1.1 Patients with Hypercholesterolemia Requiring Modifications of Lipid Profiles

SIMCOR

SIMCOR is indicated to reduce total-C, LDL-C, Apo B, non-HDL-C, TG, or to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia when treatment with simvastatin monotherapy or niacin extended-release monotherapy is considered inadequate.

SIMCOR is indicated to reduce TG in patients with hypertriglyceridemia when treatment with simvastatin monotherapy or niacin extended-release monotherapy is considered inadequate.

Limitations of use

No incremental benefit of SIMCOR on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin monotherapy and niacin monotherapy has been established.

5.1 Myopathy/Rhabdomyolysis

Simvastatin

Simvastatin, like other inhibitors of HMG-CoA reductase, 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.

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,050 patients were treated with simvastatin with 24,747 (approximately 60%) treated for at least 4 years, the incidence of myopathy was approximately 0.02%, 0.08%, and 0.53% at 20, 40, and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

Potent inhibitors of CYP3A4: The risk of myopathy appears to be increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which share this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include cyclosporine, itraconazole, ketoconazole, and other antifungal azoles, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, the antidepressant nefazodone, or large quantities of grapefruit juice (> 1 quart daily).

The risk of myopathy/rhabdomyolysis is increased by concomitant use of simvastatin and, therefore, SIMCOR with the following:

Potent inhibitors of cytochrome P-450 isoform, 3A4 (CYP 3A4):

 

Itraconazole, ketoconazole, and other antifungal azoles

 

Macrolide antibiotics erythromycin, clarithromycin, and telithromycin

 

HIV protease inhibitors

 

Antidepressant nefazodone

 

Grapefruit juice in large quantities (> 1 quart daily)

The use of SIMCOR concomitantly with these potent CYP3A4 inhibitors should be avoided. [See Drug Interactions (7.1)]

Cyclosporine or Danazol: Simvastatin dose should not exceed 10 mg daily in combination with cyclosporine or danazol. Therefore, the combined used of SIMCOR with cyclosporine or danazol should be avoided. [See Drug Interactions (7.2)]

Gemfibrozil: Simvastatin dose should not exceed 10 mg daily when concomitantly used with gemfibrozil. Therefore, the combined use of SIMCOR with gemfibrozil should be avoided. [See Drug Interactions (7.4)]

Other Fibrates: Combined use of SIMCOR with drugs that cause myopathy/rhabdomyolysis when given alone, such as fibrates, should be avoided. [See Drug Interactions (7.4)]

Amiodarone or Verapamil: The dose of the simvastatin component of SIMCOR should not exceed 20 mg in patients receiving amiodarone or verapamil concomitantly. The combined use of the simvastatin at doses higher than 20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy. [See Drug Interactions (7.3)]

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 10 times 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).

5.2 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.

Liver function tests should be performed on all patients during therapy with SIMCOR. It is recommended that liver function tests be performed before treatment begins, every 12 weeks for the first 6 months, and periodically thereafter (e.g., at approximately 6-month intervals). Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality returns to normal. Should an increase in transaminase levels of more than 3x ULN persist, or if transaminase elevations are associated with symptoms of nausea, fever, and/or malaise, withdrawal of SIMCOR therapy is recommended.

5.3 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.

6.1 Clinical Studies Experience

SIMCOR

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The safety data described below reflect exposure to SIMCOR in 403 patients in a controlled study for a period of 6 months.

Flushing: Flushing (warmth, redness, itching and/or tingling) occurred in up to 59% of patients treated with SIMCOR. Flushing resulted in study discontinuation for 6.0% of patients.

More Common Adverse Reactions: In addition to flushing, adverse reactions occurring in ≥ 3% of patients (irrespective of investigator causality) treated with SIMCOR are shown in Table 3 below:

Simvastatin

In pre-marketing controlled clinical studies and their open extensions (2,423 patients with mean duration of follow-up of approximately 18 months) 1.4% of patients discontinued due to adverse reactions. The most commonly reported adverse reactions (incidence > 1%) in simvastatin controlled clinical trials were: headache (3.5%), abdominal pain (3.5%), constipation (2.3%), upper respiratory infection (2.1%), diarrhea (1.9%), and flatulence (1.9%).

