Dosing & Uses
Dosage Forms & Strengths
simvastatin/ezetimibe
tablet
- 10mg/10mg
- 10mg/20mg
- 10mg/40mg
- 10mg/80mg
Hypercholesterolemia
10 mg/10 mg/day-10 mg/40 mg/day PO qHS
Usual starting dose: 10 mg/20 mg PO qHS
Simvastatin 80 mg/day should only be used for individuals who have been taking a simvastatin dose of 80 mg for 12 months or longer without evidence of myopathy
Prescribing information advises if patients are taking simvastatin 40 mg/day without meeting their LDL goal to switch to a different statin rather than increase to 80 mg/day
Dosage Modifications
Coadministration with dronedarone, verapamil, or diltiazem: Do not exceed 10 mg/day
Coadministration with amiodarone, amlodipine, or ranolazine: Do not exceed 20 mg/day
Coadministration with lomitapide: Reduce simvastatin dose by 50% and do not exceed 20 mg/day (or 40 mg/day in those previously tolerating 80 mg/day) when initiating lomitapide
Grapefruit juice: Avoid large quantities of grapefruit juice (ie, ≥1 quart/day)
Renal impairment
- GFR ≥60 mL/min/1.73 m²: Dose adjustment not necessary
- GFR <60 mL/min/1.73 m²: 10 mg ezetimibe and 20 mg simvastatin PO qDay; may use higher doses with caution
Hepatic impairment
- Mild: Dosage adjustment not required
- Moderate-to-severe: Not recommended
Dosage Forms & Strengths
simvastatin/ezetimibe
tablet
- 10mg/10mg
- 10mg/20mg
- 10mg/40mg
Heterozygous Familial Hypercholesterolemia
<10 years: Safety and efficacy not established
10-18 years: 10 mg/10 mg/day-10 mg/40 mg/day PO qHS
Simvastatin 80 mg/day should only be used for individuals who have been taking a simvastatin dose of 80 mg for 12 months or longer without evidence of myopathy
FDA advises if patients are taking simvastatin 40 mg/day without meeting their LDL goal to switch to a different statin rather than increase to 80 mg/day
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (33)
- atazanavir
atazanavir will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Contraindicated. Increased risk for rhabdomyolysis with drugs that increase simvastatin systemic exposure
- ceritinib
ceritinib will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- clarithromycin
clarithromycin will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Increased risk for rhabdomyolysis with drugs that increase simvastatin systemic exposure
clarithromycin will increase the level or effect of simvastatin by Other (see comment). Contraindicated. OATP1B1 inhibitors may increase risk of myopathy - cobicistat
cobicistat will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Potential for serious reactions such as myopathy including rhabdomyolysis
- cyclosporine
cyclosporine will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Contraindicated. Increased risk for rhabdomyolysis with drugs that increase simvastatin systemic exposure.
cyclosporine will increase the level or effect of simvastatin by Other (see comment). Contraindicated. OATP1B1 inhibitors may increase risk of myopathy - danazol
danazol increases toxicity of simvastatin by decreasing metabolism. Contraindicated. Contraindicated. Increased risk for rhabdomyolysis with drugs that increase simvastatin systemic exposure.
- darunavir
darunavir will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Increased risk for rhabdomyolysis with drugs that increase simvastatin systemic exposure
- elvitegravir/cobicistat/emtricitabine/tenofovir DF
elvitegravir/cobicistat/emtricitabine/tenofovir DF increases levels of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Cobicistat is a CYP3A4 inhibitor; contraindicated with CYP3A4 substrates for which elevated plasma concentrations are associated with serious and/or life-threatening events.
- erythromycin base
erythromycin base will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Increased risk for rhabdomyolysis with drugs that increase simvastatin systemic exposure
- erythromycin ethylsuccinate
erythromycin ethylsuccinate will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Increased risk for rhabdomyolysis with drugs that increase simvastatin systemic exposure
erythromycin ethylsuccinate increases toxicity of simvastatin by Other (see comment). Contraindicated. Comment: OATP1B1 inhibitors may increase risk of myopathy. - erythromycin lactobionate
erythromycin lactobionate will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Increased risk for rhabdomyolysis with drugs that increase simvastatin systemic exposure
erythromycin lactobionate increases toxicity of simvastatin by Other (see comment). Contraindicated. Comment: OATP1B1 inhibitors may increase risk of myopathy. - erythromycin stearate
erythromycin stearate will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Increased risk for rhabdomyolysis with drugs that increase simvastatin systemic exposure
erythromycin stearate increases toxicity of simvastatin by Other (see comment). Contraindicated. Comment: OATP1B1 inhibitors may increase risk of myopathy. - fosamprenavir
fosamprenavir will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Contraindicated. Increased risk for rhabdomyolysis with drugs that increase simvastatin systemic exposure
- gemfibrozil
gemfibrozil, simvastatin. Either increases effects of the other by pharmacodynamic synergism. Contraindicated. Contraindicated with other lipid-lowering drugs that can cause myopathy.
gemfibrozil will increase the level or effect of simvastatin by Other (see comment). Contraindicated. OATP1B1 inhibitors may increase risk of myopathy - idelalisib
idelalisib will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Strong CYP3A4 inhibitors increase systemic statin exposure and risk of myopathy, including rhabdomyolysis
- indinavir
indinavir will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
simvastatin will increase the level or effect of indinavir by P-glycoprotein (MDR1) efflux transporter. Contraindicated.
indinavir increases toxicity of simvastatin by Other (see comment). Contraindicated. Comment: OATP1B1 inhibitors may increase risk of myopathy. - itraconazole
itraconazole will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Contraindicated during and 2 weeks after itraconazole treatment. Increased risk for rhabdomyolysis with drugs that increase simvastatin systemic exposure.
