Simcor

HMG-CoA Reductase Inhibitors/Statins and Other Lipid Modifying Agent Combinations

Oral Administration

Administer at bedtime, with a low-fat snack. Since peak cholesterol synthesis occurs in the early morning hours, evening dosing is preferable. Administration on an empty stomach is not recommended. To minimize flushing, avoid alcohol, hot beverages, and spicy foods around the time of administration.
Tablets should be taken whole and should not be broken, crushed, or chewed before swallowing.
Niacin-induced flushing of the skin may be reduced in frequency or severity by pretreatment with a dose (e.g., 325 mg) of aspirin (taken up to about 30 minutes prior to the niacin dose) or an NSAID product such as ibuprofen, if appropriate for the individual patient.

Severe

immune-mediated necrotizing myopathy / Delayed / 0-1.0
rhabdomyolysis / Delayed / 0-1.0
lupus-like symptoms / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
vasculitis / Delayed / Incidence not known
hemolytic anemia / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
erythema multiforme / Delayed / Incidence not known
laryngeal edema / Rapid / Incidence not known
peptic ulcer / Delayed / Incidence not known
renal tubular obstruction / Delayed / Incidence not known
myoglobinuria / Delayed / Incidence not known
cirrhosis / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
hepatic necrosis / Delayed / Incidence not known
muscle paralysis / Delayed / Incidence not known

Moderate

constipation / Delayed / 2.3-2.3
myopathy / Delayed / 0-0.6
angina / Early / Incidence not known
edema / Delayed / Incidence not known
orthostatic hypotension / Delayed / Incidence not known
dyspnea / Early / Incidence not known
sinus tachycardia / Rapid / Incidence not known
peripheral vasodilation / Rapid / Incidence not known
hypotension / Rapid / Incidence not known
palpitations / Early / Incidence not known
bullous rash / Early / Incidence not known
peripheral edema / Delayed / Incidence not known
eosinophilia / Delayed / Incidence not known
leukopenia / Delayed / Incidence not known
myasthenia / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
cholestasis / Delayed / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known
peripheral neuropathy / Delayed / Incidence not known
amnesia / Delayed / Incidence not known
impotence (erectile dysfunction) / Delayed / Incidence not known
depression / Delayed / Incidence not known
confusion / Early / Incidence not known
diabetes mellitus / Delayed / Incidence not known
hyperglycemia / Delayed / Incidence not known
hyperuricemia / Delayed / Incidence not known
hypophosphatemia / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
blurred vision / Early / Incidence not known
cataracts / Delayed / Incidence not known
interstitial lung disease / Delayed / Incidence not known
dysphagia / Delayed / Incidence not known
dysarthria / Delayed / Incidence not known

Mild

flushing / Rapid / 0-59.0
rhinitis / Early / 5.0-5.0
headache / Early / 4.5-4.5
dyspepsia / Early / 4.0-4.0
abdominal pain / Early / 3.5-3.5
pruritus / Rapid / 3.2-3.2
nausea / Early / 3.2-3.2
back pain / Delayed / 3.2-3.2
diarrhea / Early / 3.0-3.0
infection / Delayed / 2.1-2.1
flatulence / Early / 1.9-1.9
syncope / Early / Incidence not known
dizziness / Early / Incidence not known
diaphoresis / Early / Incidence not known
chills / Rapid / Incidence not known
vesicular rash / Delayed / Incidence not known
rash (unspecified) / Early / Incidence not known
photosensitivity / Delayed / Incidence not known
malaise / Early / Incidence not known
maculopapular rash / Early / Incidence not known
urticaria / Rapid / Incidence not known
asthenia / Delayed / Incidence not known
purpura / Delayed / Incidence not known
fever / Early / Incidence not known
arthralgia / Delayed / Incidence not known
myalgia / Early / Incidence not known
vomiting / Early / Incidence not known
drowsiness / Early / Incidence not known
muscle cramps / Delayed / Incidence not known
musculoskeletal pain / Early / Incidence not known
fatigue / Early / Incidence not known
insomnia / Early / Incidence not known
paresthesias / Delayed / Incidence not known
alopecia / Delayed / Incidence not known
skin discoloration / Delayed / Incidence not known

Simcor

Rx

Oral antilipemic combination product
Reduces TC, LDL-C, non-HDL-C, Apo B, TG, and increases HDL cholesterol in patients with primary type II hyperlipidemia, mixed dyslipidemia, or hypertriglyceridemia when monotherapy with niacin extended-release or simvastatin is inadequate
Compared to monotherapy with simvastatin or niacin, no additional cardiovascular morbidity or mortality benefit has been found with combination therapy

For the reduction of elevated total cholesterol, LDL-cholesterol, apolipoprotein B, non-HDL cholesterol, or triglyceride concentrations, and to increase HDL-cholesterol in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson types IIa or IIb hyperlipoproteinemia); or to treat Fredrickson Type IV (hypertriglyceridemia, increased VLDL).
NOTE: Because of the risk of hepatotoxicity related with sustained-release or time-release niacin preparations or immediate-release (crystalline) niacin, the combination product niacin; simvastatin should only be substituted for equivalent doses of niacin extended release (Niaspan).
Oral dosage Adults

For patients not currently taking extended-release niacin and patients currently taking niacin products other than extended-release formulations, the initial dose is 500 mg/20 mg PO once daily at bedtime with a low-fat snack. For patients already taking simvastatin 20—40 mg, an initial dose of 500 mg/40 mg may be used. The niacin component should not be increased by more than 500 mg/day PO every 4 weeks. The recommended maintenance dose is 1000 mg/20 mg to 2000 mg/40 mg PO once daily depending on patient tolerability and lipid profile. Safety and efficacy have not been studied in doses greater than 2000 mg/40 mg daily. If niacin; simvastatin is discontinued for more than 7 days, titrating the dose again is recommended. Flushing may be reduced by the administration of aspirin 30 minutes prior to niacin; simvastatin. NOTE: Doses of niacin; simvastatin greater than 1000 mg/20 mg PO daily should be used cautiously in Chinese patients because of the increased risk of myopathy when taking lipid-modifying doses of niacin-containing products coadministered with simvastatin (see Contraindications/Precautions).

Adults taking amiodarone, amlodipine, or ranolazine

Follow general initial dosages and titration schedule; however, because of the risk of developing myopathy and/or rhabdomyolysis, do not exceed 1000 mg/20 mg PO per day.

Hepatic Impairment

Niacin; simvastatin use is contraindicated in patients with hepatic disease.