Niacin Extended-Release

In placebo-controlled clinical trials (n=245), flushing episodes were the most common treatment-emergent adverse events (up to 88% of patients) for niacin extended-release. Other adverse events occurring in 5% or greater of patients treated with niacin extended-release are headache (9%), diarrhea (7%), nausea (5%), rhinitis (5%), and dyspepsia (4%) at a maintenance dose of 1000mg daily.

Clinical Laboratory Abnormalities:

SIMCOR

Chemistry

Elevations in serum transaminases [See Warnings and Precautions (5.2)], CK, fasting glucose, uric acid, alkaline phosphatase, LDH, amylase, γ-glutamyl transpeptidase, bilirubin, and reductions in phosphorus, and abnormal thyroid function tests.

Hematology

Reductions in platelet counts and prolongation of PT. [See Warnings and Precautions (5.3)]

6.2 Postmarketing Experience

Because the below reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Simvastatin

The following additional adverse reactions have been identified during postapproval use of simvastatin. Hypersensitivity reaction including one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, vasculitis, purpura, thrombocytopenia, leucopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, photosensitivity, chills, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, urticaria, fever, dyspnea, and arthralgia; pancreatitis, hepatitis, hepatic failure, pruritus, cataracts, polymyositis, dermatomyositis, polymyalgia rheumatica, global amnesia, tendon rupture, peripheral neuropathy, memory impairment.

NIASPAN

The following additional adverse reactions have been identified during post-approval use of NIASPAN. Hypersensitivity reaction including one or more of the following features: anaphylaxis, dyspnea, angioedema, tongue edema, larynx edema, face edema, laryngismus; tachycardia, atrial fibrillation, other cardiac arrhythmias, palpitations, hypotension, postural hypotension, dizziness, syncope, flushing, burning sensation/skin burning sensation, paresthesia, urticaria, vesiculobullous rash, maculopapular rash, sweating, dry skin, skin discoloration, blurred vision, macular edema, myalgia, myopathy, peptic ulcers, eructation, flatulence, hepatitis, jaundice, peripheral edema, asthenia, nervousness, insomnia, migraine, gout, and decreased glucose tolerance.

7.1 CYP3A4 Inhibitors

Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of CYP3A4. Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4.

Potent inhibitors of CYP3A4 include:

Itraconazole, ketoconazole, and other antifungal azoles,

Macrolide antibiotics erythromycin, clarithromycin, and telithromycin,

HIV protease inhibitors,

Antidepressant nefazodone,

Grapefruit juice in large quantities (> 1 quart daily).

Potent inhibitors of CYP3A4 increase the risk of myopathy by reducing the elimination of simvastatin. Hence when simvastatin is used with a potent inhibitor of CYP3A4, elevated plasma levels of HMG-CoA reductase inhibitory activity can increase the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. [See Warnings and Precautions (5.1)]

Serious skeletal muscle disorder, e.g., rhabdomyolysis, have been reported during concomitant therapy of simvastatin or other HMG-CoA reductase inhibitors with cyclosporine, danazol, itraconazole, ketoconazole, gemfibrozil, niacin, erythromycin, clarithromycin, telithromycin, nefazodone or HIV protease inhibitors.

Concomitant use of drugs labeled as potent inhibitors of CYP3A4 should be avoided unless the benefits of combined therapy outweigh the increased risk. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with SIMCOR should be suspended during the course of treatment.