- ketoconazole
ketoconazole will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Contraindicated. Increased risk for rhabdomyolysis with drugs that increase simvastatin systemic exposure
ketoconazole increases toxicity of simvastatin by Other (see comment). Contraindicated. Comment: OATP1B1 inhibitors may increase risk of myopathy. - letermovir
letermovir increases levels of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Coadministration of letermovir and simvastatin is not recommended. When letermovir is coadministered with cyclosporine, use of either simvastatin is contraindicated due to significantly increased pitavastatin or simvastatin concentrations and risk of myopathy or rhabdomyolysis. .
- levoketoconazole
levoketoconazole will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Contraindicated. Increased risk for rhabdomyolysis with drugs that increase simvastatin systemic exposure
levoketoconazole increases toxicity of simvastatin by Other (see comment). Contraindicated. Comment: OATP1B1 inhibitors may increase risk of myopathy. - lonafarnib
lonafarnib will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- lopinavir
lopinavir increases levels of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Contraindicated. Increased risk for rhabdomyolysis with drugs that increase simvastatin systemic exposure.
- mifepristone
mifepristone increases levels of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Contraindicated due to increased risk of rhabdomyolysis.
mifepristone increases toxicity of simvastatin by Other (see comment). Contraindicated. Comment: OATP1B1 inhibitors may increase risk of myopathy. - nefazodone
nefazodone will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Contraindicated. Increased risk for rhabdomyolysis with drugs that increase simvastatin systemic exposure.
- nelfinavir
nelfinavir will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
simvastatin will increase the level or effect of nelfinavir by P-glycoprotein (MDR1) efflux transporter. Contraindicated.
nelfinavir increases toxicity of simvastatin by Other (see comment). Contraindicated. Comment: OATP1B1 inhibitors may increase risk of myopathy. - nirmatrelvir
nirmatrelvir will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions. Discontinue simvastatin at least 12 hr before initiating nirmatrelvir/ritonavir.
- nirmatrelvir/ritonavir
nirmatrelvir/ritonavir will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions. Discontinue simvastatin at least 12 hr before initiating nirmatrelvir/ritonavir, during the 5 days of treatment, and for 5 days after completing.
- ombitasvir/paritaprevir/ritonavir & dasabuvir (DSC)
ombitasvir/paritaprevir/ritonavir & dasabuvir (DSC) will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Increased risk of myopathy, including rhabdomyolysis
ombitasvir/paritaprevir/ritonavir & dasabuvir (DSC) increases toxicity of simvastatin by Other (see comment). Contraindicated. Comment: OATP1B1 inhibitors may increase risk of myopathy. - posaconazole
posaconazole will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Contraindicated. Increased risk for rhabdomyolysis with drugs that increase simvastatin systemic exposure
posaconazole will increase the level or effect of simvastatin by P-glycoprotein (MDR1) efflux transporter. Contraindicated. Contraindicated. Increased risk for rhabdomyolysis with drugs that increase simvastatin systemic exposure - red yeast rice
simvastatin, red yeast rice. Either increases toxicity of the other by pharmacodynamic synergism. Contraindicated. May increase creatine kinase levels and increase risk of myopathy or rhabdomyolysis; red yeast rice contains monocolin K (reportedly identical to lovastatin).
- ritonavir
ritonavir will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
simvastatin will increase the level or effect of ritonavir by P-glycoprotein (MDR1) efflux transporter. Contraindicated.
ritonavir increases toxicity of simvastatin by Other (see comment). Contraindicated. Comment: OATP1B1 inhibitors may increase risk of myopathy. - saquinavir
simvastatin will increase the level or effect of saquinavir by P-glycoprotein (MDR1) efflux transporter. Contraindicated.
saquinavir increases levels of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Contraindicated. Increased risk for rhabdomyolysis with drugs that increase simvastatin systemic exposure.
saquinavir increases toxicity of simvastatin by Other (see comment). Contraindicated. Comment: OATP1B1 inhibitors may increase risk of myopathy. - tipranavir
tipranavir increases levels of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. This interaction is the net effect of tipranavir being coadministered with ritonavir (boosted therapy); increased risk of myopathy including rhabdomyolysis.
Serious - Use Alternative (79)
- afatinib
simvastatin increases levels of afatinib by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Reduce afatinib daily dose by 10 mg if not tolerated when coadministered with P-gp inhibitors.
- amiodarone
amiodarone increases toxicity of simvastatin by decreasing metabolism. Avoid or Use Alternate Drug. Do not exceed simvastatin 20 mg daily when given concurrently. Potential for increased risk of myopathy/rhabdomyolysis.
