 65 % of those seen after a single dose (See reference number 2). Therefore, effect of ciclosporin on bosentan AUC may be twice those described in this study (i.e. up to a fourfold increase in AUC of bosentan). The manufacturers of bosentan say that when bosentan is given with ciclosporin its plasma levels were markedly raised (30-fold after a single dose and three- to fourfold at steady state). They also list ciclosporin as an example of a drug, like bosentan, that inhibits bile salt export pump, and is therefore expected to increase risk of liver toxicity when used with bosentan. They therefore contraindicate combination (See reference number 2). Further study is needed, as some consider combination to have clinical potential.

The combination of tacrolimus or sirolimus with bosentan has not been studied but based on information available for ciclosporin, manufacturers of bosentan advise against concurrent use, but if it is required, close monitoring is recommended (See reference number 2).

Binet I,Wallnöfer A, Weber C, Jones R, Thiel G. Renal hemodynamics and pharmacokineticsof bosentan with and without cyclosporine A. Kidney Int (2000) 57, 224–31.

Tracleer (Bosentan monohydrate). Actelion Pharmaceuticals UK. UK Summary of productcharacteristics,October 2006.

Ciclosporin serum levels are normally unchanged by use ofciprofloxacin, but increased serum levels and nephrotoxicity mayoccur in a small number of patients. There is also some evidencethat immunosuppressant effects of ciclosporin are reduced byciprofloxacin. One study,and two case reports describe rises inciclosporin levels in patients given norfloxacin, but another studyfound no change. Similar results have been found with levofloxacin. No significant interaction appears to occur betweenciclosporin and enoxacin,ofloxacin, pefloxacin and trovafloxacin.

A single-dose study in 10 healthy subjects found that after taking ciprofloxacin 500mg twice daily for 7 days pharmacokinetics of oral ciclosporin 5 mg/kg were unchanged (See reference number 1). Five other studies confirm lack of a pharmacokinetic interaction in:

There were no changes in serum ciclosporin levels or evidence of nephrotoxicity. In contrast,a handful of cases of nephrotoxicity have been reported, with

three cases of increased ciclosporin levels (See reference number 7,8). A heart transplant patient developed acute renal failure within 4 days of being given ciprofloxacin 750mg every 8 hrs (See reference number 9). Another patient who had undergone a kidney transplant developed reversible nephrotoxicity (See reference number 10). Decreased renal function in a heart-lung transplant patient has been described in another report (See reference number 7). This patient and another also had increased ciclosporin blood levels when given ciprofloxacin 500mg three times daily (See reference number 7). Acute interstitial nephritis in a cardiac transplant patient has also been reported (See reference number 11-13). A patient taking ciclosporin for red cell aplasia had an increase in ciclosporin levels from 120 nanograms/mL to 297 nanograms/mL,requiring a dose reduction from 250mg to 200mg daily, when intravenous ciprofloxacin 200mg two or three times daily [exact dose unclear] was started. A ciclosporin dose increase back to 250mg daily was required when ciprofloxacin course was finished (See reference number 8).

A case-control study in 42 kidney transplant patients suggested that proportion of cases experiencing at least one episode of biopsy-proved rejection within 1 to 3 months of receiving a transplant were significantly greater in those who had taken ciprofloxacin (45%) than in those who had not (19%). There was also a marked increase in incidence of rejection associated with ciprofloxacin use (29%) compared with controls (2%) (See reference number 14)

A single-dose study in 12 healthy subjects found that levofloxacin 500mg had no effect on pharmacokinetics of ciclosporin oral solution (Sandimmune) (See reference number 16). A case report in a patient taking oral ciclosporin 250mg daily (as emulsion formulation) found no change in ciclosporin levels when he was given intravenous levofloxacin 500mg daily for 9 days (See reference number 8)

In contrast, in a study in 5 kidney transplant patients taking ciclosporin (microemulsion formulation) maximum ciclosporin blood concentration was increased by 23 % when levofloxacin 500mg twice daily for 5 days was taken for a urinary-tract infection. The authors concluded that this interaction may be clinically significant, and warned about extrapolating results from single-dose studies in healthy subjects (as above) to patients with transplants (See reference number 17).

Six renal transplant patients given norfloxacin 400mg twice daily for 3 to 23 days for urinary tract infections,(See reference number 18) and 4 heart transplant patients given norfloxacin 400mg for 7 to 140 days had no changes in their serum ciclosporin levels (See reference number 5). However,two reports describe rises, one marked, in serum ciclosporin levels in a heart transplant patient and a kidney transplant patient given norfloxacin (See reference number 19). A comparative study in 5 children (mean age,8 years) found that while receiving norfloxacin 5 to 10 mg/kg daily their daily dose of ciclosporin was 4.5 mg/kg daily compared with a control group of 6 children not taking norfloxacin who needed 7.4 mg/kg daily (See reference number 20).

