Mycophenolate + Polycarbophil calcium - Drug Interactions

Polycarbophil calcium reduces bioavailability of mycophenolate

Clinical evidence,mechanism, importance and management

A study in 5 healthy subjects given a single 1-g dose of mycophenolate alone or with polycarbophil calcium 2.4 g found that AUC and peak serum levels of mycophenolic acid were reduced by about 51 % and 69%, respectively. The authors suggest that this interaction was probably result of reduced absorption due to chelate-complex formation between mycophenolate and calcium ions, which they demonstrated in an in vitro study. It was concluded that mycophenolate and polycarbophil calcium should not be taken at same time (See reference number 1). A suitable interval was not specified,but a separation of 2 hrs has been suggested with antacids, , which interact by a similar mechanism. Further study is needed.

1. Kato R,Ooi K, Ikura-Morii M, Tsuchishita Y, Hashimoto H, Yoshimura H, Uenishi K, Kawai M, Tanaka K, Ueno K. Impairment of mycophenolate mofetil absorption by calcium polycarbophil. J Clin Pharmacol (2002) 42, 1275–80.

Mycophenolate + Methotrexate - Drug Interactions

A study in patients with rheumatoid arthritis found that combination of methotrexate and mycophenolate mofetil was well tolerated and there were no pharmacokinetic interactions

1. Yocum D,Kremer J, Blackburn W, Caldwell J, Furst D, Nunez M, Zuzga J, Zeig S, GutierrezM, Merrill J, Dumont E, B Leishman. Cellcept:4.4pt; font-weight:normal; color:#000000″>(See reference number ®) (mycophenolate mofetil – MMF) and methotrexate (MTX) safety and pharmacokinetic (PK) interaction study in rheumatoid arthritis patients. Arthritis Rheum (1999) 42 (9 Suppl), S83.

Corticosteroids + H2-receptor antagonists - Drug Interactions

Cimetidine does not interact with prednisolone,prednisone ordexamethasone, and ranitidine does not interact with prednisone.

Clinical evidence,mechanism, importance and management

Prednisone is a pro-drug, which must be converted to prednisolone within body to become active. A double-blind crossover study in 9 healthy subjects found that cimetidine 300mg every 6 hrs or ranitidine 150mg twice daily for 4 days did not significantly alter pharmacokinetics of prednisolone after a single 40mg oral dose of prednisone (See reference number 1). Another double-blind,crossover study found that cimetidine 1 g daily only caused minor changes in plasma prednisolone levels following a 10mg dose of enteric-coated prednisolone (See reference number 2). Similarly, another study found that cimetidine 600mg twice daily for 7 days had no effect on pharmacokinetics of a single 8mg intravenous dose of dexamethasone sodium phosphate (See reference number 3).

There would therefore seem to be no reason for avoiding concurrent use. Information about other corticosteroids appears to be lacking,but no interaction is anticipated.

1. Sirgo MA,Rocci ML, Ferguson RK, Eshelman FN Vlasses PH. Effects of cimetidine and ranitidine on the conversion of prednisone to prednisolone. Clin Pharmacol Ther (1985) 37, 534–

8.

Morrison PJ,Rogers HJ, Bradbrook ID, Parsons C. Concurrent administration of cimetidineand enteric-coated prednisolone: effect on plasma levels of prednisolone. Br J Clin Pharmacol (1980) 10, 87–9.

Peden NR,Rewhorn I, Champion MC, Mussani R, Ooi TC. Cortisol and dexamethasone elimination during treatment with cimetidine. Br J Clin Pharmacol (1984) 18, 101–3.

Corticosteroids + Mifepristone - Drug Interactions

The UK manufacturers of mifepristone say that efficacy ofcorticosteroids (included inhaled corticosteroids) is expected to bereduced in 3 to 4 days following use of mifepristone, because of antiglucocorticoid activity of mifepristone.(See reference number 1) Patients taking corticosteroids should be monitored during this time, andconsideration given to increasing corticosteroid dose. However, US manufacturers contraindicate use of mifepristonein those receiving long-term corticosteroid therapy.(See reference number 2)

Mifegyne (Mifepristone). Exelgyn Laboratories. UK Summary of product characteristics,February 2006.

Mifeprex (Mifepristone). Danco Laboratories,LLC. US Prescribing information, July 2005.

Ciclosporin + Sucrose polyesters - Drug Interactions

Olestra) may reduce bioavailability and peak levels of ciclosporin

Clinical evidence,mechanism, importance and management

A study in 7 kidney transplant patients aged 9 to 18 years, found that addition of sucrose polyesters (Olestra), in a single 0.35-g/kg dose (maximum of 16 g) reduced ciclosporin AUC and peak levels by almost 19 % and 27%, respectively. Ciclosporin trough levels and elimination rate were not affected by Olestra. The reduced bioavailability was thought to be due to Olestra reducing absorption of ciclosporin. Olestra is marketed as a non-absorbable,non-calorific fat ingredient in snack foods. The authors note that Olestra is mainly consumed by children and adolescents, with age group of 13 to 17-year-olds being reported to eat 16.2 g of Olestra per snack,and therefore this interaction could be of particular significance for young transplant patients taking ciclosporin (See reference number 1). However, note that changes in AUC of ciclosporin of this size are very modest.