7.2 Cyclosporine or Danazol

Although the mechanism is not fully understood, cyclosporine has been shown to increase the area under the curve (AUC) of HMG-CoA reductase inhibitors. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4. The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol particularly with higher doses of simvastatin. [See Warnings and Precautions (5.1)]

7.3 Amiodarone or Verapamil

The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil with higher doses of simvastatin. [See Warnings and Precautions (5.1)]

7.4 Gemfibrozil and other Fibrates

Coadministration of gemfibrozil (600 mg twice daily for 3 days) with simvastatin (40 mg daily) resulted in clinically significant increases in simvastatin acid AUC (185%) and peak plasma concentration (Cmax,112%), possibly due to inhibition of simvastatin acid glucuronidation by gemfibrozil. The increase in simvastatin exposure increases the risk of myopathy when coadministred with gemfibrozil. The combined use of SIMCOR with gemfibrozil should be avoided [See Warnings and Precautions (5.1)]. The risk of myopathy also increases to a lesser extent when simvastatin is used in combination with other fibrates. Coadministration of 160 mg fenofibrate daily with 80 mg simvastatin daily for 7 days had no effect on plasma AUC (and Cmax) of either total HMG-CoA reductase inhibitory activity or fenofibric acid; there was a modest reduction (approximately 35%) of simvastatin acid which was not considered clinically significant.

7.5 Propranolol

In healthy male volunteers there was a significant decrease in mean Cmax, but no change in AUC, for simvastatin total and active inhibitors with concomitant administration of single doses of simvastatin and propranolol. The clinical relevance of this finding is unclear. The pharmacokinetics of the enantiomers of propranolol were not affected.

7.6 Digoxin

Concomitant administration of a single dose of digoxin in healthy male volunteers receiving simvastatin resulted in a slight elevation (less than 0.3 ng/mL) in digoxin concentrations in plasma (as measured by a radioimmunoassay) compared to concomitant administration of placebo and digoxin. Patients taking digoxin should be monitored appropriately when SIMCOR is initiated.

7.7 Coumarin Anticoagulants

In normal volunteers and hypercholesterolemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants since the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteers and patients, respectively. With other reductase inhibitors, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting SIMCOR and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of SIMCOR is changed or discontinued, the same procedure should be repeated.

Niacin

7.8 Aspirin

Concomitant use of aspirin may decrease the metabolic clearance of niacin. The clinical relevance of this finding is unclear.

7.9 Antihypertensive Therapy

Niacin may potentiate the effects of ganglionic blocking agents and vasoactive drugs resulting in postural hypotension.

7.10 Bile Acid Sequestrants

An in vitro study was carried out investigating the niacin-binding capacity of colestipol and cholestyramine. About 98% of available niacin was bound to colestipol, with 10 to 30% binding to cholestyramine. These results suggest that 4 to 6 hours, or as great an interval as possible, should elapse between the ingestion of bile acid-binding resins and the administration of SIMCOR.

7.11 Other

Nutritional supplements containing large doses of niacin or related compounds may potentiate the adverse effects of SIMCOR.

8.1 Pregnancy

Pregnancy Category X – [See Contraindications (4)]

SIMCOR is contraindicated in women who are or may become pregnant. Lipid lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Serum cholesterol and triglycerides increase during normal pregnancy. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of SIMCOR use during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to HMG-CoA reductase inhibitors in utero. Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. SIMCOR may cause fetal harm when administered to a pregnant woman. If SIMCOR is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

SIMCOR contains simvastatin (a HMG-CoA reductase inhibitor) and niacin (nicotinic acid). There are rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed those expected in the general population. However, the study was only able to exclude a 3- to 4-fold increased risk of congenital anomalies over the background rate. In 89% of these cases, drug treatment was initiated prior to pregnancy and was discontinued during the first trimester when pregnancy was identified. It is not known whether niacin at doses used for lipid disorders can cause fetal harm when administered to a pregnant woman.

Simvastatin was not teratogenic in rats or rabbits at doses that resulted in 3 times the human exposure based on mg/m2 surface area. However, in studies with another structurally-related HMG-CoA reductase inhibitor, skeletal malformations were observed in rats and mice. Animal reproduction studies have not been conducted with niacin.

Women of childbearing potential, who require SIMCOR treatment for a lipid disorder, should use effective contraception. Patients trying to conceive should contact their prescriber to discuss stopping SIMCOR treatment. If pregnancy occurs, SIMCOR should be immediately discontinued.

8.3 Nursing Mothers

It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Niacin is excreted into human milk but the actual infant dose or infant dose as a percent of the maternal dose is not known. Because of the potential for serious adverse reactions in nursing infants, nursing mothers who require SIMCOR treatment should not breastfeed their infants. A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. [see Contraindications (4)].

