Simvastatin Niacin Extended Release

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 (HMGCoA) 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.

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.

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 extendedrelease 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).

Drug Interaction

Effect Of Other Drugs On Simvastatin

Table 5 : Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure

Coadministered Drug or Grapefruit Juice	Dosing of Coadministered Drug or Grapefruit Juice	Dosing of Simvastatin	Geometric Mean Ratio (Ratio* with / without coadministered drug) No Effect = 1.00
				AUC	Cmax
Contraindicated with simvastatin [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
Telithromycin†	200 mg QD for 4 days	80 mg	simvastati nacid‡	12	15
			simvastatin	8.9	5.3
Nelfinavir†	1250 mg BID for 14 days	20 mg QD for 28 days	simvastatin acid‡
			simvastatin	6	6.2
Itraconazole†	200 mg QD for 4 days	80 mg	simvastatin acid‡		13.1
			simvastatin		13.1
Posaconazole	100 mg (oral suspension) QD for 13 days	40 mg	simvastatin acid	7.3	9.2
			simvastatin	10.3	9.4
	200 mg (oral suspension) QD for 13 days	40 mg	simvastatin acid	8.5	9.5
			simvastatin	10.6	11.4
Gemfibrozil	600 mg BID for 3 days	40 mg	simvastatin acid	2.85	2.18
			simvastatin	1.35	0.91
Avoid > 1 quart of grapefruit juice with simvastatin [see WARNINGS AND PRECAUTIONS]
Grapefruit Juice§ (high dose)	200 mL of double-strength TID¶	60 mg single dose	simvastati nacid	7
			simvastatin	16
Grapefruit Juice§ (low dose)	8 oz (about 237 mL) of singlestrength#	20 mg single dose	simvastatin acid	1.3
			simvastatin	1.9
Avoid taking with > 10 mg simvastatin, based on clinical and/or post-marketing experience [see WARNINGS AND PRECAUTIONS]
Verapamil SR	240 mg QD Days 1-7 then 240 mg BID on Days 8-10	80 mg on Day 10	simvastatin acid	2.3	2.4
			simvastatin	2.5	2.1
Diltiazem	120 mg BID for 10 days	80 mg on Day 10	simvastatin acid	2.69	2.69
			simvastatin	3.10	2.88
Diltiazem	120 mg BID for 14 days	20 mg on Day 14	simvastatin	4.6	3.6
Avoid taking with > 20 mg simvastatin, based on clinical and/or post-marketing experience [see WARNINGS AND PRECAUTIONS]
Amiodarone	400 mg QD for 3 days	40 mg on Day 3	simvastatin acid	1.75	1.72
			simvastatin	1.76	1.79
Amlodipine	10 mg QD for 10 days	80 mg on Day 10	simvastatin acid	1.58	1.56
			simvastatin	1.77	1.47
Ranolazine SR	1000 mg BID for 7 days	80 mg on Day 1, and Day 6-9	simvastatin acid	2.26	2.28
			simvastatin	1.86	1.75
No dosing adjustmentsrequired for the following:
Fenofibrate	160 mg QD for 14 days	80 mg QD on Days 8-14	simvastatin acid	0.64	0.89
			simvastatin	0.89	0.83
Niacin extended-release Þ	2 g single dose	20 mg single dose	simvastatin acid	1.6	1.84
			simvastatin	1.4	1.08
Propranolol	80 mg single dose	80 mg single dose	total inhibitor	0.79	↓ from 33.6 to 21.1 ng-eq/mL
			active inhibitor	0.79	↓ from 7.0 to 4.7 ng-eq/mL
*Results based on a chemical assay except results with propranolol as indicated. †Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone. ‡Simvastatin acid refers to the β-hydroxyacid of simvastatin. The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied. ¶Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3. #Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3. ÞBecause Chinese patients have an increased risk for myopathy with simvastatin coadministered with lipid-modifying doses ( ≥ 1 gram/day niacin) of niacin-containing products, and the risk is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products [see WARNINGS AND PRECAUTIONS].

Simvastatin Effect On Other Drugs

In a study of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4, and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4.

Coadministration of simvastatin (40 mg QD for 10 days) resulted in an increase in the maximum mean levels of cardioactive digoxin (given as a single 0.4 mg dose on day 10) by approximately 0.3 ng/mL.

Niacin Effect On Other Drugs

Niacin did not affect fluvastatin pharmacokinetics.

