Simvastatin Danazol

Ezetimibe/Simvastatin (Vytorin) [Antilipemic/HMG CoA Reductose Inhibitor] Uses H rp cholest olemia Action X Absorption of cholesterol phytost ol w/ HMG-CoA reductase inhibitor Dose 10/10-10/80 mg/d PO w/ cyclosporine or danazol 10/10 mg/d max w/ amio-darone or verapamil 10/20 mg/d max -1- w/ sev e renal insuff Caution [X, -] w/ CYP3A4 inhibitors (Table VI-8), gemfibrozil, niacin >lg/d, danazol, amiodarone, verapamil Contra PRG/lactation livCT Dz, t LFTs Disp Tabs SE HA, GI upset, myalgia, myopathy (muscle pain, weakness, or tendOTiess w/ CK 10 x ULN, rhab-domyolysis), Hep, Infxn Interactions t Risk of myopathy W7 clarithromycin, erythromycin, itraconazole, ketoconazole EMS None OD Sxs unknown symptomatic and supportive... 

A potential drug interaction between simvastatin and danazol, causing rhabdomyolysis and acute renal insufficiency, has been reported (43). Rhabdomyolysis can occur with all statins when they are used alone and particularly when they are combined with other drugs that are themselves myotoxic or that increase the concentration of the statin. Statins are particularly susceptible to the latter effect because of their metabolism by the CYP450 system and their low oral systemic availability. 

Andreou ER. Potential drug interaction between simvastatin and danazol causing rhabdomyolysis. Can J Clin Pharmacol 2003 10 172-4. 

Clinically important, potentially hazardous interactions with amiloride, aminoglycosides, amphotericin B, ampicillin, anisindione, anticoagulants, armodafinil, atorvastatin, azathioprine, azithromycin, bacampicillin, basiliximab, bezafibrate, bosentan, bupropion, carbenicillin, caspofungin, cholestyramine, clarithromycin, cloxacillin, co-trimoxazole, corticosteroids, cyclophosphamide, daclizumab, danazol, dicloxacillin, dicumarol, digoxin, diltiazem, disulfiram, echinacea, erythromycin, ethotoin, etoposide, ezetimibe, flunisolide, fluoxymesterone, fluvastatin, foscarnet, fosphenytoin, gemfibrozil, hemophilus B vaccine, HMG-CoA reductase inhibitors, imatinib, imipenem/cilastatin, influenza vaccines, ketoconazole, lanreotide, lopinavir, lovastatin, mephenytoin, methicillin, methoxsalen, methylphenidate, methylprednisolone, methyltestosterone, mezlocillin, mizolastine, mycophenolate, nafcillin, nisoldipine, NSAIDs, orlistat, oxacillin, penicillins, phellodendron, phenytoin, pravastatin, prednisolone, prednisone, pristinamycin, ranolazine, red rice yeast, rifabutin, rifampin, rifapentine, ritonavir, rosuvastatin, simvastatin, sirolimus, spironolactone, St John s wort, sulfacetamide, sulfadiazine, sulfamethoxazole, sulfisoxazole, sulfonamides, tacrolimus, telithromycin, tenoxicam, testosterone, ticarcillin, tolvaptan, trabectedin, triamterene, troleandomycin, ursodeoxycholic acid, vaccines, vecuronium, warfarin, zofenopril... 

Clinically important, potentially hazardous interactions with amiodarone, beta-blockers, caspofungin, cyclosporine, dairy products, danazol, erythromycin, etoricoxib, grapefruit juice, hemophilus B vaccine, HMG-CoA reductase inhibitors, ibuprofen, immunosuppressants, ketoconazole, lopinavir, lovastatin, mycophenolate, peanuts, potassium, potassium-sparing diuretics, rifabutin, rifampin, rifapentine, simvastatin, St John s wort, telithromycin, vaccines... 

Severe rhabdomyolysis and myoglobinuria developed in a man taking lovastatin about two months after danazol was added. Another report describes a similar interaction with simvastatin. 

A 68-year-old man who had been taking simvastatin 40 mg daily longterm without problem developed rhabdomyolysis (progressive muscle pain and weakness, tea-coloured urine, renal impairment, and a raised creatine phosphokinase) within 3 weeks of starting to take danazol 200 mg three times daily. He was given haemodialysis and subsequently recovered. 

It has been suggested that danazol (and the doxycycline) were possibly hepatotoxic, which led to decreased lovastatin metabolism, or that the danazol had a direct toxic effect on the muscles. Efanazol inhibits the cytochrome P450 isoenzyme CYP3A4 by which simvastatin and lovastatin are metabolised, which would result in raised statin levels, and therefore myopathy and rhabdomyolysis. This seems a more likely explanation for the effects seen. 

These appear to be the only reports of this apparent interaction, but the pharmacokinetic basis of the interaction seems to be established. The US manufacturers of lovastatin suggest that the dose should not exceed 20 mg daily in the presence of danazol. Similarly the manufacturers of simvastatin suggest that the dose should not exceed 10 mg daily in the presence of danazol. It would seem prudent to reinforce the symptoms of myopathy and tell patients to report any unexplained muscle pain, tenderness or weakness. The authors of the lovastatin report point out that, as in this case, severe lovastatin muscle toxicity may be very slow to develop. See also muscle toxicity , (p.l086), for further guidance on monitoring, and risk factors for muscle toxicity. 

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