8.4 Pediatric Use

The safety and effectiveness of SIMCOR in pediatric patients have not been established.

8.5 Geriatric Use

There were 281 (30.8%) patients aged 65 years and older treated with SIMCOR in Phase III clinical studies. No overall differences in safety and effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. A pharmacokinetic study with simvastatin showed the mean plasma level of HMG-CoA reductase inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age.

8.6 Gender

Data from the clinical trials suggest that women have a greater hypolipidemic response than men at equivalent doses of niacin extended-release. No consistent gender differences in efficacy and safety were observed in SIMCOR studies.

8.7 Renal Impairment

No pharmacokinetic studies have been conducted in patients with renal impairment for SIMCOR. Caution should be exercised when SIMCOR is administered to patients with renal disease. For patients with severe renal insufficiency, SIMCOR should not be started unless the patient has already tolerated treatment with simvastatin at a dose of 10 mg or higher. Caution should be exercised when SIMCOR is administered to these patients and they should be closely monitored.

8.8 Hepatic Impairment

No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for SIMCOR. [See Warnings and Precautions (5.2)]

12.1 Mechanism of Action

Niacin

Niacin functions in the body after conversion to nicotinamide adenine dinucleotide (NAD) in the NAD coenzyme system. The mechanism by which niacin alters lipid profiles is not completely understood and may involve several actions, including partial inhibition of release of free fatty acids from adipose tissue, and increased lipoprotein lipase activity (which may increase the rate of chylomicron triglyceride removal from plasma). Niacin decreases the rate of hepatic synthesis of VLDL-C and LDL-C, and does not appear to affect fecal excretion of fats, sterols, or bile acids.

Simvastatin

Simvastatin is a prodrug and is hydrolyzed to its active ß-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C.

12.2 Pharmacodynamics

A variety of clinical studies have demonstrated that elevated levels of Total-C, LDL-C, and Apo B promote human atherosclerosis. Similarly, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiological investigations have established that cardiovascular morbidity and mortality vary directly with the level of Total-C and LDL-C, and inversely with the level of HDL-C.

Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate-density lipoprotein (IDL), and their remnants, can also promote atherosclerosis. Elevated plasma TG are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease (CHD). As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

SIMCOR

SIMCOR reduces total-C, LDL-C, non-HDL-C, Apo B, TG, and Lp(a) levels and increases HDL-C in patients with primary hyperlipidemia, mixed dyslipidemia, or hypertriglyceridemia.

Niacin

Niacin (but not nicotinamide) in gram doses reduces LDL-C, Apo B, Lp(a), TG, and Total-C, and increases HDL-C. The magnitude of individual lipid and lipoprotein responses may be influenced by the severity and type of underlying lipid abnormality. The increase in HDL-C is associated with an increase in apolipoprotein A-I (Apo A-I) and a shift in the distribution of HDL subfractions. These shifts include an increase in the HDL2:HDL3 ratio, and an elevation in lipoprotein A-I (Lp A-I, an HDL-C particle containing only Apo A-I). Niacin treatment also decreases serum levels of apolipoprotein B-100 (Apo B), the major protein component of the very low-density lipoprotein (VLDL) and LDL fractions, and of Lp(a), a variant form of LDL independently associated with coronary risk. In addition, preliminary reports suggest that niacin causes favorable LDL particle size transformations, although the clinical relevance of this effect requires further investigation.

Simvastatin

Simvastatin reduces elevated total-C, LDL-C, Apo B, and TG, and increases HDL-C in patients with primary heterozygous familial and nonfamilial hypercholesterolemia and mixed dyslipidemia. Simvastatin reduces total-C and LDL-C in patients with homozygous familial hypercholesterolemia. Simvastatin decreases VLDL, total-C/HDL-C ratio, and LDL-C/HDL-C ratio.