- amlodipine
amlodipine increases levels of simvastatin by Other (see comment). Avoid or Use Alternate Drug. Comment: Benefits of combination therapy should be carefully weighed against the potential risks of combination. Potential for increased risk of myopathy/rhabdomyolysis. Limit simvastatin dose to no more than 20 mg/day when used concurrently.
- apalutamide
apalutamide will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of apalutamide, a strong CYP3A4 inducer, with drugs that are CYP3A4 substrates can result in lower exposure to these medications. Avoid or substitute another drug for these medications when possible. Evaluate for loss of therapeutic effect if medication must be coadministered. Adjust dose according to prescribing information if needed.
- aprepitant
aprepitant will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- armodafinil
armodafinil will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- artemether/lumefantrine
artemether/lumefantrine will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- bosentan
bosentan will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- bosutinib
simvastatin increases levels of bosutinib by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.
- butabarbital
butabarbital will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- butalbital
butalbital will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- carbamazepine
carbamazepine will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- cimetidine
cimetidine will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- colchicine
colchicine, simvastatin. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Increased risk of rhabdomyolysis (incl a fatality).
- conivaptan
conivaptan will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- cyclosporine
cyclosporine, ezetimibe. Either increases effects of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Monitor for potential adverse effects of cyclosporine and ezetimibe if coadministered, especially in patients with severe renal impairment.
- darifenacin
darifenacin will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- darolutamide
darolutamide will increase the level or effect of simvastatin by Other (see comment). Avoid or Use Alternate Drug. Darolutamide is a BCRP inhibitor. Avoid coadministration with BCRP inhibitors. If use is unavoidable, closely monitor for adverse reactions and consider dose reduction of BCRP substrate drug (refer BCRP substrate prescribing information).
- dasatinib
dasatinib will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- dexamethasone
dexamethasone will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- diltiazem
diltiazem will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Benefits of combination therapy should be carefully weighed against the potential risks of combination. Limit simvastatin dose to no more than 10 mg/day and dilitazem dose to no more than 240 mg/day when used concurrently.
- eltrombopag
eltrombopag will increase the level or effect of simvastatin by Other (see comment). Avoid or Use Alternate Drug. OATP1B1 inhibitors may increase risk of myopathy
- eluxadoline
simvastatin increases levels of eluxadoline by decreasing metabolism. Avoid or Use Alternate Drug. Decrease eluxadoline dose to 75 mg PO BID if coadministered with OATP1B1 inhibitors. .
- enzalutamide
enzalutamide will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- etravirine
etravirine will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- fenofibrate
fenofibrate, simvastatin. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Fenofibrate may further increase risk for rhabdomyolysis when added to optimal statin regimen to further decrease TG and increase HDLs.
- fenofibrate micronized
fenofibrate micronized, simvastatin. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Fenofibrate may further increase risk for rhabdomyolysis when added to optimal statin regimen to further decrease TG and increase HDLs.
- fenofibric acid
fenofibric acid, simvastatin. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Fenofibrate may further increase risk for rhabdomyolysis when added to optimal statin regimen to further decrease TG and increase HDLs.
- fexinidazole
fexinidazole will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Fexinidazole inhibits CYP3A4. Coadministration may increase risk for adverse effects of CYP3A4 substrates.
- fluconazole
fluconazole will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- fosaprepitant
fosaprepitant will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- fosphenytoin
fosphenytoin will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- glecaprevir/pibrentasvir
glecaprevir/pibrentasvir increases levels of simvastatin by Other (see comment). Avoid or Use Alternate Drug. Comment: Increased statin concentrations resulting from OATP1B1 inhibition may increase risk of myopathy, including rhabdomyolysis. Coadministration of glecaprevir/pibrentasvir with simvastatin is not recommended.
- grapefruit
grapefruit will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid consuming large quantities of grapefruit or juice (ie, >1 quart/day)
- griseofulvin
griseofulvin will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- hydrocortisone
hydrocortisone will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- isoniazid
isoniazid will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- ivosidenib
ivosidenib will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP3A4 substrates with ivosidenib or replace with alternative therapies. If coadministration is unavoidable, monitor patients for loss of therapeutic effect of these drugs.
- lapatinib
lapatinib will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- lasmiditan
lasmiditan increases levels of simvastatin by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.
lasmiditan increases effects of simvastatin by Other (see comment). Avoid or Use Alternate Drug. Comment: Lasmiditan inhibits BCRP in vitro. Avoid coadministration of lasmiditan with BCRP substrates. - leniolisib
leniolisib will increase the level or effect of simvastatin by Other (see comment). Avoid or Use Alternate Drug. Leniolisib, a BCRP, OATP1B1, and OATP1B3 inhibitor, may increase systemic exposure of these substrates
leniolisib will increase the level or effect of ezetimibe by Other (see comment). Avoid or Use Alternate Drug. Leniolisib, an OATP1B1 and OATP1B3 inhibitor, may increase systemic exposure of these substrates - lomitapide
lomitapide increases levels of simvastatin by decreasing metabolism. Avoid or Use Alternate Drug. Reduce simvastatin dose by 50% when initiating lomitapide dosing.
- trofinetide
trofinetide will increase the level or effect of ezetimibe by Other (see comment). Avoid or Use Alternate Drug. Trofinetide (an OATP131 and OATP13B inhibitor) may increase plasma levels of OATP131 or OATP13B substrates. Avoid coadministration with sensitive substrates.