Renal Impairment

Use with caution in patients with renal disease. Niacin; simvastatin should only be administered to patients with severe renal disease if the patient has tolerated simvastatin at a daily dose of 10 mg or higher, and caution should be exercised in these patients.

Acarbose: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Acetohexamide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Albiglutide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients on antidiabetic therapy for blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen and adjust dosages as clinically warranted (Minor) Coadministration of albiglutide with simvastatin results in an increased Cmax of simvastatin and its active metabolite simvastatin acid by approximately 18% and 98%, respectively. In the same trial, AUC of simvastatin decreased by 40% and AUC of simvastatin acid increased by 36%. The mechanism of the interaction is not known, nor is the clinical significance of this potential interaction. If simvastatin and albiglutide are co-prescribed, it may be prudent to initially monitor the patient for altered simvastatin effect.
Aliskiren; Amlodipine: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Alogliptin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Alogliptin; Metformin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary. (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Alogliptin; Pioglitazone: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Alpha-blockers: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Alpha-glucosidase Inhibitors: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Amiodarone: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amiodarone due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amiodarone, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amiodarone and simvastatin against the potential risks. Amiodarone increases the simvastatin exposure by approximately 2-fold.
Amlodipine: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Amlodipine; Atorvastatin: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold. (Moderate) The risk of myopathy increases when HMG-Co-A reductase inhibitors are administered concurrently with antilipemic doses of niacin (i.e., 1 g per day or more). Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Amlodipine; Benazepril: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Amlodipine; Olmesartan: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Amlodipine; Telmisartan: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Amlodipine; Valsartan: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Amoxicillin; Clarithromycin; Lansoprazole: (Severe) The concurrent use of clarithromycin and simvastatin is contraindicated due to the risk of myopathy and rhabdomyolysis. If no alternative to a short course of clarithromycin therapy is available, simvastatin use must be suspended during clarithromycin treatment. Simvastatin is metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4.
Amoxicillin; Clarithromycin; Omeprazole: (Severe) The concurrent use of clarithromycin and simvastatin is contraindicated due to the risk of myopathy and rhabdomyolysis. If no alternative to a short course of clarithromycin therapy is available, simvastatin use must be suspended during clarithromycin treatment. Simvastatin is metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4.
Amprenavir: (Severe) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Angiotensin II receptor antagonists: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Angiotensin-converting enzyme inhibitors: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Aprepitant, Fosaprepitant: (Moderate) Use caution if simvastatin and aprepitant, fosaprepitant are used concurrently and monitor for an increase in simvastatin-related adverse effects, including myopathy and rhabdomyolysis, for several days after administration of a multi-day aprepitant regimen. Simvastatin is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of simvastatin. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aspirin, ASA; Pravastatin: (Moderate) The risk of myopathy increases when HMG-Co-A reductase inhibitors are administered concurrently with antilipemic doses of niacin (i.e., 1 g per day or more). Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Atazanavir: (Severe) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Atazanavir; Cobicistat: (Severe) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor. (Severe) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Atorvastatin: (Moderate) The risk of myopathy increases when HMG-Co-A reductase inhibitors are administered concurrently with antilipemic doses of niacin (i.e., 1 g per day or more). Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Atorvastatin; Ezetimibe: (Moderate) The risk of myopathy increases when HMG-Co-A reductase inhibitors are administered concurrently with antilipemic doses of niacin (i.e., 1 g per day or more). Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Moderate) HMG-CoA reductase inhibitors have been administered safely with niacin (nicotinic acid) in some patients; however the risk of potential myopathy should be considered. Rare cases of rhabdomyolysis have been reported in patients taking niacin (nicotinic acid) in lipid-altering doses (i.e., >=1 g/day) and HMG-CoA reductase inhibitors (Statins) concurrently. The serious risk of myopathy or rhabdomyolysis should be carefully weighed against the potential risks. Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy.
Barbiturates: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with simvastatin, which is metabolized by CYP3A4.
Beta-blockers: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Bile acid sequestrants: (Moderate) In vitro studies have shown that bile acid sequestrants bind niacin. Roughly 98% of niacin was bound to colestipol, and 10 to 30% of niacin was bound to cholestyramine. These results suggest that at least 4 to 6 hours should elapse between the ingestion of bile-acid-binding resins and the administration of niacin.
Boceprevir: (Severe) The concurrent use of simvastatin and boceprevir is contraindicated due to the potential for serious/life-threatening reactions. Boceprevir is a potent inhibitor of CYP3A4, which is responsible simvastatin metabolism. Coadministration may result in large increases in simvastatin serum concentrations, which could cause adverse events such as myopathy and rhabdomyolysis.
Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like HMG-CoA reductase inhibitors; the risk of peripheral neuropathy may be additive.
Bosentan: (Moderate) Co-administration of bosentan decreases the plasma concentrations of simvastatin, a CYP3A4 substrate, and its active metabolite, by approximately 50%. The possibility of reduced anti-lipemic efficacy should be considered. Patients receiving simvastatin should have cholesterol levels monitored after adding bosentan therapy to evaluate the need for anti-lipemic dosage adjustment.
Brigatinib: (Moderate) Monitor for decreased efficacy of simvastatin if coadministration with brigatinib is necessary. Simvastatin is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of simvastatin may decrease.
Calcium-channel blockers: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents, especially calcium-channel blockers. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Canagliflozin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Canagliflozin; Metformin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary. (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Carbamazepine: (Moderate) Niacin may inhibit the CYP3A4 metabolism of carbamazepine, resulting in elevated carbamazepine plasma concentrations. Serum carbamazepine concentrations should be monitored if niacin is added during carbamazepine therapy. It may be necessary to reduce the dose of carbamazepine. (Minor) Carbamazepine, which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates, including simvastatin.
Central-acting adrenergic agents: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise. Clonidine has been shown to inhibit niacin-induced flushing. The interaction is harmless unless niacin augments the hypotensive actions of clonidine.
Ceritinib: (Major) Avoid coadministration of ceritinib with simvastatin due to increased simvastatin exposure. If coadministration is unavoidable, monitor for simvastatin-related adverse reactions, including myopathy and rhabdomyolysis. Ceritinib is a CYP3A4 inhibitor and simvastatin is primarily metabolized by CYP3A4.
Cerivastatin: (Severe) The risk of myopathy increases when HMG-Co-A reductase inhibitors are administered concurrently with antilipemic doses of niacin.
Chlorpropamide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Cimetidine: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administion of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
Ciprofloxacin: (Moderate) Use caution and monitor for evidence of myopathy, including rhabdomyolysis, during coadministration of ciprofloxacin and simvastatin. There are case reports of rhabdomyolysis in patients stabilized on a simvastatin regimen after the addition of ciprofloxacin. Simvastatin is a substrate for CYP3A4; ciprofloxacin is a weak inhibitor of CYP3A4. Coadministration of simvastatin with CYP3A4 inhibitors may significantly increase the exposure to simvastatin. However, because ciprofloxacin is a weak inhibitor of CYP3A4, it has been theorized that other mechanisms, including P-glycoprotein (P-gp) or multiple drug resistance associated proteins (MRPs) may contribute to this potential interaction.