A study in kidney transplant patients taking corticosteroids, azathioprine and ciclosporin found that pharmacokinetics of ciclosporin were not significantly changed by pefloxacin 400mg twice daily for 4 days (See reference number 22).

A placebo-controlled crossover study in 7 stable kidney transplant patients treated with ciclosporin (Sandimmune) found that pharmacokinetics of ciclosporin were not significantly altered by trovafloxacin 200mg daily for 7 days (See reference number 23)

The interaction between ciclosporin and norfloxacin probably occurs because norfloxacin inhibits cytochrome P450 isoenzyme CYP3A4, resulting in a reduction in ciclosporin metabolism (See reference number 20). The interaction between ciclosporin and ciprofloxacin may possibly be due to some antagonism by ciprofloxacin of ciclosporin-dependent inhibition of interleukin-2, which thereby opposes its immunosuppressant action (See reference number 14).

Information seems to be limited to these reports. They indicate that in children and adults dosage of ciclosporin will probably need to be reduced in presence of norfloxacin. Information with levofloxacin is currently limited,but a modest increase in ciclosporin levels may occur, and increased monitoring seems advisable.

There is also some evidence that immunosuppressant effects of ciclosporin may be reduced (See reference number 14)

There seem to be no reports of problems with enoxacin,ofloxacin, pefloxacin or trovafloxacin.

Tan KKC,Trull AK, Shawket S. Co-administration of ciprofloxacin and cyclosporin: lack ofevidence for a pharmacokinetic interaction. Br J Clin Pharmacol (1989) 28, 185–7.

Lang J,Finaz de Villaine J, Garraffo R, Touraine J-L. Cyclosporine (cyclosporin A) pharmacokinetics in renal transplant patients receiving ciprofloxacin. Am J Med (1989) 87 (Suppl 5A), 82S–85S.

Van Buren DH,Koestner J, Adedoyin A, McCune T, MacDonell R, Johnson HK, Carroll J,Nylander W, Richie RE. Effect of ciprofloxacin on cyclosporine pharmacokinetics. Transplantation (1990) 50, 888–9.

Krüger HU,Schuler U, Proksch B, Göbel M, Ehninger G. Investigation of potential interaction of ciprofloxacin with cyclosporine in bone marrow transplant recipients. Antimicrob Agents Chemother (1990) 34, 1048–52.

Robinson JA,Venezio FR, Costanzo-Nordin MR, Pifarre R, O’Keefe PJ. Patients receivingquinolones and cyclosporine after heart transplantation. J Heart Transplant (1990) 9, 30–1.

Hooper TL,Gould FK, Swinburn CR, Featherstone G, Odom NJ, Corris PA, Freeman R, Mc-Gregor CGA. Ciprofloxacin: a preferred treatment for legionella infections in patients receiving cyclosporin A. J Antimicrob Chemother (1988) 22, 952–3.

Nasir M,Rotellar C, Hand M, Kulczycki L, Alijani MR, Winchester JF. Interaction betweenciclosporin and ciprofloxacin. Nephron (1991) 57, 245–6.

Borrás-Blasco J,Conesa-García V, Navarro-Ruiz A, Marín-Jiménez F, González-DelgadoM, Gomez-Corrons A. Ciprofloxacin, but not levofloxacin, affects cyclosporine blood levelsin a patient with pure red blood cell aplasia. Am J Med Sci (2005) 330, 144–6.

Avent CK,Krinsky JK, Kirklin JK, Bourge RC, Figg WD. Synergistic nephrotoxicity due tociprofloxacin and cyclosporine. Am J Med (1988) 85, 452–3.

Elston RA,Taylor J. Possible interaction of ciprofloxacin with cyclosporin A. J Antimicrob Chemother (1988) 21, 679–80.

Rosado LJ,Siskind MS, Copeland JG. Acute interstitial nephritis in a cardiac transplant patient receiving ciprofloxacin. J Thorac Cardiovasc Surg (1994) 107, 1364.

Bourge RC. Invited letter concerning: acute interstitial nephritis in a cardiac transplant recipients receiving ciprofloxacin. J Thorac Cardiovasc Surg (1994) 107,1364–5.

Rosado LJ,Siskind MS, Nolan PE, Copeland JG. Invited letter concerning: acute interstitialnephritis in a cardiac transplant recipients receiving ciprofloxacin. J Thorac Cardiovasc Surg (1994) 107, 1365–6.

Wrishko RE,Levine M, Primmett DRN, Kim S, Partovi N, Lewis S, Landsberg D, KeownPA. Investigation of a possible interaction between ciprofloxacin and cyclosporine in renaltransplant patients. Transplantation (1997) 64, 996–999.