12.3 Pharmacokinetics

Absorption and Bioavailability

SIMCOR

The relative bioavailability of niacin (Nicotinuric acid, NUA, Cmax and total urinary excretion as the surrogate), simvastatin, and simvastatin acid was evaluated under a light snack conditions in healthy volunteers (n=42), following administration of two 1000/20 mg SIMCOR tablets. Niacin exposure (Cmax and AUC) after SIMCOR was similar to that of a niacin extended-release formulation. However, simvastatin and simvastatin acid AUC after SIMCOR increased by 23% and 41%, respectively, compared to those of a simvastatin immediate release formulation. The mean time to Cmax (Tmax) for niacin ranged from 4.6 to 4.9 hours and simvastatin from 1.9 to 2.0 hours. Following administration of 2 x 1000/20 mg SIMCOR, the mean Cmax, Tmax and AUC(0-t) for simvastatin acid, active metabolite of simvastatin, were 3.29 ng/mL, 6.56 hours and 30.81 ng.hr/mL respectively.

Bioequivalence has not been evaluated among different SIMCOR dosage strengths except between 1000/40 and 500/20 mg. SIMCOR tablets 1000/40 mg and 500/20 mg were bioequivalent following a single dose of 2000/80 mg. Therefore, dosage strengths of SIMCOR should not be considered exchangeable except between these two strengths.

Niacin

Due to extensive and saturable first-pass metabolism, niacin concentrations in the general circulation are dose dependent and highly variable. Peak steady-state niacin concentrations were 0.6, 4.9, and 15.5 mcg/mL after doses of 1000, 1500, and 2000 mg NIASPAN once daily (given as two 500 mg, two 750 mg, and two 1000 mg tablets, respectively). To reduce the risk of gastrointestinal upset, administration of niacin extended-release with a low-fat meal or snack is recommended.

Simvastatin

Since simvastatin undergoes extensive first-pass extraction in the liver, the availability of the drug to the general circulation is low (<5%). Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. Following an oral dose of 14C-labeled simvastatin in man, plasma concentration of total radioactivity (simvastatin plus 14C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal.

Metabolism

SIMCOR

Following administration of SIMCOR, niacin and simvastatin undergo rapid and extensive first-pass metabolism as described in the following niacin and simvastatin sections. Following administration of 2 x 1000/20 mg SIMCOR in healthy volunteers, 10.2%, 10.7%, and 29.5% of the administered niacin dose was recovered in urine as niacin metabolites, NUA, N-methylnicotinamide (MNA), and N-methyl-2-pyridone-5-carboxamide (2PY), respectively. Following administration of 2 x 1000/20 mg SIMCOR, the mean Cmax, Tmax, and AUC(0-t) for the simvastatin metabolite, simvastatin acid were 3.29 ng/mL, 6.56hours, and 30.81ng·hr/mL respectively.

Niacin

Niacin undergoes rapid and extensive first-pass metabolism that is dose-rate specific and, at the doses used to treat dyslipidemia, saturable. In humans, one pathway is through a simple conjugation step with glycine to form NUA. NUA is then excreted, although there may be a small amount of reversible metabolism back to niacin. The other pathway results in the formation of nicotinamide adenine dinucleotide (NAD). It is unclear whether nicotinamide is formed as a precursor to, or following the synthesis of, NAD. Nicotinamide is further metabolized to at least MNA and nicotinamide-N-oxide NNO. MNA is further metabolized to two other compounds, 2PY and N-methyl-4-pyridone-5-carboxamide (4PY). The formation of 2PY appears to predominate over 4PY in humans.

Simvastatin

Simvastatin is a substrate of CYP3A4. Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of simvastatin and its 6’-hydroxy, 6’-hydroxymethyl, and 6’-exomethylene derivatives.

Elimination

SIMCOR

Following 2 x 1000/20 mg SIMCOR administration, approximately 54% of the niacin dose administered was recovered in urine in 96 hours as niacin and metabolites of which 3.6% was recovered as niacin.

After SIMCOR administration, the mean terminal plasma half-life for simvastatin was 4.2 to 4.9 hours and for simvastatin acid was 4.6 to 5.0 hours.

