Niacin and Simvastatin

Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. No drug interactions have been evaluated for the combination of niacin and simvastatin by the manufacturer. However, the following drugs have been noted to have interactions with niacin and simvastatin:

• medications that block the enzyme CYP3A4 such as some macrolide antibiotics (clarithromycin, telithromycin), some HIV protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir), some HCV protease inhibitors (boceprevir, telaprevir), some azole antifungals (ketoconazole, itraconazole, posaconazole, voriconazole), conivaptan (Vaprisol), delavirdine (Rescriptor), and nefazodone (Serzone)
• calcium channel blockers such as amlodipine (Norvasc), verapamil (Calan, Isoptin, Covera, Verelan), and diltiazem (Cardizem)
• fibrates such as gemfibrozil (Lopid) or fenofibrate (TriCor)
• ranolazine (Ranexa)
• propranolol (Inderal)
• digoxin (Lanoxin)
• warfarin (Coumadin, Jantoven)
• colchicine (Colcrys)
• aspirin
• medicines that lower blood pressure such as guanethidine (Ismelin), methyldopa (Aldomet), beta-blockers like bisoprolol (Zebeta) , vasodilators like hydralazine (Apresoline), angiotensin-­converting enzyme (ACE) inhibitors like enalapril (Vasotec, Vaseretic), angiotensin receptor II blockers (ARBs) like valsartan (Diovan) and direct renin inhibitors (DRIs) like aliskiren (Tekturna)
• cholestyramine (Questran) and colestipol (Colestid)
• nutritional supplements containing large doses of niacin or related compounds

This is not a complete list of potential niacin and simvastatin drug interactions. Ask your doctor or pharmacist for more information.

Grapefruit and grapefruit juice may interact with niacin and simvastatin and lead to potentially dangerous effects, including muscle injury. Discuss the use of grapefruit products with your doctor. 

Avoid alcohol, hot beverages, and spicy foods around the time you take niacin and simvastatin to minimize flushing.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

• your blood pressure
• previous medications used and the doses tried
• how you respond to this medication
• your other medical conditions

The recommended starting doses of niacin and simvastatin to treat high cholesterol and high triglycerides are listed below.

• not currently on niacin extended-release or currently on niacin products other than niacin extended-release: a single 500/20 mg tablet daily at bedtime, with a low fat snack
• already taking simvastatin 20 to 40 mg and need additional treatment: 500/40 mg once daily at bedtime, with a low fat snack
  • ​The dose of niacin extended-release should not be increased by more than 500 mg daily every 4 weeks

​The recommended maintenance dose for niacin and simvastatin is 1000/20 mg to 2000/40 mg (two 1000/20 mg tablets) once daily.

• The efficacy and safety of doses of niacin and simvastatin greater than 2000/40 mg daily have not been studied and are therefore not recommended.
• Patients taking amiodarone, amlodipine or ranolazine should not exceed a dose of 1000/20 mg/day of niacin and simvastatin.
• Because of an increased risk for a disease of muscle tissue (myopathy) in Chinese patients taking simvastatin 40 mg along with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. Caution should be used when using niacin and simvastatin in doses that exceed 1000/20 mg/day in Chinese patients. 

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, variable release, oral:

Simcor:

500/20: Niacin 500 mg [extended release] and simvastatin 20 mg [immediate release] [DSC]

500/40: Niacin 500 mg [extended release] and simvastatin 40 mg [immediate release] [DSC]

750/20: Niacin 750 mg [extended release] and simvastatin 20 mg [immediate release] [DSC]

1000/20: Niacin 1000 mg [extended release] and simvastatin 20 mg [immediate release] [DSC]

1000/40: Niacin 1000 mg [extended release] and simvastatin 40 mg [immediate release] [DSC]

Niacin: False elevations in some fluorometric determinations of plasma or urinary catecholamines; false-positive urine glucose (Benedict's reagent)

Reactions/percentages reported with combination product; also see individual agents.