Ryerson BA,Toothaker RD, Posvar EL, Sedman AJ, Koup JR. Effect of enoxacin on cyclosporine pharmacokinetics in healthy subjects. Intersci Conf Antimicrob Agents Chemother (1991) 31, 198.

Doose DR,Walker SA, Chien SC, Williams RR, Nayak RK. Levofloxacin does not alter cyclosporine disposition. J Clin Pharmacol (1998) 38, 90–3.

Federico S,Carrano R, Capone D, Gentile A, Palmiero G, Basile V. Pharmacokinetic interaction between levofloxacin and ciclosporin or tacrolimus in kidney transplant recipients.Clin Pharmacokinet (2006) 45, 169–75.

Jadoul M,Pirson Y, van Ypersele de Strihou C. Norfloxacin and cyclosporine-a safe combination. Transplantation (1989) 47, 747–8.

Thomson DJ,Menkis AH, McKenzie FN. Norfloxacin-cyclosporine interaction. Transplantation (1988) 46, 312–13.

McLellan RA,Drobitch RK, McLellan DH, Acott PD, Crocker JFS, Renton KW. Norfloxacin interferes with cyclosporine disposition in pediatric patients undergoing renal transplantation. Clin Pharmacol Ther (1995) 58, 322–7.

Vogt P,Schorn T, Frei U. Ofloxacin in the treatment of urinary tract infection in renal transplant recipients. Infection (1988) 16, 175–8.

Lang J,Finaz de Villaine J, Guemei A, Touraine JL, Faucon C. Absence of pharmacokineticinteraction between pefloxacin and cyclosporin A in patients with renal transplants. Rev Infect Dis (1989) 11 (Suppl 5), S1094.

Johnson HJ,Swan SK, Heim-Duthoy KL, Pelletier SM, Teng R, Vincent J. The effect of trovafloxacin on steady-state pharmacokinetics of cyclosporine (CSA) in stable renal transplantpatients. Pharm Res (1997) 14 (11 Suppl), S-509.

Two kidney transplant patients on ciclosporin developed acute renal failure 10 to 42 days after starting to take enalapril 5 to 10mg twice daily. Recovery was complete when enalapril was stopped in one of patients, and when both enalapril and ciclosporin were stopped in other. The latter patient had no problems when ciclosporin was restarted. Both recovered renal function after 10 to 30 days. Neither had any previous evidence of renal artery stenosis or chronic rejection,which are conditions known to predispose to renal failure during ACE inhibitor treatment. Two other patients appeared to tolerate concurrent use well (See reference number 1). Two further kidney transplant patients developed acute renal failure when given enalapril. Neither had renal arterial stenosis or acute rejection (See reference number 2). The manufacturer briefly mentions that transient oliguria was seen in a kidney transplant patient given ciclosporin and captopril (See reference number 3).

0.2 mmol/L). Potassium levels were not increased above 5.5 mmol/L in any of patients studied. Uric acid levels were also increased by enalapril but decreased by losartan,although this was not statistically significant. No changes in ciclosporin trough levels were seen during study and serum creatinine remained stable (See reference number 4). Another study in kidney transplant patients taking ciclosporin with either enalapril (33 patients) or enalapril plus amlodipine (32 patients) found that potassium and serum creatinine levels did not increase in enalapril/amlodipine group whereas they increased by 0.2 mmol/L and 9 micromol/L, respectively, in group who received enalapril alone. Ciclosporin levels remained stable in all patients (See reference number 5).

A study in kidney transplant patients taking ciclosporin with losartan found that serum creatinine was only slightly and non-significantly increased in 5 patients

5 mmol/L) developed in 4 patients but potassium had fallen to below

5.5 mmol/L by week 12 in all patients. Ciclosporin levels were remained stable during study and no significant dose changes were made, although one patient was withdrawn from study due to ciclosporin toxicity which authors state was not related to use of losartan (See reference number 6). Another study in 14 kidney transplant patients taking ciclosporin with losartan 50 to 100mg daily for 8 weeks found serum creatinine,potassium and ciclosporin levels were unaffected (See reference number 7). Another study in 41 kidney transplant patients with proteinuria taking ciclosporin found that addition of candesartan 4 to 12mg daily had no significant effects on creatinine clearance or ciclosporin levels (See reference number 8).

Not understood. One suggestion is that ciclosporin reduces renal blood flow and reduces perfusion through glomerulus, which is worsened when angiotensin II is inhibited by ACE inhibitor (See reference number 1). One study suggested that larger increase in potassium levels may be related to changes in aldosterone levels seen with enalapril (See reference number 4).