1. Terrill CJ,Lill J, Somerville KT, Sherbotie JR. Modifications in cyclosporine (CsA) microemulsion blood concentrations by Olestra. J Ren Nutr (2003) 13, 26–30.

Ciclosporin + Somatostatin analogues - Drug Interactions

Octreotide causes a marked reduction in blood levels of ciclosporin and inadequate immunosuppression may result

A diabetic man with kidney and pancreatic segment transplants was successfully immunosuppressed with azathioprine,methylprednisolone and ciclosporin. When he was also given subcutaneous octreotide 100 micrograms twice daily to reduce fluid collection around pancreatic graft, his trough ciclosporin blood levels fell below assay detection limit of 50 nanograms/mL. Serum creatinine increased dramatically, which was interpreted as a selective rejection episode of kidney transplant. Nine other diabetics similarly treated with octreotide for peripancreatic fluid collection and fistulas after pancreatic transplantation also had significant falls in their ciclosporin blood levels within 24 to 48 hours,in 3 of them to undetectable levels (See reference number 1). A similar interaction was seen in another patient (See reference number 2).

A suggestion is that octreotide reduces intestinal absorption of ciclosporin (See reference number 1,2)

The interaction between octreotide and ciclosporin is established and clinically important, although documentation is limited. The authors of one report recommend that before giving octreotide oral dosage of ciclosporin should be increased on average by 50 % and serum levels monitored daily (See reference number 1). The manufacturers of lanreotide say that, as with other somatostatin analogues, it may reduce absorption of ciclosporin from gut (See reference number 3). As yet there appear to be no reports of this interaction in practice; however, it would be prudent to monitor outcome of use of lanreotide with ciclosporin.

1. Landgraf R,Landgraf-Leurs MMC, Nusser J, Hillebrand G, Illner W-D, Abendroth D, Land

W. Effect of somatostatin analogue (SMS 201–995) on cyclosporine levels. Transplantation (1987) 44,724–5.

Rosenberg L,Dafoe DC, Schwartz R, Campbell DA, Turcotte JG, Tsai S-T, Vinik A. Administration of somatostatin analog (SMS 201–995) in the treatment of a fistula occurring afterpancreas transplantation. Interference with cyclosporine suppression. Transplantation (1987) 43, 764–6.

Somatuline LA (Lanreotide acetate). Ipsen Ltd. UK Summary of product characteristics,August 2003.

Ciclosporin + Protease inhibitors - Drug Interactions

Protease inhibitors significantly increase levels of ciclosporin.Ciclosporin may increase time to maximum nelfinavir levels

A HIV-positive patient taking ciclosporin 250 to 350mg twice daily (to maintain a therapeutic ciclosporin trough level of 300 to 400 nanograms/mL) was restarted on his usual HAART regimen of tenofovir,lamivudine and fosamprenavir 1.4 g twice daily on day 12 post-liver transplantation. Within 2 days, ciclosporin level had increased to 600 nanograms/mL, requiring a ciclosporin dose reduction to 100mg twice daily (See reference number 1).

A pilot study in 7 HIV-positive subjects taking nelfinavir 1.25 g twice daily found that a single 4-mg/kg oral dose of ciclosporin increased time to maximum serum level for nelfinavir from 2.6 to 3.2 hours. The AUC of nelfinavir was also increased but this was not significant. In same study, a single 2-mg/kg intravenous dose of ciclosporin given over

5 hrs had little effect on pharmacokinetics of oral nelfinavir. Nelfinavir did not significantly affect pharmacokinetics of either oral or intravenous ciclosporin (See reference number 2)

Three HIV-positive patients who had undergone liver transplantation required reductions in their ciclosporin doses when they started taking ritonavir-boosted HAART. One patient taking ciclosporin 150mg twice daily had an increase in his ciclosporin levels to 900 nanograms/mL when ritonavir-boosted HAART was started,and needed a dose reduction of 95 % to maintain a usual ciclosporin trough level of 75 to 150 nanograms/mL. A second patient also required a similar reduction. The third patient needed a dose reduction of 80 % when taking ritonavir-boosted lopinavir,but no further ciclosporin dose alteration was needed when his treatment was changed to ritonavir-boosted indinavir (See reference number 3).