Clarithromycin: (Severe) The concurrent use of clarithromycin and simvastatin is contraindicated due to the risk of myopathy and rhabdomyolysis. If no alternative to a short course of clarithromycin therapy is available, simvastatin use must be suspended during clarithromycin treatment. Simvastatin is metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4.
Clopidogrel: (Minor) Theoretically, clopidogrel may interact with simvastatin. CYP3A4 is involved in the hepatic biotransformation of clopidogrel to its active metabolite. Atorvastatin, a CYP3A4 substrate, has been reported to attenuate the antiplatelet activity of clopidogrel possibly by the competitive inhibition of CYP3A4 metabolism of clopidogrel to its active metabolite; however, conflicting data exists. The clinical significance of this theoretical interaction is not known. Simvastatin also is a CYP3A4 substrate and may theoretically be involved in the competitive inhibition of the CYP3A4 metabolism of clopidogrel. Patients should be monitored for a possible decrease in efficacy when clopidogrel is administered with simvastatin.
Cobicistat: (Severe) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor.
Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Severe) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor.
Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Severe) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor.
Colchicine: (Moderate) Case reports exist describing the development of myotoxicity (i.e., muscle pain and weakness, rhabdomyolysis) with the concurrent administration of colchicine and HMG-CoA reductase inhibitors (Statins). Statins involved in the reported cases include simvastatin, atorvastatin, fluvastatin, lovastatin, and pravastatin. The pharmacokinetic and/or pharmacodynamic mechanism of this interaction is not clear; however, both colchicine and statins are associated with the development of myotoxicity and concurrent use may increase the risk of myotoxicity. Patients receiving these agents concurrently should be monitored for myotoxicity.
Conivaptan: (Severe) Coadministration of conivaptan and simvastatin is contraindicated due to increased simvastatin exposure and potential for rhabdomyolysis. If treatment with conivaptan is necessary, suspend simvastatin therapy. Subsequent treatment with simvastatin may be initiated no sooner than 1 week after completion of conivaptan therapy. Conivaptan 30 mg/day IV results in a 3-fold increase in the AUC of simvastatin.
Cyclosporine: (Severe) 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.
Dabrafenib: (Major) The concomitant use of dabrafenib and simvastatin may lead to decreased simvastatin concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of simvastatin efficacy. Dabrafenib is a moderate CYP3A4 inducer and simvastatin is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
Daclatasvir: (Moderate) 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: (Severe) The use of simvastatin with danazol is contraindicated due to an increased risk of myopathy and rhabdomyolysis. A single case report has documented the onset of myositis that progressed to rhabdomyolysis with myoglobinuria after danazol was added to a regimen containing lovastatin. Although other drugs were in use concurrently, a drug interaction between danazol and lovastatin is suspected, as danazol (CYP3A4 inhibitor) is known to inhibit lovastatin metabolism.
Dapagliflozin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Dapagliflozin; Metformin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary. (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Dapagliflozin; Saxagliptin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Daptomycin: (Moderate) Daptomycin has been associated with elevated CPK in clinical trials. HMG-CoA reductase inhibitors are known to cause myopathy. Since data regarding co-administration of daptomycin with HMG-CoA reductase inhibitors are limited, temporary suspension of HMG-CoA reductase inhibitor therapy should be considered in patients receiving daptomycin.
Darunavir: (Severe) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Darunavir; Cobicistat: (Severe) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor. (Severe) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) Coadministration of paritaprevir may increase simvastatin exposure. Paritaprevir is an inhibitor of OATP1B1/3; simvastatin is a substrate of OATP1B1/3. (Severe) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Dasatinib: (Moderate) Use dasatinib and simvastatin together with caution; increased simvastatin levels and exposure have been reported. The mean simvastatin Cmax and AUC values were increased by 37% and 20%, respectively, after a single 100-mg dose of dasatinib was administered with simvastatin in 54 healthy subjects. Simvastatin is a CYP3A4 substrate and dasatinib is a weak CYP3A4 inhibitor.
Deferasirox: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as simvastatin. If these drugs are used together, monitor patients for a decrease in the effects of simvastatin.
Delavirdine: (Severe) The risk of myopathy, including rhabdomyolysis, may be increased when delavirdine is given in combination with HMG-CoA reductase inhibitors. Concomitant use of delavirdine and the CYP3A4 substrate simvastatin is not recommended. If treatment with an HMG-CoA reductase inhibitor is necessary, pravastatin should also be considered, since it is not significantly metabolized by CYP3A4 or CYP2C9 isoenzymes.
Digoxin: (Moderate) Simvastatin causes a slight elevation of serum digoxin levels. Simvastatin should be used cautiously in patients receiving digoxin.
Diltiazem: (Major) Do not exceed a simvastatin dose of 10 mg/day and a diltiazem dose of 240 mg/day if coadministered due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on diltiazem, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of diltiazem and simvastatin against the potential risks. Diltiazem increases the simvastatin exposure by approximately 5-fold. The interaction is presumed due to increased simvastatin bioavailability via inhibition of CYP3A4 metabolism by diltiazem.
Dronedarone: (Major) Do not exceed a simvastatin dose of 10 mg/day in patients taking dronedarone due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on dronedarone, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of dronedarone and simvastatin against the potential risks. Dronedarone increases the simvastatin exposure by approximately 4-fold.
Dulaglutide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients on antidiabetic therapy for blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen and adjust dosages as clinically warranted
Efavirenz: (Moderate) Efavirenz has potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with simvastatin with caution.
Efavirenz; Emtricitabine; Tenofovir: (Moderate) Efavirenz has potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with simvastatin with caution.
Elbasvir; Grazoprevir: (Moderate) The manufacturer of elbasvir; grazoprevir recommends caution during concurrent administration with simvastatin. Although this interaction has not been studied, use of these drugs together may result in elevated simvastatin plasma concentrations. Use the lowest effective simvastatin dose and monitor patients for statin-related adverse events (such as myopathy). Simvastatin is a substrate for the hepatic enzymes CYP3A; grazoprevir is a weak CYP3A inhibitor.
Eltrombopag: (Moderate) Use caution and monitor for adverse reactions if eltrombopag and simvastatin are coadministered. Eltrombopag is an inhibitor of the transporter OATP1B1. Drugs that are substrates for this transporter, such as simvastatin, may exhibit an increase in systemic exposure if coadministered with eltrombopag.
Empagliflozin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Empagliflozin; Linagliptin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Empagliflozin; Metformin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary. (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Eplerenone: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Epoprostenol: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents, especially epoprostenol. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Erlotinib: (Moderate) Concomitant use of erlotinib and HMG-coA reductase inhibitors (statins) may increase the risk for statin-induced myopathy. Myopathy and rhabdomyolysis has been observed rarely with concurrent use of statins and erlotinib during post-market use. The mechanism for this interaction is not known. Use erlotinib and statins together with caution and monitor for signs or symptoms of statin-related adverse events including myopathy (e.g., muscle pain or weakness) and rhabdomyolysis (e.g., nausea/vomiting, dark colored urine).
Erythromycin: (Severe) Erythromycin is contraindicated during simvastatin therapy. Erythromycin potently inhibits the metabolism of simvastatin via the CYP3A4 isoenzyme and increases the risk of myopathy and rhabdomyolysis. According to the manufacturer, if no alternative to a short course of erythromycin therapy is available, therapy with simvastatin must be suspended during the course of erythromycin treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
