Simcor (niacin 1000 mg simvastatin 20 mg) Dailymed

2 Dosage And Administration

• SIMCOR should be taken at bedtime with a low-fat snack. (2)
• Dose range: 500/20 mg to 2000/40 mg once daily. (2)
• Initial dose for patients naïve to or switching from immediate-release niacin: 500/20 mg once daily. (2)
• The initial dose for patients already receiving niacin extended-release should not exceed 2000/40 mg once daily. (2)
• Maintenance dose: 1000/20 mg to 2000/40 mg once daily. (2)
• Doses greater than 2000/40 mg daily are not recommended. (2)

2.1 Recommended Dosing

SIMCOR should be taken as a single daily dose at bedtime, with a low fat snack. Patients not currently on niacin extended-release and patients currently on niacin products other than niacin extended-release should start SIMCOR at a single 500/20 mg tablet daily at bedtime. Patients already taking simvastatin 20 to 40 mg who need additional management of their lipid levels may be started on a SIMCOR dose of 500/40 mg once daily at bedtime [see Warnings and Precautions (5.3)]. The dose of niacin extended-release should not be increased by more than 500 mg daily every 4 weeks - see Table 1.

* After Week 8, titrate to patient response and tolerance. If response to 1000 mg daily is inadequate, increase dose to 1500 mg daily; may subsequently increase dose to 2000 mg daily. Daily dose should not be increased more than 500 mg in a 4-week period, and doses above 2000 mg daily are not recommended.
Table 1. Recommended niacin extended-release dosing
	Week(s)	Daily dose of niacin extended-release
Initial Titration Schedule	1 to 4	500 mg
	5 to 8	1000 mg
	*	1500 mg
	*	2000 mg

The recommended maintenance dose for SIMCOR is 1000/20 mg to 2000/40 mg (two 1000/20 mg tablets) once daily depending on patient tolerability and lipid levels. The efficacy and safety of doses of SIMCOR greater than 2000/40 mg daily have not been studied and are therefore not recommended.
If SIMCOR therapy is discontinued for an extended period of time (> 7 days), re-titration as tolerated is recommended. SIMCOR tablets should be taken whole and should not be broken, crushed, or chewed before swallowing.
Due to the increased risk of hepatotoxicity with other modified-release (sustained-release or time-release) niacin preparations or immediate-release (crystalline) niacin, SIMCOR should only be substituted for equivalent doses of niacin extended-release (NIASPAN).
Flushing [see Adverse Reactions (6.1)] may be reduced in frequency or severity by pretreatment with aspirin up to the recommended dose of 325 mg (taken approximately 30 minutes prior to SIMCOR dose). Flushing, pruritus, and gastrointestinal distress are also reduced by gradually increasing the dose of niacin (refer to Table 1) and avoiding administration on an empty stomach. Concomitant alcoholic, hot drinks or spicy foods may increase the side effects of flushing and pruritus and should be avoided around the time of SIMCOR ingestion.

2.2 Coadministration with Other Drugs

Patients taking Amiodarone, Amlodipine or Ranolazine

• The dose of SIMCOR should not exceed 1000/20 mg/day [see Warnings and Precautions (5.2), Drug Interactions (7.4), and Clinical Pharmacology (12.3)].

2.3 Chinese Patients Taking SIMCOR

Because of an increased risk for myopathy in Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products, caution should be used when prescribing SIMCOR in doses that exceed 1000/20 mg/day to Chinese patients. The cause of the increased risk of myopathy is not known. It is also unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients [see Warnings and Precautions (5.2)].

SIMCOR should not be substituted for equivalent doses of immediate-release (crystalline) niacin. For patients switching from immediate-release niacin to SIMCOR, therapy with SIMCOR should be initiated at 500/20 mg and appropriately titrated to the desired therapeutic response. Patients already taking simvastatin 20-40 mg who need additional management of their lipid levels may be started on a SIMCOR dose of 500/40 mg once daily at bedtime. Doses of SIMCOR greater than 2000/40 mg are not recommended.

• Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with higher doses and concomitant use of certain medicines. Predisposing factors include advanced age (≥ 65), female gender, uncontrolled hypothyroidism, and renal impairment. Patients should be advised to report promptly any unexplained and/or persistent muscle pain, tenderness, or weakness. SIMCOR therapy should be discontinued immediately if myopathy is diagnosed or suspected. (4, 5.2, 8.5, 8.7)
• Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter. (5.3)
• Severe hepatic toxicity has occurred in patients substituting sustained-release niacin for immediate-release niacin at equivalent doses. If switching from niacin preparations other than niacin extended-release (NIASPAN), initiate with lowest SIMCOR dose; niacin extended-release can be converted at equivalent doses. (5.3)
• Niacin extended-release can increase serum glucose levels. Glucose levels should be closely monitored in diabetic or potentially diabetic patients particularly during the first few months of use. (5.4)

5.1 Mortality and Coronary Heart Disease Morbidity

The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial was a randomized placebo-controlled trial of 3414 patients with stable, previously diagnosed cardiovascular disease. Mean baseline lipid levels were LDL-C 74 mg/dL, HDL-C 35 mg/dL, non-HDL-C 111 mg/dL and median triglyceride level of 163-177 mg/dL. Ninety-four percent of patients were on background statin therapy prior to entering the trial. All participants received simvastatin, 40 to 80 mg per day, plus ezetimibe 10 mg per day if needed, to maintain an LDL-C level of 40-80 mg/dL, and were randomized to receive niacin extended-release tablets 1500-2000 mg/day (n=1718) or matching placebo (niacin immediate-release tablets, 100-150 mg, n=1696).
On-treatment lipid changes at two years for LDL-C were -12.0% for the simvastatin plus niacin extended-release group and -5.5% for the simvastatin plus placebo group. HDL-C increased by 25.0% to 42 mg/dL in the simvastatin plus niacin extended-release group and by 9.8% to 38 mg/dL in the simvastatin plus placebo group (P<0.001). Triglyceride levels decreased by 28.6% in the simvastatin plus niacin extended-release group and by 8.1% in the simvastatin plus placebo group.
The primary outcome was an ITT composite of the first study occurrence of coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome or symptom-driven coronary or cerebral revascularization procedures. The trial was stopped after a mean follow-up period of 3 years owing to a lack of efficacy. The primary outcome occurred in 282 patients in the simvastatin plus niacin extended-release group (16.4%) and in 274 patients in the simvastatin plus placebo group (16.2%) (HR 1.02 [95% CI, 0.87-1.21], P=0.79.
In an ITT analysis, there were 42 cases of first occurrence of ischemic stroke reported, 27 (1.6%) in the simvastatin plus niacin extended-release group and 15 (0.9%) in the simvastatin plus placebo group, a non-statistically significant result (HR 1.79, [95%CI = 0.95-3.36], p=0.071). The on-treatment ischemic stroke events were 19 for the simvastatin plus niacin extended-release group and 15 for the simvastatin plus placebo group [see Adverse Reactions (6.1)] .

5.2 Myopathy/Rhabdomyolysis

Simvastatin
Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment.
The risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,413 patients were treated with simvastatin with 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.
In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with ZOCOR (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day; the incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) was approximately 0.4% in patients on 80 mg/day compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
All patients starting therapy with SIMCOR, or whose dose of SIMCOR is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing SIMCOR. SIMCOR therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with SIMCOR or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. SIMCOR therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. SIMCOR therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
Drug Interactions
The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, and posaconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, or large quantities of grapefruit juice (>1 quart daily), and combination of these drugs with SIMCOR is contraindicated. If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with SIMCOR must be suspended during the course of treatment [see Contraindications (4)and Drug Interactions (7.1)]. In vitro studies have demonstrated a potential for voriconazole to inhibit the metabolism of simvastatin. Adjustment of the SIMCOR dose may be needed to reduce the risk of myopathy/rhabdomyolysis if voriconazole must be used concomitantly with simvastatin [see Drug Interactions (7.1)].
The combined use of SIMCOR with gemfibrozil, cyclosporine, or danazol is contraindicated [see Contraindications (4) and Drug Interactions (7.1)].
The combined use of SIMCOR with verapamil or diltiazem is contraindicated, because dosages of simvastatin are not to exceed 10 mg when these drugs are co-administered and all doses of SIMCOR contain simvastatin in excess of 10 mg [see Contraindications (4)and Drug Interactions (7.2)].
The combined use of SIMCOR with drugs that cause myopathy/rhabdomyolysis when given alone, such as fibrates, should be avoided [see Drug Interactions (7.3)].
Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing SIMCOR with colchicine [see Drug Interactions (7.8)].
The benefits of the combined use of SIMCOR with amlodipine or ranolazine should be carefully weighed against the potential risks of combination [see Drug Interactions (7.4)]. Periodic CK determinations may be considered in patients starting therapy with or increasing the dose of these agents, but there is no assurance that such monitoring will prevent myopathy.
Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In an ongoing, double-blind, randomized cardiovascular outcomes trial, an independent safety monitoring committee identified that the incidence of myopathy is higher in Chinese compared with non-Chinese patients taking simvastatin 40 mg coadministered with lipid modifying doses of a niacin-containing product. Caution should be used when prescribing SIMCOR in doses that exceed 1000/20 mg/day to Chinese patients. It is unknown if the risk for myopathy with coadministration of simvastatin with lipid modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients [see Dosage and Administration (2.3)].
Prescribing recommendations for interacting agents are summarized in Table 3 [see also Dosage and Administration (2.2), Contraindications (4), Drug Interactions (7), Clinical Pharmacology (12.3)].