An HIV-positive patient taking lamivudine and zidovudine,and ciclosporin for a kidney transplant, started taking saquinavir 1.2 g three times daily. Within 2 days he started to complain of fatigue,headache and gastrointestinal discomfort. On investigation his ciclosporin level was found to have risen from a range of 150 to 200 nanograms/mL up to 580 nanograms/mL,and his saquinavir AUC was increased 4.3-fold (by comparison with subjects not taking ciclosporin). His ciclosporin dose was reduced from 150mg twice daily to 75mg twice daily,and his saquinavir dose was reduced to 600mg three times daily, which resulted in ciclosporin levels similar to those achieved previously (See reference number 4).

All protease inhibitors can inhibit cytochrome P450 isoenzyme CYP3A4 to varying degrees, see Antivirals, . Ciclosporin is extensively metabolised by CYP3A4,so any inhibition of this isoenzyme is likely to increase ciclosporin levels. Ciclosporin and protease inhibitors are substrates for P-glycoprotein, which may explain raised nelfinavir and saquinavir levels.

The increase in ciclosporin levels seen with ritonavir may occur irrespective of whether it is used as an antiretroviral in its own right or as a pharmacokinetic enhancer with other antiretrovirals(See reference number 5) (usually in a lower dose of 100mg twice daily). The inhibition of ciclosporin metabolism by other protease inhibitors,either alone or in combination with ritonavir, may lead to significant increases in ciclosporin levels. Therefore, ciclosporin levels should be carefully monitored and dose adjusted accordingly during concurrent use, bearing in mind that large dose reductions may be required in some patients, as seen with ritonavir. It is also important to reduce or alter ciclosporin dose should protease inhibitor be stopped or changed to avoid ciclosporin toxicity. The clinical significance of effects of ciclosporin on nelfinavir pharmacokinetics are unclear, and further study is needed.

Guaraldi G,Cocchi S, Codeluppi M, Di Benedetto F, Bonora S, Motta A, Luzi K, Pecorari M,Gennari W, Masetti M, Gerunda GE, Esposito R. Pharmacokinetic interaction between amprenavir/ritonavir and fosamprenavir on cyclosporine in two patients with human immunodeficiency virus infection undergoing orthotopic liver transplantation. Transplant Proc (2006) 38, 1138–40.

Frassetto L,Tahi T, Aggarwal AM, Bucher P, Jacobsen W, Christians U, Benet LZ, Floren LC.Pharmacokinetic interactions between cyclosporine and protease inhibitors in HIV+ subjects.Drug Metab Pharmacokinet (2003) 18, 114–20.

Vogel M,Voight E, Michaelis H-C, Sudhop T, Wolff M, Türler A, Sauerbruch T, RockstrohJK, Spengler U. Management of drug-to-drug interactions between cyclosporine A and the protease-inhibitor lopinavir/ritonavir in liver-transplanted HIV-infected patients. Liver Transpl (2004) 10, 939–44.

Brinkman K,Huysmans F, Burger DM. Pharmacokinetic interaction between saquinavir andcyclosporine. Ann Intern Med (1998) 129, 914–15.

Norvir (Ritonavir). Abbott Laboratories Ltd. UK Summary of product characteristics,May2007.

Ciclosporin + Muromonab-CD3 - Drug Interactions

Clinical evidence,mechanism, importance and management

When muromonab-CD3 5mg daily for 10 days was given to 10 kidney transplant patients to treat acute rejection, their mean trough ciclosporin levels on day 8 were higher than before muromonab-CD3 was started, despite a 50 % reduction in ciclosporin dosage. When muromonabCD3 was withdrawn, ciclosporin dosage needed to be increased again (See reference number 1). The reasons are not understood. It is clearly necessary to titrate dosage of ciclosporin downwards if muromonab-CD3 is given to prevent an excessive rise in ciclosporin levels with attendant risks of renal toxicity.

1. Vrahnos D,Sanchez J, Vasquez EM, Pollak R, Maddux MS. Cyclosporine levels during OKT3treatment of acute renal allograft rejection. Pharmacotherapy (1991) 11, 278.

Ciclosporin + Disopyramide - Drug Interactions

An isolated report describes development of nephrotoxicity,which was attributed to an interaction between ciclosporin anddisopyramide

Clinical evidence,mechanism, importance and management

Ten months after receiving a kidney transplant a 40-year-old woman developed premature ventricular beats and was therefore given oxprenolol in addition to her usual ciclosporin and methylprednisolone. After 2 months she had shown no improvement so she started taking disopyramide 100mg three times daily. Over next week her serum creatinine rose from 88 to 159 micromol/L, at which point disopyramide was stopped. Her renal function returned to normal over next week. As she had previously been stable taking ciclosporin,and, as nephrotoxicity had not been reported with disopyramide, an interaction was suspected (See reference number 1).

This interaction is unconfirmed and of uncertain clinical significance. There is insufficient evidence to recommend increased monitoring, but be aware of potential for an interaction in case of an unexpected response to treatment.

1. Nanni G,Magalini SC, Serino F, Castagneto M. Effect of disopyramide in a cyclosporine-treated patient. Transplantation (1988) 45, 257.

Ciclosporin + Clodronate - Drug Interactions

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.