- lumefantrine
lumefantrine will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- marijuana
marijuana will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- mesterolone
mesterolone increases toxicity of simvastatin by decreasing metabolism. Avoid or Use Alternate Drug. Risk of rhabdomyolysis (theoretical interaction based on case reports of combination of danazol and >20 mg/day lovastatin).
- methylprednisolone
methylprednisolone will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- metronidazole
metronidazole will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- miconazole vaginal
miconazole vaginal will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- nafcillin
nafcillin will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- nevirapine
nevirapine will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- niacin
niacin, simvastatin. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Increased risk of rhabdomyolysis (>1 g/day niacin).
- nifedipine
nifedipine will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- nilotinib
nilotinib will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- oxcarbazepine
oxcarbazepine will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- pentobarbital
pentobarbital will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- pexidartinib
simvastatin and pexidartinib both increase inhibition of GI absorption. Applies only to oral form of both agents. Avoid or Use Alternate Drug. Pexidartinib can cause hepatotoxicity. Avoid coadministration of pexidartinib with other products know to cause hepatoxicity.
- phenobarbital
phenobarbital will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- phenytoin
phenytoin will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- pomalidomide
simvastatin increases levels of pomalidomide by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.
- pretomanid
simvastatin, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- primidone
primidone will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- quinupristin/dalfopristin
quinupristin/dalfopristin will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- ranolazine
ranolazine increases levels of simvastatin by Other (see comment). Avoid or Use Alternate Drug. Comment: Benefits of combination therapy should be carefully weighed against the potential risks of combination. Potential for increased risk of myopathy/rhabdomyolysis. Limit simvastatin dose to no more than 20 mg/day when used concurrently. .
- rifabutin
rifabutin will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- rifampin
rifampin will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- rifapentine
rifapentine will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- riociguat
simvastatin will increase the level or effect of riociguat by decreasing metabolism. Avoid or Use Alternate Drug. Coadministration of riociguat (substrate of CYP isoenzymes 1A1, 2C8, 3A, 2J2) with strong CYP inhibitors may require a decreased initial dose of 0.5 mg PO TID; monitor for signs of hypotension and reduce dose if needed
- rufinamide
rufinamide will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- secobarbital
secobarbital will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- St John's Wort
St John's Wort will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- topiramate
topiramate will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- trofinetide
trofinetide will increase the level or effect of simvastatin by Other (see comment). Avoid or Use Alternate Drug. Trofinetide (an OATP131 and OATP13B inhibitor) may increase plasma levels of OATP131 or OATP13B substrates. Avoid coadministration with sensitive substrates.
- tucatinib
tucatinib will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.
- verapamil
verapamil will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Do not exceed simvastatin 10 mg daily when given concurrently. Potential for increased risk of myopathy/rhabdomyolysis.
- voriconazole
voriconazole will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Simvastatin prescribing information recommends a reduced simvastatin dose be considered when coadministered with voriconazole to reduce the risk of myopathy, including rhabdomyolysis
- voxelotor
voxelotor will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.
- zafirlukast
zafirlukast will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- zavegepant intranasal
ezetimibe will increase the level or effect of zavegepant intranasal by Other (see comment). Avoid or Use Alternate Drug. NTCP inhibitors may result in a significant increase in systemic exposure of zavegepant (a NTCP substrate).
simvastatin will increase the level or effect of zavegepant intranasal by Other (see comment). Avoid or Use Alternate Drug. NTCP inhibitors may result in a significant increase in systemic exposure of zavegepant (a NTCP substrate).
Monitor Closely (93)
- amitriptyline
simvastatin will increase the level or effect of amitriptyline by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- apalutamide
apalutamide will decrease the level or effect of simvastatin by increasing elimination. Use Caution/Monitor. Apalutamide induces UGT and weakly induces BCRP and may decrease systemic exposure of drugs that are substrates of both UGT and BCRP.
apalutamide will decrease the level or effect of ezetimibe by increasing elimination. Use Caution/Monitor. Apalutamide induces UGT and weakly induces OATP1B1 and may decrease systemic exposure of drugs that are substrates of both UGT and OATP1B1. - atorvastatin
simvastatin will increase the level or effect of atorvastatin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- cholestyramine
cholestyramine decreases levels of ezetimibe by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. Separate by 2-4 hours.
- azithromycin
azithromycin will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- bazedoxifene/conjugated estrogens
simvastatin will increase the level or effect of bazedoxifene/conjugated estrogens by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- bempedoic acid
bempedoic acid increases levels of simvastatin by unknown mechanism. Modify Therapy/Monitor Closely. Avoid concomitant use with simvastatin dose >20 mg.
- budesonide
simvastatin will increase the level or effect of budesonide by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- carbamazepine
carbamazepine will increase the level or effect of simvastatin by Other (see comment). Use Caution/Monitor. OATP1B1 inhibitors may increase risk of myopathy
- caspofungin
caspofungin will increase the level or effect of simvastatin by Other (see comment). Use Caution/Monitor. OATP1B1 inhibitors may increase risk of myopathy
- cenobamate
cenobamate will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increase dose of CYP3A4 substrate, as needed, when coadministered with cenobamate.
- ceritinib
simvastatin increases levels of ceritinib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- cholestyramine
cholestyramine decreases levels of simvastatin by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.