>10%: Cardiovascular: Flushing (≤59%)

1% to 10%:

Central nervous system: Headache (5%)

Dermatologic: Pruritus (3%)

Gastrointestinal: Diarrhea (3%), nausea (3%)

Neuromuscular & skeletal: Back pain (3%)

Frequency not defined:

Endocrine & metabolic: Abnormal thyroid function test, decreased serum phosphate, increased amylase, increased gamma-glutamyl transferase, increased lactate dehydrogenase, increased uric acid

Hematologic & oncologic: Increase in fasting plasma glucose, prolonged prothrombin time, thrombocytopenia

Hepatic: Increased serum alkaline phosphatase, increased serum bilirubin, increased serum transaminases

Neuromuscular & skeletal: Increased creatine phosphokinase

Concerns related to adverse effects:

• Flushing/pruritus: Flushing and pruritus, common adverse effects of niacin, may be attenuated with a gradual increase in dose, administering with food, avoidance of concurrent ingestion of ethanol or hot liquids, and/or by taking aspirin (adults: 325 mg) 30 minutes before dosing (Stone, 2013). Avoid concurrent ingestion of ethanol, hot liquids, or spicy foods to minimize flushing. Flushing associated with extended-release preparation is significantly reduced (Guyton, 2007). Niacin should not be used if patient experiences persistent severe cutaneous symptoms during therapy (Stone, 2013).

• Gastrointestinal effects: May cause gastrointestinal distress, vomiting, diarrhea, or aggravate peptic ulcer; gastrointestinal distress may be attenuated with a gradual increase in dose and administration with food. Use is contraindicated in patients with active peptic ulcer disease; use with caution in patients with a past history of peptic ulcer. Niacin should not be used if patient experiences unexplained abdominal pain or gastrointestinal symptoms or unexplained weight loss during therapy (Stone, 2013).

• Hematologic effects: Dose-related reductions in platelet count and increases of prothrombin time may occur.

• Hepatotoxicity: Cases of severe hepatotoxicity, including fulminant hepatic necrosis, have occurred when immediate release (crystalline) niacin products have been substituted with sustained-release (modified release, timed-release) niacin products at equivalent doses. Patients should be initiated with low doses with titration to achieve desired response. Postmarketing reports of fatal and nonfatal hepatic failure with simvastatin are rare. If serious hepatotoxicity with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, interrupt therapy. If an alternate etiology is not identified, do not restart simvastatin. Liver enzyme tests should be obtained at baseline and as clinically indicated; routine periodic monitoring of liver enzymes is not necessary. Ethanol may enhance the potential of adverse hepatic effects; instruct patients to avoid excessive ethanol consumption. Niacin should not be used if hepatic transaminase elevations >2-3 times upper limit of normal occur during therapy (Stone, 2013).

• Hypophosphatemia: Has been associated with small but statistically significant dose-related reductions in phosphorus levels. Monitor phosphorus levels periodically in patients at risk for hypophosphatemia.

• Immune-mediated necrotizing myopathy (IMNM): IMNM, an autoimmune-mediated myopathy, has been reported (rarely) with HMG-CoA reductase inhibitor therapy. IMNM presents as proximal muscle weakness with elevated CPK levels, which persists despite discontinuation of HMG-CoA reductase inhibitor therapy; additionally, muscle biopsy may show necrotizing myopathy with limited inflammation. Immunosuppressive therapy (eg, corticosteroids, azathioprine) may be used for treatment.

• Myopathy/rhabdomyolysis: Patients receiving HMG-CoA reductase inhibitors have developed rhabdomyolysis with acute renal failure and/or myopathy; patients should be monitored closely. This risk is dose-related and is increased with high doses (simvastatin 80 mg), concurrent use of other lipid-lowering medications (fibric acid derivatives, or niacin at doses ≥1 g/day), other interacting drugs (eg, moderate-to-strong CYP3A4 inhibitors), age ≥65 years, female gender, uncontrolled hypothyroidism, and renal dysfunction. Use with caution in patients taking other drugs associated with myopathy (eg, colchicine); these patients are predisposed to myopathy. Patients should be instructed to report unexplained muscle pain, tenderness, weakness, or brown urine. Discontinue treatment if CK levels rise to >10 times ULN with concomitant muscle symptoms.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with unstable angina or MI. In patients with pre-existing coronary artery disease, the incidence of atrial fibrillation was observed more frequently in those receiving immediate release (crystalline) niacin as compared to placebo (Coronary Drug Project Research Group, 1975). Niacin should not be used if patient experiences new-onset atrial fibrillation during therapy (Stone, 2013).