Erythromycin; Sulfisoxazole: (Severe) Erythromycin is contraindicated during simvastatin therapy. Erythromycin potently inhibits the metabolism of simvastatin via the CYP3A4 isoenzyme and increases the risk of myopathy and rhabdomyolysis. According to the manufacturer, if no alternative to a short course of erythromycin therapy is available, therapy with simvastatin must be suspended during the course of erythromycin treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
Eslicarbazepine: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as simvastatin, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of simvastatin if coadministered with eslicarbazepine. Adjust the dose of simvastatin if clinically significant alterations in serum lipds are noted.
Ethanol: (Moderate) Ethanol-containing beverages or hot beverages/foods can exacerbate cutaneous vasodilation caused by niacin and should be avoided around the time of niacin ingestion. In general, this interaction would not be harmful, but might decrease patient tolerance of niacin. Ethanol and niacin, particularly sustained-release niacin, are both potentially hepatotoxic. Although no data are available regarding enhanced hepatotoxicity, excessive ethanol use should be discouraged.
Etravirine: (Moderate) The risk of myopathy, including rhabdomyolysis, may be increased when antiretrovirals are given in combination with HMG-CoA reductase inhibitors. Concomitant use of etravirine and simvastatin (CYP3A4 substrate) may result in lower plasma concentrations of the HMG-CoA reductase inhibitor; dose adjustments for may be necessary.
Exenatide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients on antidiabetic therapy for blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen and adjust dosages as clinically warranted
Ezetimibe; Simvastatin: (Moderate) The risk of myopathy increases when HMG-Co-A reductase inhibitors are administered concurrently with antilipemic doses of niacin (i.e., 1 g per day or more). Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Fenofibrate: (Major) Fenofibrate and simvastatin should administered concomitantly only with caution. Fenofibrate may increase the risk of myopathy, rhabdomyolysis, and acute renal failure; this risk is increased with higher doses of simvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Fenofibric Acid: (Major) Fenofibric Acid and simvastatin should administered concomitantly only with caution. Fenofibric Acid may increase the risk of myopathy, rhabdomyolysis, and acute renal failure. This risk of myopathy, rhabdomyolysis, and acute renal failure is increased with higher doses of simvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Flibanserin: (Moderate) In a cross-over study in 12 healthy men and women, the effect of flibanserin 50 mg twice daily for 4 days on the pharmacokinetics of simvastatin 40 mg once daily was evaluated. Flibanserin increased the AUC of simvastatin, a substrate of CYP3A4, by 1.3-fold and the Cmax by 1.2-fold. The AUC and Cmax of simvastatin acid were increased by 1.5-fold and 1.4-fold, respectively.
Fluconazole: (Major) The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with CYP3A4 inhibitors including systemic fluconazole. There are no known adverse effects with short-term discontinuation of simvastatin; discontinuation of simvastatin may be advisable when concurrent short-term therapy with systemic fluconazole is needed.
Fluvastatin: (Moderate) The risk of myopathy increases when HMG-Co-A reductase inhibitors are administered concurrently with antilipemic doses of niacin (i.e., 1 g per day or more). Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Fluvoxamine: (Moderate) Coadministration of fluvoxamine (CYP3A4 inhibitor) and simvastatin (CYP3A4 substrate) would be expected to result in an increase in simvastatin serum concentrations. Elevation of simvastatin serum concentrations can increase the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. Monitor patients receiving concomitant simvastatin and fluvoxamine closely for muscle pain or weakness.
Food: (Moderate) Hot beverages and foods can exacerbate cutaneous vasodilation caused by niacin and should be avoided around the time of niacin ingestion. In general, this interaction would not be harmful, but might decrease patient tolerance of niacin.
Fosamprenavir: (Severe) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Gemfibrozil: (Severe) The use of simvastatin with gemfibrozil is contraindicated due to an increased risk for myopathy and rhabdomyolysis. Gemfibrozil can cause myopathy when used alone, and the risk of myopathy and rhabdomyolysis is increased by concomitant use with simvastatin. In addition, the AUC and Cmax of simvastatin are increased with concomitant gemfibrozil use. This may be due to inhibition of OATP1B1 by gemfibrozil; simvastatin is a substrate of OATP1B1.
Glecaprevir; Pibrentasvir: (Major) Coadministration of glecaprevir with simvastatin is not recommended due to an increased risk of myopathy, including rhabdomyolysis. Coadministration may increase the plasma concentrations of simvastatin. Simvastatin is a substrate of OATP1B1/3; glecaprevir is an inhibitor of OATP1B1/3. In drug interaction studies, coadministration of simvastatin with glecaprevir; pibrentasvir resulted in more than a 2-fold increase in the AUC of simvastatin. (Major) Coadministration of pibrentasvir with simvastatin is not recommended due to an increased risk of myopathy, including rhabdomyolysis. Coadministration may increase the plasma concentrations of simvastatin. Simvastatin is a substrate of the drug transporters OATP1B1/3; pibrentasvir is an inhibitor of OATP1B1/3. In drug interaction studies, coadministration of simvastatin with glecaprevir; pibrentasvir resulted in more than a 2-fold increase in the AUC of simvastatin.
Glimepiride: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Glimepiride; Pioglitazone: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Glimepiride; Rosiglitazone: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Glipizide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Glipizide; Metformin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary. (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Glyburide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Glyburide; Metformin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary. (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Grapefruit juice: (Major) Large quantities of grapefruit juice are contraindicated during simvastatin therapy due to the increased risk of myopathy. Grapefruit juice contains compounds that inhibits the CYP3A4 isozyme in the gut wall. Coadministration with grapefruit juice increases the peak serum concentrations and the AUC of lovastatin and may have a similar effect on the serum concentrations of simvastatin. Grapefruit juice should be avoided or minimized in patients taking simvastatin to avoid the potential for myopathy and rhabdomyolysis.
HMG-CoA reductase inhibitors: (Moderate) The risk of myopathy increases when HMG-Co-A reductase inhibitors are administered concurrently with antilipemic doses of niacin (i.e., 1 g per day or more). Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Hydantoins: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, such as simvastatin, leading to reduced efficacy of simvastatin.
Hydrochlorothiazide, HCTZ; Propranolol: (Minor) After administration of single doses of simvastatin and propranolol, there was a significant decrease in mean Cmax, with no change in AUC, of simvastatin. The clinical significance of this interaction is unknown. Monitor for potential reduced cholesterol-lowering efficacy when propranolol is coadministered with niacin; simvastatin.
Idelalisib: (Severe) Coadministration of idelalisib, a strong CYP3A inhibitor, with simvastatin, a CYP3A substrate, is contraindicated as simvastatin toxicities, including the risk for myopathy, may be significantly increased. Consider an alternative to simvastatin.
Iloprost: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Imatinib: (Major) Imatinib, STI-571 inhibits the metabolism of simvastatin via CYP3A4. Concurrent use of simvastatin and imatinib resulted in 2- and 3.5-fold increases in simvastatin Cmax and AUC values, respectively. Increases in serum concentrations of simvastatin may lead to myopathy and rhabdomyolysis.
Incretin Mimetics: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients on antidiabetic therapy for blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen and adjust dosages as clinically warranted
Indinavir: (Severe) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Insulin Degludec; Liraglutide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients on antidiabetic therapy for blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen and adjust dosages as clinically warranted
Insulin Glargine; Lixisenatide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients on antidiabetic therapy for blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen and adjust dosages as clinically warranted
Insulins: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when niacin, niacinamide is instituted or discontinued. Dosage adjustments may be necessary. Niacin interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy.
Isavuconazonium: (Moderate) Closely monitor for evidence of myopathy, including rhabdomyolysis if simvastatin and isavuconazonium are coadministered. Concomitant use of isavuconazonium with simvastatin may result in

