Simvastatin Ciclosporin

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... 

A 59-year-old woman taking pravastatin 20 mg/day tolerated immunosuppression with ciclosporin, prednisone, and mycophenolate mofetil for 4 years after heart transplantation. After switching from pravastatin to simvastatin she developed severe muscle weakness and laboratory evidence of muscle breakdown. The biochemical markers of rhabdomyolysis did not normalize until after repeat hemodialysis. Clinical improvement did not occur until after 5 months. 

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 a patient with glucocorticoid-resistant nephrotic syndrome taking simvastatin and ciclosporin, there was an increase in lactic dehydrogenase activity, suggesting tissue injury, in the absence of an increase in creatine kinase (42). 

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 To avoid severe myopathy, ciclosporin concentrations should be monitored frequently and statins should be withdrawn or the dosage should be reduced, as long as azoles need to be prescribed in transplant recipients.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. 

A 52-year-old man developed rhabdomyolysis while taking simvastatin, digoxin, ciclosporin, and verapamil (298). The authors proposed that this had been due in part to inhibition of the biliary secretion of simvastatin by digoxin however, it is likely that the major mechanism of the interaction was inhibition of CYP3A4 by ciclosporin. 

This topic has been re-analysed in a systematic review of published papers, in which relevant information from a total of 34 patients was identified (163). AU but two patients were also taking concomitant drugs known to affect the muscles, among which glucocorticoids, simvastatin, lovastatin, colchicine, and pyrazinamide were the most frequently cited. Ciclosporin is therefore difficult to implicate in most patients, but at least one case with positive ciclosporin re-administration supported a causative role. The clinical picture was non-specific, with myalgia, cramps, and muscle weakness, sometimes associated with raised serum creatine kinase activity, and heterogeneous histopathology. FinaUy, skeletal muscle abnormalities have rarely been described in patients without muscle symptoms. 

From an analysis of changes in ciclosporin clearance and systemic availability obtained from the medical records of 100 transplant patients, atorvastatin, fluvastatin, pravastatin, and simvastatin were found to affect ciclosporin pharmacokinetics (228). 

In a study of the safety and efficacy of simvastatin in hyperlipidemia after renal transplantation in 15 patients, the Cmax and AUC of simvastatin were increased seven-fold by ciclosporin (260). In contrast, in 17 patients, tacrolimus had no effect. Although there were no complications, such as myopathy or rhabdomyolysis, creatine kinase activity must be monitored during co-administra-tion of simvastatin and ciclosporin. 

Mibefradil inhibits CYP3A4 (2). Other drugs that are metabolized by this pathway accumulate as a result. Drugs that were commonly affected included amiodarone, astemizole, ciclosporin, cisapride, erythromycin, imi-pramine, lovastatin, propafenone, quinidine, simvastatin (9), tacrohmus (10), tamoxifen, terfenadine, thioridazine, and drugs that impair sinoatrial node function (for example beta-blockers) (6). 

Arnadottir M, Eriksson LO, Thysell H, Karkas JD. Plasma concentration profiles of simvastatin 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitory activity in kidney transplant recipients with and without ciclosporin. Nephron 1993 65 410-113. 

Single-dose ciclosporin slightly increased the absorption of sitagliptin, although this was not considered clinically relevant. Sitagliptin does not have a clinically relevant effect on the pharmacokinetics of digoxin, oral contraceptives, simvastatin or warfarin. 

The concurrent use of ranolazine and moderate or potent inhibitors of CYP3A4, such as some azoles, diltiazem, grapefruit juice, macrolides, protease inhibitors, or verapamil will result in increased levels of ranolazine, and can predispose the patient to adverse effects including QT interval prolongation. Cimetidine and paroxetine do not interact to a clinically significant extent. Ranolazine may increase levels of ciclosporin, digoxin or simvastatin. 

Caution is recommended when eplerenone is used with alpha blockers, antipsychotics, amifostine, baclofen, corticosteroids, tetracosactide and tricyclic antidepressants. Lithium, ciclosporin, and tacrolimus should generally not be used with eplerenone. Antacids, cisapride, midazolam and simvastatin had no effect on eplerenone pharmacokinetics. Eplerenone had no important effect on cisapride, midazolam, warfarin or contraceptive steroid pharmacokinetics, but caused a slight increase in digoxin levels. 

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). 

The clinical relevance of the verapamil interaction was demonstrated in a 63-year-old man, who developed rhabdomyolysis about 1 month after extended-release verapamil 240 mg daily was added to established treatment with simvastatin 40 mg daily and ciclosporin. Verapamil and simvastatin were discontinued and he recovered over the following 14 days. An in vitro study using human liver microsomes also found that verapamil moderately inhibits simvastatin metabolism. " ... 

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 ciclosporin. A study found that the ciclosporin levels of 12 renal transplant patients fell from 334 to 235 micrograms/L after simvastatin 5 to 15 mg daily was added. A retrospective study by the same authors confirmed these results in 12 patients. In contrast, a single-dose pharmacokinetic study suggested that simvastatin increases the maximum levels and AUC of ciclosporin by a modest 8% and 13%, respectively. ... 

Blaison G, Weber JC, Sachs D, Korganow AS, Martin T, Kretz JG, PasquaU JL. Rhabdomy-olyse causee par la simvastatine chez un transplante cardiaque sous ciclosporine. RevMedln-teme ( 992) 13, 61-3. 

Meier C, Stey C, Brack T, Maggiorini M, Risti B, Krahenbuhl Rhabdomyol bei mit simvastatin und ciclosporin behandelten patienten Rolle der aktivitat des cytodircni-P450-en- msystems der leber. Schweiz K ed fVochenschr ( 995) 125,1342-6. 

Simvastatin A 45-year-old woman developed severe myoglobinuric acute kidney injury after taking ciclosporin 200 mg bd and simvastatin 20mg/day for 4 weeks [23 ]. Both drugs are metabolized by CYP3A4. 

Teutonico A, Libutti P, Lomonte C, Basile C. Simvastatin-induced myoglobi-nuric acute kidney injury following ciclosporin treatment for alopecia universalis. Nephrol Dial Transplant 2010 3 273-5. 

Especially the inhibition or induction of cytochrome P450 subtype 3A4 (CYP 3A4) is clinically relevant, because a variety of active substances and food substances (e.g. grapefruit juice) are able to affect this enzyme. Substances inhibiting CYP 3A4 include ciclosporin, dihydropyridines, verapamil, midazolam, paclitaxel, simvastatin, lovastatin, atorvastatin, cimetidine, erythromycin, troleandomycin, ketoconazole (and other azoles). Substances inducing CYP 3A4 include steroids, rifampicin, phenobarbital and St John s wort. 

HMG CoA reductase inhibitors Rhabdo-myolysis and renal failure in a 55-year-old man has been attributed to inhibition by concomitant ciclosporin and risperidone of the metabolism of simvastatin by CYP3A4 [22 ]. 

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