Simvastatin Verapamil

Simvastatin Verapamil Increase in AUC (4.6-fold) and Cmax (2.6-fold)... 

Anti-infective artemether, saguinavir Antilipemic atorrastatin, lovastatin, simvastatin Cardiovascular carvedilol, cilostazole, felodipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, verapamil... 

Concomitant amiodarone or verapamil- In patients taking amiodarone or verapamil concomitantly with simvastatin, the dose should not exceed 20 mg/day. 

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... 

Itraconazole Alfentanil, alprazolam, astemizole, atorvastatin, buspirone, cisapride, cyclosporine, delavirdine, diazepam, digoxin, felodipine, indinavir, loratadine, lovastatin, midazolam, nisoldipine, phenytoin, quinidine, ritonavir, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, triazolam, verapamil, warfarin... 

The catabolism of lovastatin, simvastatin, and atorvastatin proceeds chiefly through CYP3A4, whereas that of fluvastatin and rosuvastatin is mediated by CYP2C9. Pravastatin is catabolized through other pathways, including sulfation. The 3A4-dependent reductase inhibitors tend to accumulate in plasma in the presence of drugs that inhibit or compete for the 3A4 cytochrome. These include the macrolide antibiotics, cyclosporine, ketoconazole and its congeners, HIVprotease inhibitors, tacrolimus, nefazodone, fibrates, and others (see Chapter 4). Concomitant use of reductase inhibitors with amiodarone or verapamil also causes an increased risk of myopathy. 

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... 

Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 1998 64(2) 177-82. 

Oral rifampin dose and AUC changes abstracted from alfentanil (205), buspirone (208), gefitinib (209), L-a-acetylmethadol (210), midazolam (77) nifedipine (62), simvastatin (211), tamoxifen (212), toremifene (212), triazolam (213), and verapamil (60). 

CYP3A4 Inhibition Amiodarone, clarithromycin, erythromycin, cimetidine, cyclosporine, fluoxetine fluvoxamine, itraconazole, ketoconazole, nefazodone, verapamil, diltiazem HIV antivirals delaviridine, indanavire, nelfmavire, ritonavire, sequinavire Atorvastatin Lovastatin Simvastatin ... 

CALCIUM CHANNEL BLOCKERS STATINS t plasma levels of atorvastatin, lovastatin and simvastatin case reports of myopathy when atorvastatin and simvastatin are co-administered with diltiazem or verapamil Uncertain, but postulated to be due to inhibition of CYP3A4-mediated metabolism of statins in the intestinal wall. Also, diltiazem and verapamil inhibit intestinal P-gp, which may t the bioavailability of statins Watch for side-effects of statins. It has been suggested that the dose of simvastatin should not exceed 20 mg when given with verapamil, and 40 mg when given with diltiazem... 

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. 

The effects of a combination of erythromycin and verapamil on the pharmacokinetics of a single dose of simvastatin have been studied in a randomized, double-blind, cross-over study in 12 healthy volunteers simultaneously taking the three drugs. Both erythromycin and verapamil interacted with simvastatin, producing significant increases in the serum concentrations of simvastatin and its active metabolite simvastatin acid. The mean C ax of active simvastatin acid was increased about five-fold and the AUCo 24 four-fold by erythromycin verapamil increased the C ax of simvastatin acid 3.4-fold and the AUCo 24 2.8-fold. There was a substantial interindividual variation in the extent of these interactions. Concomitant use of erythromycin, verapamil, and simvastatin should be avoided (35). 

D Rifampin significantly reduces the plasma concentrations of the calcium channel blockers verapamil, diltiazem, and nifedipine. Diltiazem is a substrate of Gi P3A4 and rifampin is an inducer of CYP3A4. Rifampin does not interact with metoprolol, aspirin, pravastatin, or nitroglycerin. However, if the patient had been on another HMG-CoA reductase inhibitor such as atorvastatin, lova-statin, or simvastatin instead of pravastatin, rifampin would have reduced the plasma concentrations of these agents since they are also metabolized via CYP3A4. 

Clinically important, potentially hazardous interactions with abarelix, acenocoumarol, amisulpride, amprenavir, anisindione, anticoagulants, arsenic, astemizole, carbimazole, celiprolol, ciprofloxacin, dabigatran, degarelix, dicumarol, digoxin, diltiazem, enoxacin, fentanyl, fosamprenavir, gatifloxacin, grapefruit juice, lomefloxacin, methotrexate, moxifloxacin, nilotinib, norfloxacin, ofloxacin, oxprenolol, quinidine, quinolones, rifabutin, rifampin, rifapentine, ritonavir, simvastatin, sparfloxacin, sulpiride, tacrolimus, tipranavir, verapamil, warfarin, zuclopenthixol... 