When NIASPAN 2000 mg and lovastatin 40 mg were co-administered, NIASPAN increased lovastatin Cmax and AUC by 2% and 14%, respectively, and decreased lovastatin acid Cmax and AUC by 22% and 2%, respectively. Lovastatin reduced NIASPAN bioavailability by 2-3%.

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.

Clinical Studies

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 6). 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 7). 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 8 and 9).

Table 6: Non-HDL Treatment Response Following 24-Week Treatment Mean Percent Change from Simvastatin 20-mg Treated Baseline

Week	SIMCOR 2000/20			SIMCOR 1000/20			Simvastatin 20
	na	dose (mg/mg)	non-HDLb	na	Dose (mg/mg)	non-HDLb	na	Dose (mg/mg)	non-HDLb
Baseline	56	---	163.1 mg/dL	108	---	164.8 mg/dL	102	---	163.7 mg/dL
4	52	500/20	-12.9%	86	500/20	-12.8%	91	20	-8.3%
8	46	1000/20	-17.5%	91	1000/20	-15.5%	95	20	-8.3%
12	46	1500/20	-18.9%	90	1000/20	-14.8%	96	20	-6.4%
24	40	2000/20	-19.5%†	78	1000/20	-13.6%t	90	20	-5.0%
Dropouts by week 24:	28.6%			27.8%			11.8%
an=number of subjects with values in the analysis window at each timepoint bThe percent change from baseline is the model-based mean from a repeated measures mixed model with no imputation for missing data from study dropouts. †significant vs. simvastatin 20 mg at the primary endpoint (Week 24), p < 0.05

Table 7: Non-HDL Treatment Response Following 24-Week Treatment Mean Percent Change from Simvastatin 40-mg Treated Baseline

Week	SIMCOR 2000/40			SIMCOR 1000/40			Simvastatin 80
	na	dose (mg/mg)	non-HDLb	na	Dose (mg/mg)	non-HDLb	na	Dose (mg/mg)	non-HDLb
Baseline	98	---	144.4 mg/dL	111	---	141.2 mg/dL	113	---	134.5 mg/dL
4	96	500/40	-6.0%	108	500/40	-5.9%	110	80	-11.3%
8	93	1000/40	-15.5%	100	1000/40	-16.2%	104	80	-13.7%
12	90	1500/40	-18.4%	97	1000/40	-12.6%	100	80	-9.5%
24	80	2000/40	-7.6%c	82	1000/40	-6.7%d	90	80	-6.0%
Dropouts by week 24:	18.4%			26.1%			20.4%
an=number of subjects with values in the analysis window at each timepoint bThe percent change from baseline is the model-based mean from a repeated measures mixed model with no imputation for missing data from study dropouts. cnon-inferior to Simvastatin 80 arm; 95% confidence interval of mean difference in non-HDL for SIMCOR 2000/40 vs. Simvastatin 80 is (-7.7%, 4.5%) dnon-inferior to Simvastatin 80 arm; 95% confidence interval of mean difference in non-HDL for SIMCOR 1000/40 vs. SIMCOR 80 is (-6.6%, 5.3%)

Table 8: Mean Percent Change from Bas eline to Week 24 in Lipoprotein Lipid Levels

TREATMENT	Treatment Group A
	N	LDL-C	Total-C	HDL-C	TGa	Apo B
Baseline (mg/dL)*	266	120	207	43	209	102
Simvastatin 20 mg	102	-6.7%	-4.5%	7.8%	-15.3%	-5.6%
SIMCOR 1000/20	108	-11.9%	-8.8%	20.7%	-26.5%	-13.2%
SIMCOR 2000/20	56	-14.3%	-11.1%	29.0%	-38.0%	-18.5%
*either treatment naïve or after receiving simvastatin 20 mg amedians are reported for TG

Table 9: Mean Percent Change from Baseline to Week 24 in Lipoprotein Lipid Levels

TREATMENT	Treatment Group B
	N	LDL-C	Total-C	HDL-C	TGa	Apo B
Baseline(mg/dL)*	322	108	187	47	145	93
Simvastatin 80 mg	113	-11.4%	-6.2%	0.1%	0.3%	-7.5%
SIMCOR 1000/40	111	-7.1%	-3.1%	15.4%	-22.8%	-7.7%
SIMCOR 2000/40	98	-5.1%	-1.6%	24.4%	-31.8%	-10.5%
*after receiving simvastatin 40 mg amedians are reported for TG