There have been few specific case reports of renal failure and hyperkalaemia with ciclosporin and ACE inhibitors or angiotensin II receptor antagonists. Data from efficacy studies above suggest that incidence of renal failure and hyperkalaemia is low, nevertheless care and good monitoring are needed if ACE inhibitors or angiotensin II receptor antagonists and ciclosporin are used concurrently. Also note that manufacturers of ciclosporin warn about possible risk of hyperkalaemia with ACE inhibitors and angiotensin II receptor antagonists with ciclosporin as these drugs may raise potassium levels (See reference number 9). Monitor potassium levels more closely in initial weeks of concurrent use, bearing in mind that an increase in potassium levels may be due to worsening renal function as well as these drugs.

Murray BM,Venuto RC, Kohli R, Cunningham EE. Enalapril-associated renal failure in renaltransplants: possible role of cyclosporine. Am J Kidney Dis (1990) 16, 66–9.

Garcia TM,da Costa JA, Costa RS, Ferraz AS. Acute tubular renal necrosis in kidney transplant patients treated with enalapril. Ren Fail (1994) 16, 419–23.

Cockburn I. Cyclosporine A: a clinical evaluation of drug interactions. Transplant Proc (1986)18 (Suppl 5),50–5.

Schmidt A,Gruber U, Böhmig G, Köller E, Mayer G. The effect of ACE inhibitor and angiotensin II receptor antagonist therapy on serum uric acid levels and potassium homeostasis inhypertensive renal transplant recipients treated with CsA. Nephrol Dial Transplant (2001) 16, 1034–7.

Halimi JM,Giraudeau B, Buchler M, Al-Najjar A, Etienne I, Laouad I, Bruyere F, Lebranchu

Y. Enalapril/amlodipine combination in cyclosporine-treated renal transplant recipients: a prospective randomized trial. Clin Transplant (2007) 21,277–84.

6. del Castillo D,Campistol JM, Guirado L, Capdevilla L, Martínez JG, Pereira P, Bravo J, Pérez

R. Efficacy and safety of losartan in the treatment of hypertension in renal transplant patients.Kidney Int (1998) 54,(Suppl 68) S135–S139.

Tylicki L,Biedunkiewicz B, Chamienia A, Wojnarowski K, Zdrojewski Z, Rutkowski B. Randomized placebo-controlled study on the effects of losartan and carvedilol on albuminuria inrenal transplant recipients. Transplantation (2006) 81, 52–6.

Omoto K,Tanabe K, Tokumoto T, Shimmura H, Ishida H, Toma H. Use of candesartan cilexetil decreases proteinuria in renal transplant patients with chronic allograft dysfunction. Transplantation (2003) 76, 1170–4.

Neoral (Ciclosporin). Novartis Pharmaceuticals UK Ltd. UK Summary of product characteristics,December 2004.

Modafinil slightly reduces levels of ethinylestradiol given aspart of a combined oral contraceptive

Clinical evidence,mechanism, importance and management

In 16 healthy women taking a combined oral contraceptive (ethinylestradiol/norgestimate), modafinil 200mg daily for 7 days followed by 400mg daily for 21 days decreased AUC and maximum plasma levels of ethinylestradiol by 18 % and 11%, respectively. Increases in plasma FSH and LH were not significant (See reference number 1). Modafinil is an inducer of cytochrome P450 isoenzyme CYP3A4, which is partially responsible for metabolism of ethinylestradiol. These small changes are lower than those seen with other enzyme inducers known to reduce reliability of combined oral contraceptives (e.g. see phenytoin’,). However,it cannot be ruled out that they would be sufficient to cause failure of combined oral contraceptives in very rare cases. The UK manufacturer recommends that additional or alternative methods of contraception should be used during and for up to 2 cycles after stopping modafinil (See reference number 2). The US manufacturer gives similar guidance but advises that additional or alternative contraceptive methods need only be continued for one month after stopping modafinil (See reference number 3). Note that this advice applies to other forms of hormonal contraception including implants and patches (See reference number 3,4). The Faculty of Family Planning and Reproductive Health Care (FFPRHC) Clinical Effectiveness Unit has issued guidance on use of liver enzyme inducers with hormonal contraceptives,(See reference number 4)see ‘Hormonal contraceptives + Antiepileptics; Barbiturates or Phenytoin, for further information.

1. Robertson P,Hellriegel ET, Arora S, Nelson M. Effect of modafinil on the pharmacokineticsof ethinyl estradiol and triazolam in healthy volunteers. Clin Pharmacol Ther (2002) 71, 46–

56.

Provigil (Modafinil). Cephalon Ltd. UK Summary of product characteristics,July 2007.

Provigil (Modafinil). Cephalon,Inc. US Prescribing information, December 2004.

Faculty of Family Planning and Reproductive Health Care Clinical Effectiveness Unit.FFPRHC Guidance: Drug interactions with hormonal contraception. April 2005. Available at:http://www.ffprhc.org.uk/admin/uploads/DrugInteractionsFinal.pdf (accessed 23/08/07).