Niacin

Niacin and its metabolites are rapidly eliminated in the urine. Following single and multiple doses of 1500 to 2000 mg niacin, approximately 53 to 77% of the niacin dose administered as NIASPAN was recovered in urine as niacin and metabolites; up to 7.7% of the dose was recovered in urine as unchanged niacin after multiple dosing with 2 x 1000 mg NIASPAN. The ratio of metabolites recovered in the urine was dependent on the dose administered.

Simvastatin

Simvastatin is excreted in urine, based on studies in humans. Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces.

Special Populations

A pharmacokinetic study with simvastatin showed the mean plasma level of HMG-CoA reductase inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age.

Steady-state plasma concentrations of niacin and metabolites after administration of niacin extended-release are generally higher in women than in men, with the magnitude of the difference varying with dose and metabolite. Recovery of niacin and metabolites in urine, however, is generally similar for men and women, indicating that absorption is similar for both genders. The gender differences observed in plasma levels of niacin and its metabolites may be due to gender-specific differences in metabolic rate or volume of distribution.

Pharmacokinetic studies with a statin having a similar principal route of elimination to that of simvastatin have suggested that for a given dose level, higher systemic exposure may be achieved in patients with severe renal insufficiency (as measured by creatinine clearance).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted with SIMCOR regarding carcinogenesis, mutagenesis, or impairment of fertility.

Niacin

Niacin, administered to mice for a lifetime as a 1% solution in drinking water, was not carcinogenic. The mice in this study received approximately 6 to 8 times a human dose of 3000 mg/day as determined on a mg/m2 basis. Niacin was negative for mutagenicity in the Ames test. No studies on impairment of fertility have been performed.

Simvastatin

In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day.

In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC). In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC). A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other HMG-CoA reductase inhibitors. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after an 80 milligram daily dose. No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow. There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180 mg/kg/day, (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m2), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day, (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear.

13.2 Animal Toxicology and/or Pharmacology

SIMCOR

No animal toxicology or pharmacology studies were done with SIMCOR.

Niacin

No animal toxicology or pharmacology studies were done with niacin extended-release.

Simvastatin

Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean plasma drug level in humans taking 80 mg/day. A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.

Central Nervous System (CNS) vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels were seen in dogs treated with simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/day. Similar CNS vascular lesions have been observed with several other drugs of this class.

There were cataracts in female rats after two years of simvastatin treatment with 50 and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (19 times) and at two years at 50 mg/kg/day (5 times).

Reproductive Toxicology Studies

Simvastatin was not teratogenic in rats at doses of 25 mg/kg/day or in rabbits at doses up to 10 mg/kg/day. These doses resulted in 3 times (rat) or 3 times (rabbit) the human exposure based on mg/m2 surface area. However, in studies with another structurally-related HMG-CoA reductase inhibitor, skeletal malformations were observed in rats and mice.

14.1 Modifications of Lipid Profiles

SIMCOR

In a double-blind, randomized, multicenter, multi-national, active-controlled, 24-week study, the lipid effects of SIMCOR were compared to simvastatin 20 mg and 80 mg in 641 patients with type II hyperlipidemia or mixed dyslipidemia. Following a lipid qualification phase, patients were eligible to enter one of two treatment groups. In Group A, patients on simvastatin 20 mg monotherapy with elevated non-HDL levels and LDL-C levels at goal, per the NCEP guidelines, were randomized to one of three treatment arms: SIMCOR 1000/20 mg, SIMCOR 2000/20 mg, or simvastatin 20 mg. In Group B, patients on simvastatin 40 mg monotherapy, with elevated non-HDL levels per the NCEP guidelines regardless of attainment of LDL-C goals, were randomized to one of three treatment arms: SIMCOR 1000/40 mg, SIMCOR 2000/40 mg, or simvastatin 80 mg. Therapy was initiated at the 500 mg dose of SIMCOR and increased by 500 mg every four weeks. Thus patients were titrated to the 1000 mg dose of SIMCOR after four weeks and to the 2000 mg dose of SIMCOR after 12 weeks. All patients randomized to simvastatin monotherapy received 50 mg immediate-release niacin daily in an attempt to keep the study from becoming unblinded due to flushing in the SIMCOR groups. Patients were instructed to take one 325 mg aspirin 30 minutes prior to taking the double-blind medication to help minimize flushing effects.