increased serum concentrations of simvastatin. Simvastatin is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of CYP3A4.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
Isoniazid, INH; Rifampin: (Moderate) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
Itraconazole: (Severe) Simvastatin is contraindicated for use during and for 2 weeks after itraconazole therapy. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as itraconazole. If therapy with itraconazole is unavoidable, simvastatin therapy must be suspended during the course of itraconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
Ivacaftor: (Minor) Use caution when administering ivacaftor and simvastatin concurrently. Coadministration of ivacaftor with simvastatin may increase simvastatin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined. Simvastatin is a sensitive CYP3A4 substrate; ivacaftor is a weak CYP3A4 inhibitor.
Ketoconazole: (Severe) Concurrent use of simvastatin and ketoconazole is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as ketoconazole. If therapy with ketoconazole is unavoidable, simvastatin therapy must be suspended during the course of ketoconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
Lanthanum Carbonate: (Major) To limit absorption problems, HMG-CoA reductase inhibitors ("statins") should not be taken within 2 hours of dosing with lanthanum carbonate. Oral drugs known to interact with cationic antacids, like statin cholesterol treatments, may also be bound by lanthanum carbonate. Separate the times of administration appropriately. Monitor the patient's lipid profile to ensure the appropriate response to statin therapy is obtained.
Letermovir: (Major) Use of simvastatin with letermovir is not recommended due to increased simvastatin exposure. Concurrent use is contraindicated if the patient is also receiving cyclosporine. Administering letermovir with simvastatin significantly increases simvastatin concentration and risk for myopathy or rhabdomyolysis. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Simvastatin is a sensitive substrate of CYP3A4 and the organic anion-transporting polypeptide (OATP1B1). Both letermovir and cyclosporine are moderate CYP3A4 inhibitors and inhibitors of OATP1B1.
Linagliptin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Linagliptin; Metformin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary. (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Liraglutide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients on antidiabetic therapy for blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen and adjust dosages as clinically warranted
Lixisenatide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients on antidiabetic therapy for blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen and adjust dosages as clinically warranted
Lomitapide: (Major) Reduce the simvastatin dose by 50% when starting lomitapide due to an increased risk for myopathy, including rhabdomyolysis. In patients taking lomitapide, do not exceed a simvastatin dose of 20 mg/day in general, or 40 mg/day in patients who have previously tolerated simvastatin 80 mg/day for at least 1 year without evidence of muscle toxicity. For patients chronically receiving simvastatin 80 mg/day who need to be started on lomitapide, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of lomitapide and simvastatin against the potential risks. Lomitapide increases the simvastatin exposure by approximately 2-fold.
Loop diuretics: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Lopinavir; Ritonavir: (Severe) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Lovastatin: (Moderate) The risk of myopathy increases when HMG-Co-A reductase inhibitors are administered concurrently with antilipemic doses of niacin (i.e., 1 g per day or more). Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Lovastatin; Niacin: (Moderate) The risk of myopathy increases when HMG-Co-A reductase inhibitors are administered concurrently with antilipemic doses of niacin (i.e., 1 g per day or more). Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Lumacaftor; Ivacaftor: (Minor) Use caution when administering ivacaftor and simvastatin concurrently. Coadministration of ivacaftor with simvastatin may increase simvastatin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined. Simvastatin is a sensitive CYP3A4 substrate; ivacaftor is a weak CYP3A4 inhibitor.
Lumacaftor; Ivacaftor: (Moderate) Monitor for reduced efficacy of simvastatin if coadministered with lumacaftor; ivacaftor. Lumacaftor; ivacaftor may reduce the systemic exposure of simvastatin. Simvastatin is a sensitive substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
Metformin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Metformin; Pioglitazone: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Metformin; Repaglinide: (Moderate) Coadministration of may lead to an increase in repaglinide. This interaction could result in an increased risk of adverse effects associated with repaglinide, specifically hypoglycemia. (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary. (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Metformin; Rosiglitazone: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Metformin; Saxagliptin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary. (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Metformin; Sitagliptin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary. (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Mifepristone, RU-486: (Severe) When used in the treatment of Cushing's syndrome, coadministration of mifepristone with simvastatin is contraindicated due to significant simvastatin exposure increases which may lead to an increased risk of myopathy and rhabdomyolysis. Consider interruption of simvastatin therapy during use of mifepristone for pregnancy termination. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration. Mifepristone, RU-486 is a strong CYP3A4 inhibitor; simvastatin is a sensitive CYP3A4 substrate. Coadministration of mifepristone and simvastatin increased simvastatin and simvastatin acid exposure by 10.4-fold and 15.7-fold, respectively, in drug interaction studies.
Miglitol: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Mitotane: (Moderate) Use caution if mitotane and simvastatin are used concomitantly, and monitor for decreased efficacy of simvastatin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and simvastatin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of simvastatin.
Nateglinide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Nefazodone: (Severe) Nefazodone is contraindicated during simvastatin therapy due to the increased risk of myopathy. Nefazodone may reduce the metabolism of simvastatin via inhibition of the hepatic CYP3A4 isoenzyme. Both rhabdomyolysis and myositis have been reported in the literature secondary to concurrent administration of nefazodone with simvastatin.
Nelfinavir: (Severe) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Netupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as simvastatin. The plasma concentrations of simvastatin can increase when coadministered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Nevirapine: (Minor) Nevirapine, which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates including simvastatin. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered with HMG-CoA reductase inhibitors which are metabolized by CYP3A4.
Nicardipine: (Moderate) Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including simvastatin.
Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to simvastatin. Simvastatin is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if these drugs are used together.