- cholic acid
simvastatin increases toxicity of cholic acid by decreasing elimination. Modify Therapy/Monitor Closely. Avoid concomitant use of inhibitors of the bile salt efflux pump (BSEP). May exacerbate accumulation of conjugated bile salts in the liver and result in clinical symptoms. If concomitant use is necessary, monitor serum transaminases and bilirubin.
- clotrimazole
clotrimazole will increase the level or effect of simvastatin by Other (see comment). Use Caution/Monitor. OATP1B1 inhibitors may increase risk of myopathy
- conjugated estrogens
simvastatin will increase the level or effect of conjugated estrogens by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- conjugated estrogens, vaginal
simvastatin will increase the level or effect of conjugated estrogens, vaginal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- cortisone
simvastatin will increase the level or effect of cortisone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- crizotinib
crizotinib increases levels of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A.
- crofelemer
crofelemer increases levels of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Crofelemer has the potential to inhibit CYP3A4 at concentrations expected in the gut; unlikely to inhibit systemically because minimally absorbed.
- dabrafenib
dabrafenib will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.
- daptomycin
simvastatin, daptomycin. Either increases toxicity of the other by Other (see comment). Modify Therapy/Monitor Closely. Comment: Coadministration of daptomycin with HMG-CoA reductase inhibitors may increase CPK levels and risk for myopathy; consider temporary suspension of HMG-CoA reductase inhibitors during daptomycin therapy.
- deferasirox
deferasirox will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- deflazacort
simvastatin will increase the level or effect of deflazacort by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- dexamethasone
simvastatin will increase the level or effect of dexamethasone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- digoxin
simvastatin will increase the level or effect of digoxin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- docetaxel
simvastatin will increase the level or effect of docetaxel by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- dronedarone
dronedarone will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for signs and symptoms of myopathy in patients receiving dronedarone concurrently with simvastatin
- duvelisib
duvelisib will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration with duvelisib increases AUC of a sensitive CYP3A4 substrate which may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the coadministered sensitive CYP3A substrate.
- efavirenz
efavirenz will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- elagolix
elagolix will increase the level or effect of simvastatin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
elagolix decreases levels of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed. - elbasvir/grazoprevir
elbasvir/grazoprevir increases levels of simvastatin by unknown mechanism. Modify Therapy/Monitor Closely. If coadministered, use lowest necessary simvastatin dose.
- eliglustat
eliglustat increases levels of simvastatin by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Monitor therapeutic drug concentrations, as indicated, or consider reducing the dosage of the P-gp substrate and titrate to clinical effect.
- eluxadoline
eluxadoline increases levels of simvastatin by decreasing metabolism. Use Caution/Monitor. Eluxadoline may increase the systemic exposure of coadministered BCRP substrates. .
- encorafenib
encorafenib will increase the level or effect of ezetimibe by Other (see comment). Modify Therapy/Monitor Closely. Encorafenib (a OATP1B1 inhibitor) may increase the concentration and toxicities of OATP1B1 substrates. Closely monitor for signs and symptoms of increased exposure and consider adjusting the dose of these substrates.
encorafenib, simvastatin. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Encorafenib both inhibits and induces CYP3A4 at clinically relevant plasma concentrations. Coadministration of encorafenib with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents.
encorafenib will increase the level or effect of simvastatin by Other (see comment). Modify Therapy/Monitor Closely. Encorafenib (a OATP1B1, OATP1B3, and BCRP inhibitor) may increase the concentration and toxicities of OATP1B1, OATP1B3, and BCRP substrates. Closely monitor for signs and symptoms of increased exposure and consider adjusting the dose of these substrates. Screen reader support enabled. - eslicarbazepine acetate
eslicarbazepine acetate will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Dose adjustment of some statins may be needed if a clinically significant change in lipids is noted.
- fostemsavir
fostemsavir will increase the level or effect of ezetimibe by Other (see comment). Modify Therapy/Monitor Closely. Fostemsavir inhibits OATP1B1/3 transporter. If possible, avoid coadministration or modify dose of OATP1B1/3 substrates coadministered with fostemsavir.
- estradiol
simvastatin will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- estropipate
simvastatin will increase the level or effect of estropipate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- fedratinib
fedratinib will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP3A4 substrates as necessary.
- fludrocortisone
simvastatin will increase the level or effect of fludrocortisone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- fostemsavir
fostemsavir will increase the level or effect of simvastatin by Other (see comment). Modify Therapy/Monitor Closely. Fostemsavir inhibits OATP1B1/3 and BCRP transporters. If possible, avoid coadministration or modify dose of OATP1B1/3 or BCRP substrates coadministered with fostemsavir. Use lowest possible starting dose for statins and monitor for associated adverse events.
- glecaprevir/pibrentasvir
glecaprevir/pibrentasvir will increase the level or effect of ezetimibe by Other (see comment). Use Caution/Monitor. Coadministration with glecaprevir/pibrentasvir may increase plasma concentration of drugs that are substrates of OATP1B1 or OATP1B3
- glyburide
glyburide increases toxicity of simvastatin by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy.
- hydrocortisone
simvastatin will increase the level or effect of hydrocortisone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- iloperidone
iloperidone increases levels of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Iloperidone is a time-dependent CYP3A inhibitor and may lead to increased plasma levels of drugs predominantly eliminated by CYP3A4.