• Diabetes: Niacin may increase fasting blood glucose, although clinical data suggest increases are generally modest (<5%) (Guyton, 2007). Use niacin with caution in patients with diabetes. Monitor glucose; adjustment of diet and/or hypoglycemic therapy may be necessary. Niacin should not be used if patient experiences persistent hyperglycemia during therapy (Stone, 2013).

• Gout: May be associated with hyperuricemia. Use niacin with caution in patients with gout. Niacin should not be used if patient experiences acute gout during therapy (Stone, 2013).

• Hepatic impairment: Use with caution in patients with a past history of hepatic impairment. Use is contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases. Transaminases should be monitored during therapy; if levels elevated, repeat test (confirmatory) and monitor frequently until transaminases return to normal; therapy should be discontinued if transaminase levels >3 times ULN persist or are accompanied by symptoms (nausea, fever, malaise).

• Renal impairment: Use with caution in renal impairment; use with extreme caution or avoid in severe impairment unless patient already tolerating simvastatin doses ≥10 mg. Renal impairment may also increase risk for myopathy.

Concurrent drug therapy issues:

• High potential for interactions: If concurrent use of a contraindicated interacting medication is unavoidable, treatment with simvastatin should be suspended during use or consider the use of an alternative HMG-CoA reductase inhibitor void of CYP3A4 metabolism.

Special populations:

• Chinese patients: Concomitant use of niacin (>1 g/day) and simvastatin (>20 mg/day) should be done with caution; may increase risk of myopathy in Chinese patients.

• Elderly: Use with caution in patients ≥65 years of age; these patients are predisposed to myopathy.

• Surgical patients: The manufacturer recommends temporary discontinuation for elective major surgery, acute medical or surgical conditions, or in any patient experiencing an acute or serious condition predisposing to renal failure (eg, sepsis, hypotension, trauma, uncontrolled seizures). Based on current research and clinical guidelines (Fleisher, 2009), HMG-CoA reductase inhibitors should be continued in the perioperative period. Postoperative discontinuation of statin therapy is associated with an increased risk of cardiac morbidity and mortality.

Dosage form specific issues:

• Product interchangeability: Bioavailability of niacin formulations vary (regular release versus extended release) and are not interchangeable; cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred in patients who have substituted niacin products at equivalent doses. In addition, bioequivalence between different Simcor® dosage strengths has not been evaluated and strengths should not be considered exchangeable.

Other warnings/precautions:

• Alcohol use: Use with caution in patients who consume large amounts of ethanol due to the increased risk of liver dysfunction.

• Appropriate use: Prior to initiation, secondary causes for hypercholesterolemia (eg, poorly controlled diabetes mellitus, hypothyroidism) should be excluded; management with diet and other nonpharmacologic measures (eg, exercise or weight reduction) should be attempted prior to initiation.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?

• Patient may experience flushing or headache. Have patient report immediately to prescriber prescriber signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes),, severe dizziness, passing out, angina, tachycardia, shortness of breath, sweating a lot, urinary retention, change in amount of urine passed, severe muscle pain, or severe muscle weakness (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

There are no data regarding the use of niacin in animal reproductive studies or controlled human pregnancy studies. While animal studies with simvastatin failed to reveal evidence of teratogenicity, animal studies with other HMG-CoA reductase inhibitors revealed an increase in the incidence of skeletal malformations. There are no controlled data on the use of simvastatin in human pregnancy. However, HMG-CoA reductase inhibitors are known to inhibit biosynthetic processes necessary in fetal development. Niacin-simvastatin may cause fetal harm when administered to a pregnant woman. Niacin-simvastatin is considered contraindicated for use during pregnancy.

Nicotinic acid is excreted into human milk, but it is not known whether simvastatin is excreted into human milk. Small amounts of a similar HMG-CoA reductase inhibitor does pass into breast milk. Because of the potential for serious adverse reactions in nursing infants, women receiving niacin-simvastatin treatment should not breastfeed their infants.