In Group A, the primary efficacy analysis was a comparison of the mean percent change in non-HDL levels between the SIMCOR 2000/20 mg and simvastatin 20 mg groups, and if statistically significant, then a comparison was conducted between the SIMCOR 1000/20 mg and simvastatin 20 mg groups. In Group B, the primary efficacy analysis was a determination of whether the mean percent change in non-HDL in the SIMCOR 2000/40 mg group was non-inferior to the mean percent change in the simvastatin 80 mg group, and if so, whether the mean percent change in non-HDL in the SIMCOR 1000/40 mg group was non-inferior to the mean percent change in the simvastatin 80 mg group.

In Group A, the non-HDL-C lowering with SIMCOR 2000/20 and SIMCOR 1000/20 was statistically significantly greater than that achieved with simvastatin 20 mg after 24 weeks (p<0.05; Table 4). The completion rate after 24 weeks was 72% for the SIMCOR arms and 88% for the simvastatin 20 mg arm. In Group B, the non-HDL-C lowering with SIMCOR 2000/40 and SIMCOR 1000/40 was non-inferior to that achieved with simvastatin 80 mg after 24 weeks (Table 5). The completion rate after 24 weeks was 78% for the SIMCOR arms and 80% for the simvastatin 80 mg arm.

SIMCOR was not superior to simvastatin in lowering LDL-C in either Group A or Group B. However, SIMCOR was superior to simvastatin in both groups in lowering TG and raising HDL (Tables 6 and 7).

Limitations of use

No incremental benefit of SIMCOR on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin monotherapy and niacin monotherapy has been established.

17.1 Dosing Time

SIMCOR tablets should be taken at bedtime, after a low-fat snack. Administration on an empty stomach is not recommended.

17.2 Tablet Integrity

SIMCOR tablets should not be broken, crushed or chewed, but should be swallowed whole.

17.3 Dosing Interruption

If dosing is interrupted for any length of time, their physician should be contacted prior to re-starting therapy; re-titration is recommended.

17.4 Muscle Pain

To notify their physician of any unexplained muscle pain, tenderness, or weakness promptly. The risk of this occurring is increased when taking certain types of medication or consuming larger quantities of grapefruit juice. They should discuss all medication, both prescription and over the counter, with their physician.

17.5 Flushing

Flushing is a common side effect of niacin therapy that may subside after several weeks of consistent SIMCOR use. Flushing may vary in severity and is more likely to occur with initiation of therapy, or during dose increases. By dosing at bedtime, flushing will most likely occur during sleep. However, if awakened by flushing at night, the patient should get up slowly, especially if feeling dizzy, feeling faint, or taking blood pressure medications.

17.6 Use of Aspirin

Taking aspirin approximately 30 minutes before dosing can minimize flushing.

17.7 Diet

To avoid ingestion of alcohol, hot beverages and spicy foods around the time of taking SIMCOR to minimize flushing.

17.8 Supplements

To notify their physician if they are taking vitamins or other nutritional supplements containing niacin or nicotinamide.

17.9 Dizziness

To notify their physician if symptoms of dizziness occur.

17.10 Diabetics

If diabetic, to notify their physician of changes in blood glucose.

17.11 Pregnancy

Women of childbearing age should use an effective method of birth control to prevent pregnancy while using SIMCOR. Discuss future pregnancy plans with your healthcare professional, and discuss when to stop SIMCOR if you are trying to conceive. If you are pregnant, stop SIMCOR and call your healthcare professional.

17.12 Breastfeeding

Women who are breastfeeding should not use SIMCOR. If you have a lipid disorder and are breastfeeding, speak with your healthcare professionals about your lipid disorder and whether or not you should breastfeed your infant.

Manufactured by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617

for Abbott Laboratories North Chicago, IL 60064, U.S.A.

Relabeling and Repackaging by:   Physicians Total Care, Inc.,  Tulsa, OK  74146

Simcor® Niacin Extended-Release/ Simvastatin Tablets 1000 mg/40 mg