- irinotecan liposomal
simvastatin will increase the level or effect of irinotecan liposomal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- istradefylline
istradefylline will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of CYP3A4 substrates in clinical trials. This effect was not observed with istradefylline 20 mg/day. Consider dose reduction of sensitive CYP3A4 substrates.
istradefylline will increase the level or effect of simvastatin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of P-gp substrates in clinical trials. Consider dose reduction of sensitive P-gp substrates. - itraconazole
simvastatin will increase the level or effect of itraconazole by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- ivacaftor
ivacaftor increases levels of simvastatin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Ivacaftor and its M1 metabolite has the potential to inhibit P-gp; may significantly increase systemic exposure to sensitive P-gp substrates with a narrow therapeutic index.
- ivermectin
simvastatin will increase the level or effect of ivermectin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- lanthanum carbonate
lanthanum carbonate decreases levels of simvastatin by cation binding in GI tract. Use Caution/Monitor. Administer statin at least 2 hr before or 2 hr after lanthanum. Monitor serum concentrations.
- lenacapavir
lenacapavir will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Initiate simvastatin with the lowest starting dose and titrate carefully while monitoring for safety (eg, myopathy)
- letermovir
letermovir increases levels of ezetimibe by Other (see comment). Use Caution/Monitor. Comment: Letermovir, an OATP1B1/3 inhibitor may increase plasma concentrations of coadministered OATP1B1/3 substrates.
- levamlodipine
levamlodipine will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.
- loperamide
simvastatin will increase the level or effect of loperamide by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- lorlatinib
lorlatinib will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- lovastatin
simvastatin will increase the level or effect of lovastatin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- mestranol
simvastatin will increase the level or effect of mestranol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- methylprednisolone
simvastatin will increase the level or effect of methylprednisolone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- metyrapone
metyrapone increases toxicity of simvastatin by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy.
- mipomersen
mipomersen, simvastatin. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Both drugs have potential to increase hepatic enzymes; monitor LFTs.
- mitotane
mitotane decreases levels of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Mitotane is a strong inducer of cytochrome P-4503A4; monitor when coadministered with CYP3A4 substrates for possible dosage adjustments.
- paclitaxel
simvastatin will increase the level or effect of paclitaxel by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
paclitaxel increases toxicity of simvastatin by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy. - paclitaxel protein bound
simvastatin will increase the level or effect of paclitaxel protein bound by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- paliperidone
simvastatin will increase the level or effect of paliperidone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- pazopanib
simvastatin increases toxicity of pazopanib by Other (see comment). Use Caution/Monitor. Comment: Increased risk of elevated LFTs with pazopanib when coadministered with simvastatin.
pazopanib will increase the level or effect of simvastatin by Other (see comment). Use Caution/Monitor. OATP1B1 inhibitors may increase risk of myopathy - pioglitazone
pioglitazone increases toxicity of simvastatin by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy.
- ponatinib
ponatinib increases levels of simvastatin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
ponatinib increases levels of simvastatin by Other (see comment). Use Caution/Monitor. - posaconazole
simvastatin will increase the level or effect of posaconazole by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- prednisolone
simvastatin will increase the level or effect of prednisolone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- repaglinide
repaglinide increases toxicity of simvastatin by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy.
- ribociclib
ribociclib will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- rifampin
rifampin will increase the level or effect of simvastatin by Other (see comment). Use Caution/Monitor. OATP1B1 inhibitors may increase risk of myopathy
- risperidone
simvastatin will increase the level or effect of risperidone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- rosiglitazone
rosiglitazone increases toxicity of simvastatin by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy.
- sacubitril/valsartan
simvastatin will increase the level or effect of sacubitril/valsartan by Other (see comment). Use Caution/Monitor. The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1; coadministration with OATP1B1 inhibitors may increase valsartan systemic exposure
- sarecycline
sarecycline will increase the level or effect of simvastatin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor for toxicities of P-gp substrates that may require dosage reduction when coadministered with P-gp inhibitors.
- silodosin
simvastatin will increase the level or effect of silodosin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- sirolimus
simvastatin will increase the level or effect of sirolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- sofosbuvir/velpatasvir
sofosbuvir/velpatasvir increases levels of ezetimibe by Other (see comment). Use Caution/Monitor. Comment: Velpatasvir inhibits OATP1B1, OATP1B3, and OATP2B1 transporters. .
sofosbuvir/velpatasvir will increase the level or effect of simvastatin by Other (see comment). Modify Therapy/Monitor Closely. Velpatasvir is an inhibitor of the drug transporter BCRP. Coadministration may increase systemic exposure of drugs that are BCRP substrates. Coadministration may significantly increase simvastatin serum concentration, which is associated with increased risk of myopathy, including rhabdomyolysis. - stiripentol
stiripentol, simvastatin. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP3A4 inhibitor and inducer. Monitor CYP3A4 substrates coadministered with stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment.
stiripentol will increase the level or effect of simvastatin by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Consider reducing the dose of P-glycoprotein (P-gp) substrates, if adverse reactions are experienced when administered concomitantly with stiripentol. - tacrolimus
simvastatin will increase the level or effect of tacrolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
tacrolimus increases toxicity of simvastatin by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy. - tazemetostat
tazemetostat will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- tecovirimat
tecovirimat will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.
