iated no sooner than 1 week after completion of conivaptan therapy.
Cyclosporine: The use of simvastatin with is contraindicated due to an increased risk for myopathy and rhabdomyolysis. Cyclosporine increases the AUC of statins when administered concomitantly, and the risk for myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Although the mechanism is not fully understood, it is presumably due to inhibition of CYP3A4 and/or OAT1B1 by cyclosporine; simvastatin is a substrate of CYP3A4 and OAT1B1. Cyclosporine may significantly increase ezetimibe serum concentrations. In addition, ezetimibe can increase cyclosporine serum concentrations. In a study of twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days and a single dose of 100 mg cyclosporine on day 7 resulted in a mean 15% increase in cyclosporine AUC (up to 51%) compared to a single dose of 100 mg cyclosporine alone. In a study of eight post-renal transplant patients with mildly impaired or normal renal function (CrCl > 50 mL/min), stable doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and Cmax values of total ezetimibe 3.4-fold (range 2.3-fold to 7.9-fold) and 3.9-fold (range 3-fold to 4.4-fold), respectively, compared to a historical healthy control population (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the antilipemic benefits provided by ezetimibe. Patients who take cyclosporine concurrently with ezetimibe should be closely monitored for serum cyclosporine concentrations and for potential adverse effects of ezetimibe and cyclosporine.
Dabigatran: Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with simvastatin, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like simvastatin in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with simvastatin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
Daclatasvir: Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
Danazol: The use of simvastatin with danazol is contraindicated due to an increased risk of myopathy and rhabdomy |