Ombitasvir; Paritaprevir; Ritonavir: (Severe) Coadministration of paritaprevir may increase simvastatin exposure. Paritaprevir is an inhibitor of OATP1B1/3; simvastatin is a substrate of OATP1B1/3. (Severe) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Oxcarbazepine: (Minor) Oxcarbazepine which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates including simvastatin. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are coadministered with HMG-CoA reductase inhibitors which are metabolized by CYP3A4.
Palbociclib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions (e.g., myopathy, rhabdomyolysis) if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A and simvastatin is a sensitive CYP3A4 substrate.
Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and simvastatin, a CYP3A4 substrate, may cause an increase in systemic concentrations of simvastatin. Use caution when administering these drugs concomitantly.
Perindopril; Amlodipine: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Posaconazole: (Severe) The concurrent use of posaconazole and simvastatin is contraindicated due to the risk of myopathy, rhabdomyolysis, and acute renal failure. If therapy with posaconazole is unavoidable, simvastatin therapy must be suspended during the course of posaconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
Potassium-sparing diuretics: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Pramlintide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Pravastatin: (Moderate) The risk of myopathy increases when HMG-Co-A reductase inhibitors are administered concurrently with antilipemic doses of niacin (i.e., 1 g per day or more). Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Propranolol: (Minor) After administration of single doses of simvastatin and propranolol, there was a significant decrease in mean Cmax, with no change in AUC, of simvastatin. The clinical significance of this interaction is unknown. Monitor for potential reduced cholesterol-lowering efficacy when propranolol is coadministered with niacin; simvastatin.
Protease inhibitors: (Severe) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Quinine: (Moderate) Patients receiving concomitant simvastatin and quinine should be monitored closely for muscle pain or weakness. Simvastatin is a CYP3A4 substrate; therefore, quinine has the potential to inhibit the metabolism of simvastatin leading to an increased potential of rhabdomyolysis. Lower starting doses of simvastatin should be considered while patients are receiving quinine. Discontinue simvastatin if marked creatine phosphokinase (CPK) elevation occurs or myopathy (defined as muscle aches or muscle weakness in conjunction with CPK values greater than 10 times the upper limit of normal) is diagnosed or suspected.
Raltegravir: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
Ranolazine: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking ranolazine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on ranolazine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of ranolazine and simvastatin against the potential risks. Ranolazine increases the simvastatin exposure by approximately 2-fold.
Red Yeast Rice: (Severe) Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, red yeast rice should not be used in combination with HMG-CoA reductase inhibitors. The administration of more than one HMG-CoA reductase inhibitor at one time would be duplicative therapy and perhaps increase the risk of drug-related toxicity including myopathy and rhabdomyolysis. (Major) Since compounds in red yeast rice are chemically similar to and possess actions similar to lovastatin, patients should avoid this dietary supplement if they currently take drugs known to increase the risk of myopathy when coadministered with HMG-CoA reductase inhibitors. Niacin (as nicotinic acid, vitamin B3 in antilipemic doses) directly increases the risk of myopathy.
Repaglinide: (Moderate) Coadministration of may lead to an increase in repaglinide. This interaction could result in an increased risk of adverse effects associated with repaglinide, specifically hypoglycemia. (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Reserpine: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Ribociclib: (Moderate) Use caution if ribociclib is coadministered with simvastatin, as the systemic exposure of simvastatin may increase resulting in simvastatin-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and simvastatin is a CYP3A4 substrate.
Ribociclib; Letrozole: (Moderate) Use caution if ribociclib is coadministered with simvastatin, as the systemic exposure of simvastatin may increase resulting in simvastatin-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and simvastatin is a CYP3A4 substrate.
Rifabutin: (Minor) Rifabutin may induce the CYP3A4 metabolism of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
Rifampin: (Moderate) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
Rifapentine: (Minor) Rifapentine may induce the CYP3A4 metabolism of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
Ritonavir: (Severe) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Rosuvastatin: (Moderate) The risk of myopathy increases when HMG-Co-A reductase inhibitors are administered concurrently with antilipemic doses of niacin (i.e., 1 g per day or more). Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Saquinavir: (Severe) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Sarilumab: (Moderate) In vitro, sarilumab has the potential to affect expression of multiple CYP enzymes, including CYP3A4. A 45% decrease in simvastatin exposure was noted 1 week after a single sarilumab dose; simvastatin is a CYP3A4 substrate. Utilize caution when using sarilumab with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable such as simvastatin
Saxagliptin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Semaglutide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients on antidiabetic therapy for blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen and adjust dosages as clinically warranted
Simeprevir: (Moderate) Coadministration of simvastatin with simeprevir, an inhibitor of OATP1B1 and intestinal CYP3A4, results in increased simvastatin plasma concentrations. If these drugs are given together, titrate the simvastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Simvastatin: (Moderate) The risk of myopathy increases when HMG-Co-A reductase inhibitors are administered concurrently with antilipemic doses of niacin (i.e., 1 g per day or more). Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Simvastatin; Sitagliptin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary. (Moderate) The risk of myopathy increases when HMG-Co-A reductase inhibitors are administered concurrently with antilipemic doses of niacin (i.e., 1 g per day or more). Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Sitagliptin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Sofosbuvir; Velpatasvir: (Moderate) Initiate simvastatin at the lowest approved dose if coadministration of velpatasvir is necessary due the potential for increased simvastatin exposure and risk for adverse events, such as myopathy or rhabdomyolysis. If higher doses are needed, use the lowest necessary dose based on risk and benefit assessment. Simvastatin is a substrate of OATP1B1/3; velpatasvir is an inhibitor of OATP1B1/3.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Initiate simvastatin at the lowest approved dose if coadministration of velpatasvir is necessary due the potential for increased simvastatin exposure and risk for adverse events, such as myopathy or rhabdomyolysis. If higher doses are needed, use the lowest necessary dose based on risk and benefit assessment. Simvastatin is a substrate of OATP1B1/3; velpatasvir is an inhibitor of OATP1B1/3. (Moderate) Initiate simvastatin at the lowest approved dose if coadministration of voxilaprevir is necessary due the potential for increased simvastatin exposure and risk for adverse events, such as myopathy or rhabdomyolysis. If higher doses are needed, use the lowest necessary dose based on risk and benefit assessment. Simvastatin is a substrate OATP1B1; voxilaprevir is an inhibitor of OATP1B1.
