Simcor Information
Simcor () Indications And Usage
Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.
Simcor ()
Simcor () Dosage Forms And Strengths
Simcor () tablets are formulated for oral administration in the following strength combinations:
Simcor ()
Simcor ()
Simcor () Adverse Reactions
In a controlled clinical study, 14% of patients randomized to Simcor () discontinued therapy due to an adverse event. Flushing episodes (i.e., warmth, redness, itching and/or tingling) were the most common treatment-emergent adverse reactions, occurring in up to 59% of patients treated with Simcor () . Spontaneous reports with niacin extended-release and clinical studies of Simcor () suggest that flushing may be accompanied by symptoms of dizziness or syncope, tachycardia, palpitations, shortness of breath, sweating, burning sensation/skin burning sensation, chills, and/or edema.
Simcor () Drug Interactions
No drug interaction studies were conducted with Simcor () . However, the following interactions have been noted with the individual components of Simcor () :
Simcor () Use In Specific Populations
Pregnancy Category X –
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 . 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/m 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.
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.
Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, Simcor () should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients
Simcor () Overdosage
Supportive measures should be taken in the event of an overdose. The dialyzability of niacin, or of simvastatin and its metabolites, is not known.
A few cases of overdosage with simvastatin have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae.
Simcor () Description
Simcor () tablets contain niacin extended-release (NIASPAN) and simvastatin in combination. Simvastatin, an inhibitor of HMG-CoA reductase, and niacin are both lipid-altering agents.
Niacin is nicotinic acid, or 3-pyridinecarboxylic acid. Niacin is a white, nonhygroscopic crystalline powder that is very soluble in water, boiling ethanol, and propylene glycol. It is insoluble in ethyl ether. The empirical formula of niacin is CHNO and its molecular weight is 123.11. Niacin has the following structural formula:
Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3-7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S-[1α,3α,7β,8β(2S*4S*),-8aβ]]. Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water and freely soluble in chloroform, methanol, and ethanol. The empirical formula of simvastatin is CHO and its molecular weight is 418.57. Simvastatin has the following structural formula:
Simcor () is available for oral administration as tablets containing 500 mg of niacin extended-release (NIASPAN) and 20 mg simvastatin (Simcor () 500/20 mg), 500 mg of niacin extended-release (NIASPAN) and 40 mg simvastatin (Simcor () 500/40 mg), 750 mg of niacin extended-release (NIASPAN) and 20 mg simvastatin (Simcor () 750/20 mg), 1000 mg of niacin extended-release (NIASPAN) and 20 mg simvastatin (Simcor () 1000/20 mg) and 1000 mg of niacin extended-release (NIASPAN) and 40 mg simvastatin (Simcor () 1000/40 mg). Each tablet contains the following inactive ingredients: hypromellose, povidone, stearic acid, polyethylene glycol, butylated hydroxyanisole, FD&C Blue #2, lactose monohydrate, titanium dioxide, triacetin. Simcor () 500/20 mg, Simcor () 750/20 mg, and Simcor () 1000/20 mg also contain iron oxide.
Simcor () Clinical Pharmacology
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.
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.
Absorption and Bioavailability
Simcor ()
The relative bioavailability of niacin (Nicotinuric acid, NUA, C 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 (C 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 (T) 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 C, T and AUC 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 (
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 C, T, and AUC 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 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 C-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).
Drug Interaction
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%.
Simcor () Nonclinical Toxicology
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/m 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 alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an chromosome aberration study in CHO cells, or an 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/m), 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.
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/m surface area. However, in studies with another structurally-related HMG-CoA reductase inhibitor, skeletal malformations were observed in rats and mice.
Simcor () How Supplied/storage And Handling
Simcor () 500 mg/20 mg, 750 mg/20 mg and 1000 mg/20 mg tablets are available as blue, unscored, tablets, printed with black ink and packaged in bottles of 90 tablets. Simcor () 500 mg/40 mg and 1000 mg/40 mg tablets are available as dark blue, unscored, tablets, printed with white ink and packaged in bottles of 90 tablets. Each tablet is printed on one side with the Abbott “A” and a code number specific to the tablet strength. Please see the table below:
Storage: Store at controlled room temperature 20º-25ºC (68º-77ºF).
Simcor () Patient Counseling Information
Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel.
Patients should be advised about substances they should not take concomitantly with simvastatin . Patients should also be advised to inform other healthcare professionals prescribing a new medication or increasing the dose of an existing medication that they are taking Simcor () .
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