Clinically important, potentially hazardous interactions with alfentanil, aminophylline, amisulpride, amoxicillin, ampicillin, anticonvulsants, astemizole, atorvastatin, benzodiazepines, bromocriptine, buprenorphine, bupropion, carbamazepine, cilostazol, ciprofloxacin, cisapride, clindamycin, colchicine, cyclosporine, dasatinib, digoxin, dihydroergotamine, diltiazem, disopyramide, enoxacin, eplerenone, ergotamine, eszopiclone, everolimus, fluconazole, fluoxetine, fluvastatin, gatifloxacin, HMG-CoA reductase inhibitors, imatinib, itraconazole, ketoconazole, lomefloxacin, lorazepam, lovastatin, methadone, methylprednisolone, methysergide, midazolam, mizolastine, moxifloxacin, nitrazepam, norfloxacin, ofloxacin, paroxetine, pimozide, pravastatin, quinolones, ranolazine, repaglinide, rupatadine, sertraline, sildenafil, simvastatin, sparfloxacin, sulpiride, tacrolimus, terfenadine, triazolam, troleandomycin, vardenafil, verapamil, vinblastine, warfarin, zaleplon, zolpidem, zuclopenthixol... 

Clinically important, potentially hazardous interactions with cyclosporine, diltiazem, dofetilide, erythromycin, grapefruit, ketoconazole, quinidine, ritonavir, simvastatin, sotalol, thioridazine, verapamil, ziprasidone... 

CYP3A4 Alfentanil Alprazolam Astern izole Carbamazepine Cisapride Cyclosporine Diltiazem Erythromycin Felodipine Fluconazole Itraconazole Ketoconazole Lidocaine Lova statin Midazolam Nifedipine Quinidine Simvastatin Tacrolimus Terfenadine Verapamil... 

Methylprednisolone Midazolam Nisoldipine Phenytoin Pimozide Quinidine Ritonavir Saquinavir Sildenafil Simvastatin SiroUmus Sulfonylureas (glyburide, others) Tacrolimus Triazolam Trimetrexate Verapamil Ritonavir... 

Metoprolol Midazolam Naproxen Nifedipine Omeprazole Ondansetron Orphenadrine Phenytoin Piroxicam Progesterone Propafenone Propranolol Quinidine Rifampin Sibutramine Sildenafil Simvastatin Tacrine Tamoxifen Terfenadine Testosterone Theophylline Timolol Tolbutamide Tramadol Triazolam Verapamil Warfarin (R) Warfarin (S) Zolmitriptan Zolpidem... 

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. 

Marked rises in statin plasma levels have been seen when lovastatin or simvastatin were given with diltiazem, and when simvastatin was given with verapamil. Isolated cases of rhabdomyolysis have occurred as a result of these interactions. However, overall, it seems that problems with combinations of statins and calcium-channel blockers (particularly the dihydropyridine-type) are rare. 

Verapamil. A study in which 12 subjects were given verapamil 80 mg three times daily, found a 4.6-fold increase in the AUC of simvastatin, a 2.6-fold increase in its maximum serum levels, and about a twofold increase in its half-life. Similarly, a study in 12 healthy subjects found that extended-release verapamil 480 mg daily for 3 days caused a fivefold increase in the maximum serum levels of simvastatin 40 mg, and about a fourfold increase in its AUC. ... 

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. " ... 

Chiffoleau A, Tochu J-N, Veyrac G, Petit T, Abadie P, Bourin M, Jolliet P Rhabdemyolyse liee a I ajout du verapamil a un traitement par simvastatine et cyclo rine chez un patient tran Iante cardiaque Therapie (2003) 58,168-70... 

Information is limited, but what is known suggests that the concurrent use of these drugs is normally uneventful. Even with those pairs of drugs where the increases in plasma levels are quite large (such as when simvastatin was given with diltiazem or verapamil) problems seem to be very rare. Indeed an analysis of the 4S study and the Heart Protection Study (which used maximum simvastatin doses of 40 mg) found no evidence that the concurrent use of a calcium-channel blocker increases the risk of myopathy. Therefore concurrent use need not be avoided, but it has been suggested that treatment with a statin in a patient taking diltiazem (and probably verapamil) should be started with the lowest possible dose and titrated upwards, or, if diltiazem (or verapamil) is started, the dose of the... 

---