St. John's Wort, Hypericum perforatum: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system, including CYP3A4, CYP1A2, and potentially CYP2C9. Co-administration of St. John's wort could decrease the efficacy of some medications metabolized by these enzymes including simvastatin.
Streptogramins: (Moderate) Dalfopristin; quinupristin has been shown to inhibit CYP3A4 and may decrease the elimination of simvastatin, a CYP3A4 substrate.
Sulfonylureas: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Tacrolimus: (Moderate) The risk of developing myopathy during therapy with HMG-CoA reductase inhibitors may be increased when used with tacrolimus.
Telaprevir: (Severe) The concurrent use of simvastatin and telaprevir is contraindicated due to the potential for serious/life-threatening reactions. Telaprevir is an inhibitor of CYP3A4, which is responsible simvastatin metabolism. Coadministration may result in large increases in simvastatin serum concentrations, which could cause adverse events such as myopathy and rhabdomyolysis.
Telbivudine: (Moderate) The risk of myopathy may be increased if an HMG-CoA reductase inhibitor is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration. (Moderate) The risk of myopathy may be increased if niacin is coadministered with telbivudine. Physicians considering concomitant treatment should weigh carefully the potential benefits and risks; and should monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
Telithromycin: (Severe) Telithromycin is contraindicated during simvastatin therapy. Telithromycin potently inhibits the metabolism of simvastatin via the CYP3A4 isoenzyme and increases the risk of myopathy and rhabdomyolysis. According to the manufacturer, therapy with simvastatin must be suspended during telithromycin treatment. There are no known adverse effects with short-term discontinuation of simvastatin. Pharmacokinetic studies have reported increased simvastatin concentrations due to CYP3A4 inhibition by telithromycin. When the two drugs were coadministered, there was a 5.3-fold increase in simvastatin Cmax, an 8.9-fold increase in the AUC, a 15-fold increase in the active metabolite Cmax, and a 12-fold increase in the active metabolite AUC. In another study, when simvastatin and telithromycin were administered 12 hours apart, there was a 3.4-fold increase in simvastatin Cmax, a 4-fold increase in AUC, a 3.2-fold increase in the active metabolite Cmax, and a 4.3-fold increase in the active metabolite AUC. Increased serum concentrations of HMG-CoA reductase inhibitors are associated with myopathy. Additionally, simvastatin is a substrate for organic anion transport protein (OATP) and telithromycin may act as an inhibitor for the hepatic organic anion transport protein (OATP) uptake transporters OATP1B1 and OATP1B3.
Teriflunomide: (Moderate) Concurrent use of teriflunomide, an inhibitor of the hepatic uptake organic anion transporting polypeptide OATP1B1, with some HMG-CoA reductase inhibitors (Statins), including atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin may increase the AUC of the statin. Administration of cyclosporine, another OATP1B1 inhibitor, increased the plasma AUC of pravastatin 9.9-fold. Additive hepatotoxicity may occur. Caution should also be exercised when using combination dosage forms, such as amlodipine; atorvastatin, ezetimibe; simvastatin, lovastatin; niacin, niacin; simvastatin, and simvastatin; sitagliptin. Monitor patients for signs of myopathy or hepatotoxicity.
Tesamorelin: (Moderate) Use caution when coadministering tesamorelin with simvastatin as their concurrent use may alter simvastatin plasma concentrations. In a pharmacokinetic study, multiple 2 mg doses of tesamorelin administered with simvastatin resulted in an 8% decrease in simvastatin AUC and a 5% increase in simvastatin Cmax. The clinical impact of these pharmacokinetic changes are unknown; however, patients should be monitored for decreased simvastatin efficacy. Further, since simvastatin is a substrate for CYP3A4, it may be theorized that tesamorelin has little impact on CYP3A activity.
Thiazide diuretics: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Thiazolidinediones: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Ticagrelor: (Major) Avoid simvastatin doses > 40 mg/day PO when used concomitantly with ticagrelor as concomitant use will result in higher serum concentrations of simvastatin. Simvastatin is metabolized by CYP3A4 and ticagrelor is an inhibitor of CYP3A4.
Tipranavir: (Severe) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Tocilizumab: (Moderate) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP3A4. A 57% decrease in simvastatin exposure was noted 1 week after a single tocilizumab dose; simvastatin is a CYP3A4 substrate. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.
Tolazamide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Tolbutamide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Trandolapril; Verapamil: (Major) Do not exceed a simvastatin dose of 10 mg/day in patients taking verapamil due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on verapamil, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of verapamil and simvastatin against the potential risks. Verapamil increases the simvastatin exposure by approximately 2-fold. The interaction is presumed due to increased simvastatin bioavailability via inhibition of CYP3A4 metabolism and reduction of first-pass metabolism by verapamil.
Treprostinil: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Vasodilators: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents, especially peripheral vasodilators. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise. The interaction is harmless unless niacin augments the hypotensive actions of clonidine.
Verapamil: (Major) Do not exceed a simvastatin dose of 10 mg/day in patients taking verapamil due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on verapamil, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of verapamil and simvastatin against the potential risks. Verapamil increases the simvastatin exposure by approximately 2-fold. The interaction is presumed due to increased simvastatin bioavailability via inhibition of CYP3A4 metabolism and reduction of first-pass metabolism by verapamil.
Voriconazole: (Severe) Concurrent use of simvastatin and voriconazole is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as voriconazole. If therapy with voriconazole is unavoidable, simvastatin therapy must be suspended during voriconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
Warfarin: (Moderate) Niacin (nicotinic acid) is occasionally associated with small but statistically significant increases (mean 4%) in prothrombin time. While rare, there is a possibility that an interaction would occur in some patients stabilized on warfarin. It appears prudent to monitor the INR periodically. (Moderate) Per prescribing information for warfarin sodium (Coumadin), all HMG-CoA reductase inhibitors (statins) have been associated with potentiation of warfarin's clinical effect. However, it appears that pravastatin and atorvastatin may be less likely to significantly interact with warfarin based on drug interaction studies. In addition, atorvastatin has been reported to slightly and transiently decrease the anticoagulant activity of warfarin; these effects were not considered clinically significant. In general, it is prudent to monitor INR at baseline, at initiation of these HMG Co-A reductase inhibitors, and after subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, the INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions.
Zafirlukast: (Minor) Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as simvastatin.
Zileuton: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates, including simvastatin.

