Simvastatin 4- Protease inhibitors

LOVASTATIN, SIMVASTATIN PROTEASE INHIBITORS t risk of adverse effects Inhibition of CYP3A4-mediated metabolism of simvastatin Avoid co-administration... 

WARNING Co administration w/ ritonavir assoc w/ Hep hepatic decomp w/ fatalities. D/C w/ S/Sxs of H Uses HIV 1 Infxn w/ highly Tx-experienced pts or HIV 1 strains resistant to multiple protease inhibitors. Must be used w/ ritonavir 200 mg Action Antiretroviral HIV-1 protease inhibitor Dose 500 mg PO bid w/ food, administer w/ ritonavir 200 mg PO bid Caution [C, -] Sulfa aU gy, Uvct Dz Contra Mod-severe hepatic insuff concomitant use w/ amiodarone, astemizole, bepridil, cisapride, ergots, flecainide, lovastatin, midazolam, pimozide, propafenone, quinidine, rifampin, simvastatin, terfenadine, triazolam, St. John s wort Disp Caps SE HA, GI distress, rash, fati e, fat redistribution, hyperglycemia, Hep, liver Dz, lipid elevations Interactions T Effects OF anticoagulants, antipits, azole antifun-... 

Chemotherapy Cyclophosphamide, erlotlnlb, ifos-famide, paclitaxel, tamoxifen, vinblastine, vincristine HIV protease inhibitors Amprenavir, atazanavir, indinavir, nelfinavir, ritonavir, saquinavir HMG-CoA reductase inhibitors Atorvastatin, lovastatin, simvastatin... 

Simvastatin (Zocor) [Anrilipemic/HMG-CoA Reductase Inhibitor] Uses X Cholesterol Action HMG-CoA reductase inhibitor Dose Adults. 5-80 mg PO w/ meals X in renal insuff Peds. 10-17 y 10 mg, 40 mg/daily max Caution [X, —] Avoid concurrent use of gemfibrozil Contra PRG, liver Dz Disp Tabs 5,10, 20, 40, 80 mg SE HA, GI upset, myalgia, myopathy (muscle pain, tenderness or weakness w/ creatine kinase 10 x ULN), Hep Interactions T Effects OF digoxin, warfarin T risk of myopathy/iiiabdomyolysis W/ amiodarone, cyclosporine, CYP3A4 inhibitors, fibrates, HIV protease inhibitors, macrolides, niacin, verapamil, grapefruit juice X effects W/ cholestyramine, colestipol, fluvas-tatin, isradipine, propranolol EMS T Effects of warfarin use amiodarone and... 

Healthy volunteers were given protease inhibitors and statins, and the authors concluded that simvastatin should be avoided and that atorvastatin could be used with caution in people taking ritonavir and saquinavir (111). Dosage adjustment of pravastatin may be necessary with co-administration of ritonavir and saquinavir. Pravastatin does not alter the pharmacokinetics of nelfinavir, and thus appears to be safe for co-administration. 

Grapefruit juice has also been shown to inhibit CYP3A4 and P-gp in the small intestine, and hence, can elevate the oral bioavailability of lipophilic drugs [98,99]. Concomitant intake of grapefruit juice with the lipophilic cholesterol-lowering medication simvastatin caused a 16-fold increase in the AUC of simvastatin [100]. The oral bioavailability of the lipophilic HIV protease inhibitor saquinavir was doubled following concomitant administration with grapefruit juice [101]. 

Since HMG CoA reductase inhibitors (statins) are partially or completely metabolized by CYP3A4, drug interactions with protease inhibitors can be expected. When nelfinavir was combined with atorvastatin and simvastatin, their AUCs increased by 74 and 505% respectively (17). As myopathy and rhabdomyolysis are concentration-related, simvastatin is contraindicated with any protease inhibitor, not just nelfinavir. Based on the data, the starting dose of atorvastatin should be reduced by about 50%. 

Reported bioanalytical applications that use SS-LLE products include both tlie cartridge (tube) format and the microplate format. Some of these applications include the determination of mexiletine [44], amiodarone [45] and other antiarrhythmic drugs [46], proxyphylline [47], 16(3-hydroxystanozolol [48], dextromethorphan [49], and simvastatin [50] from biological fluids. Microplate applications for SS-LLE include a crude purification of crude combinatorial library samples [51], carboxylic acid-based matrix metallo-protease inhibitors [52], and a p3-adrenergic receptor agonist [53]. 

CYP3A4 alprazolam, calcium channel blockers, cisapride, clarithromycin, cyclosporin A, erythromycin, HIV protease inhibitors, lidocaine, midazolam, simvastatin, terfenadine carbamazepine, dexamethsone, phenobarbital, phenytoin, rifampicin, St John s wort cimetidine, erythromycin, grapefruit juice, HIV protease inhibitors, itraconazole, ketoconazole... 

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. 

A 51-year-old woman was admitted to hospital with a 4-day history of muscular aches and weakness. Among other drugs, she had been taking zidovudine, lamivudine, indinavir, and simvastatin for 2 years. Ritonavir 100 mg twice daily had been added to her usual regimen 2 weeks previously. The rhabdomyolysis was therefore attributed to an interaction between ritonavir and simvastatin. Another similar case has also been reported. See also (b) above and (e) below for interactions of ritonavir combined with other protease inhibitors. 

The protease inhibitors, especially ritonavir, are known to be strong inhibitors of the cytochrome P450 isoenzyme CYP3A4. The levels of statins metabolised by this isoenzyme (notably simvastatin, and to some extent atorvastatin) are therefore increased. See Lipid regulating drugs , (p.l086) for information on the metabolism of the individual statins. 

The interactions of the protease inhibitors and atorvastatin or simvastatin appear to be established by the pharmacokinetic studies cited here, and supported by a few ease reports. It is generally recommended that simvastatin and lovastatin, which is similarly metalxrlised, should be avoided in patients taking protease inhibitors, and several manufacturers of simvastatin contraindicate concurrent use. Atorvastatin should be used in low doses (i.e.lO mg) with care. See also muscle toxicity , (p.l086), for further guidance on monitoring, and risk factors for muscle toxicity. 

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