Statins Ciclosporin

Most drug interactions associated with rhabdomyolysis occur when ciclosporin is combined with simvastatin or lovastatin. It has been suggested that if a statin is to be combined with ciclosporin, pravastatin or fluvastatin should be chosen instead (80). 

In two cases, rhabdomyolysis was caused by itraconazole in heart transplant recipients taking long-term ciclosporin and simvastatin (48,49). To avoid severe myopathy, ciclosporin concentrations should be monitored frequently and statins should be withdrawn or the dosage should be reduced, as long as azoles need to be prescribed in transplant recipients. Patients need to be educated about signs and symptoms that require immediate physician intervention. 

STATINS- ATORVASTATIN, LOVASTATIN, ROSUVASTATIN, SIMVASTATIN CICLOSPORIN t plasma concentrations of these statins, with risk of myopathy and rhabdomyolysis Cidosporin is a moderate inhibitor of CYP3A4, which metabolizes these statins 1 statins to lowest possible dose (do not give simvastatin in doses >10 mg). Monitor LFTs and CK closely warn patients to report any features of rhabdomyolysis. This interaction does not occur with pravastatin... 

Statins are well absorbed after administration orally, and are metabolised in the liver. They are well tolerated, the commonest adverse effect being transient, and usually minor abnormality of liver function tests in some 1% of patients. Asymptomatic elevation of muscle enzymes (creatine phos-phokinase, CPK) and myositis (with a generalised muscle discomfort) occur more rarely, but is more frequent when statins are combined with other anti-hyperlidaemic drugs such as fibrates and nicotinic acid patients should be counseled about myositis when these drugs are co-administered. Myositis is also more likely with co-administered anti-HIV protease inhibitors, and with drugs that interfere with metabolism of some statins, e.g. ciclosporin. 

Bosmuller C, Steurer W, Konigsrainer A, WiUeit J, Margreiter R. Increased risk of central nervous system toxicity in patients treated with ciclosporin and imipenem/cila-statin. Nephron 1991 58(3) 362-4. 

Dosages of statins should be reduced in patients taking ciclosporin, because of pharmacodynamic and pharmacokinetic interactions. 

Modafinil is an inducer of the cytochrome P450 isoenzyme CYP3A4. The manufacturers therefore predict that it may reduce the levels of drugs that are CYP3A4 substrates. They specifically name the protease inhibitors, buspirone, calcium-channel blockers, ciclosporin, midazolam, and the statins [note that only some statins, namely atorvastatin, lovastatin and... 

The evidence suggests that all the azole antifungals can raise ciclosporin levels to a greater or lesser degree. Ketoconazole may cause five- to tenfold rises, while itraconazole, fluconazole and voriconazole may cause two- to threefold rises. A case report suggests that intravenous miconazole interacts similarly and in theory, miconazole oral gel may also interact. Posaconazole may also modestly raise ciclosporin levels. Rhabdomyolysis has been reported with the combination of ciclosporin and itraconazole, but four of these cases were complicated by the presence of statins. 

Rhabdomyolysis has been reported in 3 lung transplant patients and 2 heart transplant patients when itraconazole was used in combination with ciclosporin. However, in three of these cases the concurrent use of simvastatin and in one case concurrent simvastatin and gemfibrozil would also have been factors, " as both ciclosporin and itraconazole can increase simvastatin levels (see Statins -i- Ciclosporin , p.l097, and also Statins + Azoles , p.l093). 

Additional caution is required where ciclosporin and azoles are used in patients taking statins, and either ciclosporin dose reduction, replace-... 

In order to reduce the risk of myopathy the CSM in the UK have advised that statins should be used with care in patients who are at increased risk of this adverse effect. Among other risk factors, they mention concomitant use with fibrates, such as gemfibrozil , (p.llOO), and with inhibitors of CYP3A4 such as ciclosporin , (p.l097), macrolides ,(p.ll04), azoles , (p.l093), and protease inhibitors , (p.1108). They also recommend that patients should be made aware of the risks of myopathy and rhabdomyolysis, and asked to promptly report muscle pain, tenderness, or weakness, especially if accompanied by malaise, fever, or dark urine. A 2002 advisory on the use of statins gives some important safety recommendations, which are useful in the context of interactions ... 

Ciclosporin can cause marked rises in the plasma levels of atorv-astatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin, and for some of the statins this has led to the development of serious myopathy (rhabdomyolysis) accompanied by renal failure. The plasma levels of ciclosporin appear not to be affected by fluvastatin, lovastatin, pravastatin, or rosuvastatin, but some moderate changes in ciclosporin levels have been seen when atorvastatin or simvastatin were given. 

Effect on atorvastatin. In an open study the eoneurrent use of atorvastatin 10 mg daily with eielosporin resulted in a sixfold inerease in atorvastatin levels, when eompared with historieal eontrols not taking ciclosporin. A further analysis of this study has been reported elsewhere. A case of rhabdomyolysis has been deseribed in a woman who took both drugs for 2 months. She had also been taking diltiazem. In a review of the FDA spontaneous reports of statin-assoeiated rhabdomyolysis eovering the period November 1997 to Mareh 2000, eielosporin was potentially implicated in 5 eases of rhabdomyolysis involving atorvastatin. ... 

Ezetimibe can be added to a statin to improve the concentrations of atherogenic hpopro-teins in patients who have undergone organ transplantation and who are taking ciclosporin. The addition of ezetimibe did not increase the frequency of adverse... 

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