Adults

2000 mg/day PO niacin with 40 mg/day PO simvastatin; simvastatin maximum of 20 mg/day PO if taking amlodipine or ranolazine.

Geriatric

2000 mg/day PO niacin with 40 mg/day PO simvastatin; simvastatin maximum of 20 mg/day PO if taking amlodipine or ranolazine.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

NOTE: This monograph discusses the use of niacin; simvastatin combination products. Clinicians may wish to consult the individual monographs for more information about each agent.Mechanism of Action: Niacin; simvastatin combines two antilipemic agents, niacin extended-release and simvastatin. Simvastatin is an HMG-CoA reductase inhibitor, while niacin (nicotinic acid) is a B-complex vitamin.•Niacin: Niacin is utilized by the body after conversion to nicotinamide adenine dinucleotide (NAD) in the NAD coenzyme system, which is found in erythrocytes and other tissues. In addition to its role as a vitamin, niacin has other dose-related pharmacologic properties. Niacin, when used for therapeutic purposes, acts on the peripheral circulation, producing dilation of cutaneous blood vessels and increasing blood flow, mainly in the face, neck, and chest. This action produces the characteristic 'niacin-flush'. Niacin-induced vasodilation may be related to release of histamine and/or prostacyclin. Histamine secretion can increase gastric motility and acid secretion. Flushing may result in concurrent pruritus, headaches, or pain. The mechanism by which niacin alters the lipid profile is unknown but is unrelated to its biochemical role as a vitamin. Several mechanisms have been proposed, including inhibition of free fatty acid release from adipose tissue, increased lipoprotein lipase activity, decreased triglyceride synthesis, decreased VLDL-triglyceride transport, and an inhibition of lipolysis. This last mechanism may be due to niacin's inhibitory action on lipolytic hormones. Nicotinic acid possibly reduces LDL secondary to decreased VLDL production or enhanced hepatic clearance of LDL precursors. Nicotinic acid elevates total HDL by an unknown mechanism, but is associated with an increase in serum levels of apolipoprotein A-I and lipoprotein A-I, and a decrease in serum levels of apolipoprotein-B. Nicotinic acid is effective at elevating HDL even in patients whose only lipid abnormality is a low-HDL value. Niacin does not appear to affect the fecal excretion of fats, sterols, or bile acids.•Simvastatin: Simvastatin is a prodrug with little or no inherent activity. The 6-membered lactone ring is hydrolyzed in vivo to generate mevinolinic acid. Mevinolinic acid, one of simvastatin's several active metabolites, is structurally similar to hydroxymethylglutaryl CoA (HMG-CoA). Once hydrolyzed, simvastatin competes with HMG-CoA for HMG-CoA reductase, a hepatic microsomal enzyme. Interference with the activity of this enzyme reduces the quantity of mevalonic acid, a precursor of cholesterol. This process occurs within the hepatocyte and is one of two mechanisms that generate cholesterol. Cholesterol can also be taken up from LDL by endocytosis. Since de novo synthesis of cholesterol is impaired by simvastatin, cholesterol uptake is augmented. Thus, simvastatin also enhances clearance of LDL.

Niacin; simvastatin is administered orally.  Niacin is conjugated with glycine to form nicotinuric acid (NUA), which is then excreted in the urine. Some reversible metabolism from NUA back to niacin may occur in small amounts. This other pathway results in the formation of nicotinamide adenine dinucleotide (NAD). Nicotinamide is most likely released after the formation of NAD. Nicotinamide does not have hypolipidemic activity, and is further metabolized in the liver to produce N-methylnicotinamide (MNA) and nicotinamide-N-oxide (NNO). MNA is metabolized to two other N-methylated compounds known as 2PY and 4PY, which are excreted in the urine. The formation of 2PY predominates over 4PY in humans. Greater proportions of niacin are renally excreted unchanged as dosages exceed 1000 mg/day and metabolic pathways become saturated. Simvastatin is a substrate for CYP3A4 and is readily hydrolyzed in vivo to beta-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Major active metabolites of simvastatin include the beta-hydroxyacid of simvastatin and its 6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives. After the administration of two niacin; simvastatin 1000/20 mg tablets, 54% of the niacin dose is recovered in the urine by 96 hours as niacin and metabolites; the mean terminal half-life for simvastatin and simvastatin acid was 4.2—4.9 hours and 4.6—5 hours, respectively.

Oral Route

After the administration of two niacin; simvastatin 1000/20 mg tablets, niacin Cmax and AUC were similar to the niacin extended-release formulation; however, the simvastatin and simvastatin acid AUC increased by 23% and 41%, respectively, compared to immediate-release simvastatin. The mean time to Cmax for niacin ranged from 4.6—4.9 hours and for simvastatin from 1.9—2 hours. Following oral administration of niacin; simvastatin, each component undergoes rapid, extensive first-pass metabolism. The first-pass metabolism for niacin is dose-rate specific and is saturable at doses used to treat dyslipidemia.

Pregnancy

Niacin; simvastatin is contraindicated for use in women who are breast-feeding. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for infant growth and development, including synthesis of steroids and cell membranes. HMG-CoA reductase inhibitors to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway; these drugs may also produce other adverse effects in nursing infants. The importance of continued niacin; simvastatin therapy to the mother should be considered in making the decision whether to discontinue breast-feeding or discontinue the medication. If pharmacotherapy is necessary in the nursing mother, a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol should be considered. These agents do not enter the bloodstream and thus will not be excreted during lactation. However, resins bind fat-soluble vitamins and prolonged use may result in deficiencies of these vitamins in the mother and her nursing infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.