- ticagrelor
ticagrelor increases levels of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid simvastatin doses greater than 40 mg.
- tolvaptan
simvastatin will increase the level or effect of tolvaptan by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- valoctocogene roxaparvovec
simvastatin and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.
- valsartan
simvastatin will increase the level or effect of valsartan by Other (see comment). Use Caution/Monitor. The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1; coadministration with OATP1B1 inhibitors may increase valsartan systemic exposure
- vinblastine
simvastatin will increase the level or effect of vinblastine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- vincristine
simvastatin will increase the level or effect of vincristine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- vincristine liposomal
simvastatin will increase the level or effect of vincristine liposomal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- warfarin
simvastatin increases effects of warfarin by anticoagulation. Use Caution/Monitor.
Minor (23)
- acetazolamide
acetazolamide will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
- aliskiren
simvastatin will increase the level or effect of aliskiren by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.
- alvimopan
simvastatin will increase the level or effect of alvimopan by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.
- ambrisentan
simvastatin will increase the level or effect of ambrisentan by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.
- anastrozole
anastrozole will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
- armodafinil
simvastatin will increase the level or effect of armodafinil by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.
- coenzyme Q10
simvastatin decreases levels of coenzyme Q10 by unspecified interaction mechanism. Minor/Significance Unknown.
- colestipol
colestipol decreases levels of simvastatin by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.
- cyclophosphamide
cyclophosphamide will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
- fenofibrate
fenofibrate increases levels of ezetimibe by unspecified interaction mechanism. Minor/Significance Unknown.
- fenofibrate micronized
fenofibrate micronized increases levels of ezetimibe by unspecified interaction mechanism. Minor/Significance Unknown.
- fenofibric acid
fenofibric acid increases levels of ezetimibe by unspecified interaction mechanism. Minor/Significance Unknown.
- fexofenadine
simvastatin will increase the level or effect of fexofenadine by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.
- gemfibrozil
gemfibrozil increases levels of ezetimibe by enhancing GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.
- isradipine
isradipine decreases levels of simvastatin by unknown mechanism. Minor/Significance Unknown.
- larotrectinib
larotrectinib will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
- loratadine
simvastatin will increase the level or effect of loratadine by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.
- orlistat
orlistat increases effects of simvastatin by pharmacodynamic synergism. Minor/Significance Unknown.
- sacubitril/valsartan
sacubitril/valsartan increases toxicity of simvastatin by Other (see comment). Minor/Significance Unknown. Comment: OATP1B1 inhibitors may increase risk of myopathy.
- telmisartan
telmisartan increases toxicity of simvastatin by Other (see comment). Minor/Significance Unknown. Comment: OATP1B1 inhibitors may increase risk of myopathy.
- trazodone
trazodone increases levels of simvastatin by unspecified interaction mechanism. Minor/Significance Unknown.
- valsartan
valsartan increases toxicity of simvastatin by Other (see comment). Minor/Significance Unknown. Comment: OATP1B1 inhibitors may increase risk of myopathy.
- voclosporin
voclosporin will increase the level or effect of ezetimibe by Other (see comment). Minor/Significance Unknown. Information suggests voclosporin (an OATP1B1 inhibitor) may increase in the concentration of OATP1B1 substrates is possible. Monitor for adverse reactions of OATP1B1 substrates when coadministered with voclosporin.
voclosporin will increase the level or effect of simvastatin by Other (see comment). Minor/Significance Unknown. Information suggests voclosporin (an OATP1B1 inhibitor) may increase in the concentration of OATP1B1 substrates is possible. Monitor for adverse reactions of OATP1B1 substrates when coadministered with voclosporin.