Table 3 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors, e.g.,ItraconazoleKetoconazole PosaconazoleErythromycinClarithromycinTelithromycinHIV protease inhibitorsBoceprevirTelaprevirNefazodoneGemfibrozilCyclosporineDanazolVerapamilDiltiazem	Contraindicated with SIMCOR
AmiodaroneAmlodipineRanolazine	Do not exceed 1000/20 mg SIMCOR daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

SIMCOR
Myopathy and/or rhabdomyolysis have been reported when simvastatin is used in combination with lipid-altering doses (≥ 1 gram/day) of niacin. Physicians contemplating the use of SIMCOR, a combination of simvastatin and niacin extended-release (NIASPAN), should weigh the potential benefits and risks, and should carefully monitor for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial month of treatment or during any period of upward dosage titration of either drug. Periodic determination of serum creatine kinase (CK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent myopathy.
Patients starting therapy with SIMCOR should be advised of the risk of myopathy, and told to report promptly unexplained muscle pain, tenderness, or weakness. A CK level above ten times the upper limit of normal (ULN) in a patient with unexplained muscle symptoms indicates myopathy. SIMCOR therapy should be discontinued if myopathy is diagnosed or suspected.
In patients with complicated medical histories predisposing to rhabdomyolysis, such as renal insufficiency, dose escalation requires caution. Also, as there are no known adverse consequences of brief interruption of therapy, treatment with SIMCOR should be stopped for a few days before elective major surgery and when any major acute medical or surgical condition supervenes (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).

5.3 Liver Dysfunction

Cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred in patients who have substituted sustained-release (modified-release, timed-release) niacin products for immediate-release (crystalline) niacin at equivalent doses. Patients previously receiving niacin products other than niacin extended-release (NIASPAN) should be started on SIMCOR at the lowest recommended starting dose [see Dosage and Administration (2)].
SIMCOR should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of SIMCOR [see Contraindications (4)].
Niacin extended-release (NIASPAN) and simvastatin can cause abnormal liver tests. In a simvastatin-controlled, 24 week study with SIMCOR in 641 patients, there were no persistent increases (to more than 3x the ULN) in serum transaminases. In three placebo-controlled clinical studies of niacin extended-release, patients with normal serum transaminases levels at baseline did not experience any transaminase elevations greater than 3x the ULN. Persistent increases (to more than 3x the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies. When drug treatment was interrupted or discontinued in these patients, the transaminases levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity.
It is recommended that liver enzyme tests be obtained prior to initiating therapy with SIMCOR and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with SIMCOR, promptly interrupt therapy. If an alternate etiology is not found do not restart SIMCOR. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy [see Warnings and Precautions (5.2)].

5.4 Laboratory Abnormalities

Increase in Blood Glucose: Niacin treatment can increase fasting blood glucose. In a simvastatin-controlled, 24-week study with SIMCOR the change from baseline in glycosylated hemoglobin levels was 0.2% for SIMCOR-treated patients and 0.2% for simvastatin-treated patients. Diabetic or potentially diabetic patients should be observed closely during treatment with SIMCOR, particularly during the first few months of therapy. Adjustment of diet and/or hypoglycemic therapy or discontinuation of SIMCOR may be necessary.
Reduction in platelet count: Niacin can reduce platelet count. In a simvastatin-controlled, 24-week study with SIMCOR the mean percent change from baseline for patients treated with 2000/40 mg daily was -5.6%.
Increase in ProthrombinTime (PT): Niacin can cause small increases in PT. In a simvastatin-controlled, 24-week study with SIMCOR this effect was not seen.
Increase in Uric Acid: Elevated uric acid levels have occurred with niacin therapy. In a simvastatin-controlled, 24-week study with SIMCOR this effect was not seen. Nevertheless, in patients predisposed to gout, SIMCOR therapy should be used with caution.
Decrease in Phosphorus: Small dose-related reductions in phosphorous levels were seen in clinical studies with niacin. In a simvastatin-controlled, 24-week study with SIMCOR this effect was not seen.

5.5 Endocrine Function

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including simvastatin.