Adverse Effects
1-10%
Headache (6.8%)
Upper respiratory tract infection (3.9%)
Myalgia (3.5%)
Increased ALT (4%)
Influenza (2.6%)
Pain in extremity (2.3%)
Postmarketing Reports
Erectile dysfunction
Interstitial lung disease
Rare reports of cognitive impairment (eg, memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use
Warnings
Contraindications
Hypersensitivity to either component
Active liver disease, or unexplained elevated transaminases
Women who are pregnant or may become pregnant
Lactation
Concomitant administration with strong CYP3A4 inhibitors (eg, itraconazole, ketoconazole, erythromycin, clarithromycin, posaconazole, voriconazole, HIV protease inhibitors, nefazodone, cobicistat), fibrates (including gemfibrozil), cyclosporine, and danazol
Cautions
Discontinue if markedly elevated CPK levels occur or myopathy is diagnosed or suspected
Increased HbA1c and fasting serum glucose levels reported with HMG-CoA reductase inhibitors
Avoid use in severe renal impairment
High potential for drug interactions
Liver function
- Monitor liver function tests before initiating treatment and thereafter when clinically indicated; reports of fatal and non-fatal hepatic failure in patients taking statins
- If serious liver injury with clinical symptomsand/or hyperbilirubinemia or jaundice occurs during treatment, promptly interrupt therapy; ifan alternate etiology not found do not restart therapy
- Note that ALT may emanate from muscle,therefore ALT rising with CK may indicate myopathy
- Therapy should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease; active liver diseases or unexplained persistent transaminase elevations are contraindications to the use of this medication
Simvastatin and myopathy risk
- Dose adjustment required when coadministered with niacin, amiodarone, verapamil, diltiazem, amlodipine, and ranolazine
- Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment; chinese patients may be at increased risk for myopathy
- Risk of myopathy is increased by elevated plasma levels of simvastatin and simvastatin acid
- In clinical trials, the incidence of myopathy, including rhabdomyolysis, was highest during first year and then notably decreased during subsequent years of treatment
- Patients should be advised of increased risk of myopathy, including rhabdomyolysis, and to report promptly any unexplained muscle pain, tenderness or weakness; if symptoms occur, treatment should be discontinued immediately
- Therapy should be temporarily withheld in any patient experiencing acute or serious condition predisposing to development of renal failure secondary to rhabdomyolysis, eg, sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy
- Risk of myopathy is greater in patients taking simvastatin 80 mg/day, especially in the 1st year of treatment
- The 10/80-mg dose should be used only in patients who have been taking the 10/80 mg dose chronically (eg, for 12 months or more) without evidence of muscle toxicity; if, however, a patient who is currently tolerating the 10/80-mg dose needs to be initiated on interacting drug that is contraindicated or associated with dose cap for simvastatin, patient should be switched to an alternative statin or statin-based regimen with less potential for drug-drug interaction
Immune-mediated necrotizing myopathy
- Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, reported with statin use
- IMNM is characterized by muscle biopsy showing necrotizing myopathy without significant inflammation improvement with immunosuppressive agents, proximal muscle weakness, and elevated serum creatine kinase, which persist despite discontinuation of statin treatment
- Treatment with immunosuppressive agents may be required
- Advice all patients starting therapy or whose dose is being increased, about the risk of myopathy, including rhabdomyolysis
- Patients should report promptly any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing therapy; additional neuromuscular and serologic testing may be necessary
- Therapy should be discontinued immediately if myopathy is diagnosed or suspected
- Discontinue therapy if markedly elevated creatine kinase (CK) levels occur or if myopathy diagnosed or suspected
- Therapy should be temporarily withheld in any patient experiencing an acute or serious condition predisposing to development of renal failure secondary to rhabdomyolysis, eg, sepsis; hypotension; dehydration; major surgery; trauma; severe metabolic, endocrine, and electrolyte disorders; or uncontrolled epilepsy
- Consider risk of IMNM carefully prior to initiation of a different statin
- If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM
- Additional neuromuscular and serologic testing may be necessary
- Treatment with immunosuppressive agents may be required
- Consider risk of IMNM carefully prior to initiation of a different statin
- If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM
Coadministration with niacin
- Myopathy/rhabdomyolysis observed with simvastatin coadministered with lipid-modifying niacin doses (ie, ≥1 g/day); also observed when coadministered with daptomycin
- Risk of myopathy is greater in Chinese patients, and therefore, coadministration of simvastatin with lipid-modifying niacin doses is not recommended in Chinese patients
- Unknown if this risk applies to other patients of Asian descent
Pregnancy & Lactation
Pregnancy
Contraindicated in women who are or may become pregnant
Lipid lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development
Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy
There are no adequate and well-controlled studies of use with statins during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero
Lactation
Unknown if simvastatin excreted in human milk; because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not breastfeed
A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Simvastatin: HMG-CoA reductase inhibitor, inhibits the rate-limiting step in cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase
Ezetimibe: Inhibits intestinal absorption of cholesterol at brush border
Pharmacokinetics
Simvastatin
- Onset: >3 days; 2 weeks (peak effect)
- Bioavailability: <5%
- Protein binding: 95%
- Peak plasma time: 1.3-2.4 hr
- Excretion: Feces (60%); urine (13%)
Ezetimibe
- Bioavailability: Variable
- Peak plasma time: 4-12 hr
- Excretioin: Feces (78%); urine (11%)
- Half-life: 22 hr
- Metabolism: Undergoes glucuronide conjugation in the small intestine and liver
Pharmacogenomics
SLCO1B1 (OATP1B1) CC genotype significantly increases AUCs of parent drug and metabolites compared with the CT or TT genotypes
This polymorphism is proposed to reduced transport into the liver, the main site of statin metabolism and elimination, resulting in elevated plasma concentrations
SLCO1B1 polymorphism is thought to have a lesser effect on the more hydrophilic statins (eg, rosuvastatin, fluvastatin) compared with more those that are more lipophilic (eg, atorvastatin, pravastatin, simvastatin)
Other genetic polymorphisms of elimination (eg, CYP450, P-glycoprotein) for each individual drug must also be considered to explain variability for statin clearance among patients that exhibit SCLO1B1 polymorphism
SLCO1B1 CC genotype is most common in Caucasians and Asians (15%)
Risk of myopathy is 2.6- to 4.3-fold higher if the C allele is present and 16.9-fold higher in CC homozygotes compared with TT homozygotes
Genetic testing laboratories
- Optivia Biotechnology, Inc (http://optiviabio.com/index.html)
Administration
Oral Administration
Patient should be placed on standard cholesterol-lowering diet before receiving drug
Administer >2 hr before or >4 hr after bile acid sequestrant (eg, cholestyramine)
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Formulary
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