text:
vytorin (ezetimibe and simvastatin) tablet
[Merck/Schering-Plough Pharmaceuticals]
VYTORIN contains ezetimibe, a selective inhibitor of intestinal cholesterol and related phytosterol absorption, and simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor.
The chemical name of ezetimibe is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]- 4(S)-(4-hydroxyphenyl)-2-azetidinone. The empirical formula is C24H21F2NO3 and its molecular weight is 409.4.
Ezetimibe is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water. Its structural formula is:
Simvastatin, an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form, which is an inhibitor of HMG-CoA reductase. 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]]. The empirical formula of simvastatin is C25H38O5 and its molecular weight is 418.57.
Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol. Its structural formula is:
VYTORIN is available for oral use as tablets containing 10 mg of ezetimibe, and 10 mg of simvastatin (VYTORIN 10/10), 20 mg of simvastatin (VYTORIN 10/20), 40 mg of simvastatin (VYTORIN 10/40), or 80 mg of simvastatin (VYTORIN 10/80). Each tablet contains the following inactive ingredients: butylated hydroxyanisole NF, citric acid monohydrate USP, croscarmellose sodium NF, hydroxypropyl methylcellulose USP, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, and propyl gallate NF.
Clinical studies have demonstrated that elevated levels of total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (Apo B), the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of high-density lipoprotein cholesterol (HDL-C) are associated with the development of atherosclerosis. Epidemiologic studies 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 very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering triglycerides (TG) on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. VYTORIN contains ezetimibe and simvastatin, two lipid-lowering compounds with complementary mechanisms of action. VYTORIN reduces elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C through dual inhibition of cholesterol absorption and synthesis.
Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. In a 2-week clinical study in 18 hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E and did not impair adrenocortical steroid hormone production.
Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of HMG-CoA reductase inhibitors (see CLINICAL STUDIES).
Simvastatin reduces cholesterol by inhibiting the conversion of HMG-CoA to mevalonate, an early step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C.
VYTORIN is bioequivalent to coadministered ezetimibe and simvastatin.
After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide).
Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as 10-mg tablets. The Cmax value of ezetimibe was increased by 38% with consumption of high-fat meals.
Relative to the fasting state, the plasma profiles of both active and total inhibitors of HMG-CoA reductase were not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal.
Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.
Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. When radiolabeled simvastatin was administered to rats, simvastatin-derived radioactivity crossed the blood-brain barrier.
Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation with subsequent biliary and renal excretion. Minimal oxidative metabolism has been observed in all species evaluated.
In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.
Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma.
Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose.
Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is a basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin. 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.
Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (simvastatin plus 14C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Since simvastatin undergoes extensive first-pass extraction in the liver, the availability of the drug to the general circulation is low (<5%).
In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2-fold higher in older (≥65 years) healthy subjects compared to younger subjects.
In a study including 16 elderly patients between 70 and 78 years of age who received simvastatin 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18-30 years of age.
In a multiple-dose study with ezetimibe given 10 mg once daily for 7 days, the absorption and metabolism of ezetimibe were similar in adolescents (10 to 18 years) and adults. Based on total ezetimibe, there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population <10 years of age are not available.
In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (<20%) in women than in men.
Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe were similar to those seen in Caucasian subjects.
After a single 10-mg dose of ezetimibe, the mean exposure (based on area under the curve [AUC]) to total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic insufficiency (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe increased approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic insufficiency, the mean AUC for total ezetimibe and ezetimibe increased approximately 4-fold compared to healthy subjects.
After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤30 mL/min/1.73 m2), the mean AUC for total ezetimibe and ezetimibe increased approximately 1.5-fold, compared to healthy subjects (n=9).
Pharmacokinetic studies with another 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).
(See also PRECAUTIONS, Drug Interactions)
No clinically significant pharmacokinetic interaction was seen when ezetimibe was coadministered with simvastatin. Specific pharmacokinetic drug interaction studies with VYTORIN have not been performed.
Cytochrome P450: Ezetimibe had no significant effect on a series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a "cocktail" study of twelve healthy adult males. This indicates that ezetimibe is neither an inhibitor nor an inducer of these cytochrome P450 isozymes, and it is unlikely that ezetimibe will affect the metabolism of drugs that are metabolized by these enzymes.
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.
Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4.
Simvastatin is a substrate for CYP3A4. Potent inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy. (See WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions.)
Antacids: In a study of twelve healthy adults, a single dose of antacid (SupraloxTM 20 mL) administration had no significant effect on the oral bioavailability of total ezetimibe, ezetimibe-glucuronide, or ezetimibe based on AUC values. The Cmax value of total ezetimibe was decreased by 30%.
Cholestyramine: In a study of forty healthy hypercholesterolemic (LDL-C ≥130 mg/dL) adult subjects, concomitant cholestyramine (4 g twice daily) administration decreased the mean AUC of total ezetimibe and ezetimibe approximately 55% and 80%, respectively.
Cyclosporine: In a study of eight post-renal transplant patients with mildly impaired or normal renal function (creatinine clearance of >50 mL/min), stable doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and Cmax values of total ezetimibe 3.4-fold (range 2.3- to 7.9-fold) and 3.9-fold (range 3.0- to 4.4-fold), respectively, compared to a historical healthy control population (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. In a two-period crossover study in twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days with a single 100-mg dose of cyclosporine on Day 7 resulted in a mean 15% increase in cyclosporine AUC (range 10% decrease to 51% increase) compared to a single 100-mg dose of cyclosporine alone (see PRECAUTIONS, Drug Interactions).
Fenofibrate: In a study of thirty-two healthy hypercholesterolemic (LDL-C ≥130 mg/dL) adult subjects, concomitant fenofibrate (200 mg once daily) administration increased the mean Cmax and AUC values of total ezetimibe approximately 64% and 48%, respectively. Pharmacokinetics of fenofibrate were not significantly affected by ezetimibe (10 mg once daily).
Coadministration of fenofibrate (160 mg daily) with simvastatin (80 mg 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 (see WARNINGS, Myopathy/Rhabdomyolysis, PRECAUTIONS, Drug Interactions).
Gemfibrozil: In a study of twelve healthy adult males, concomitant administration of gemfibrozil (600 mg twice daily) significantly increased the oral bioavailability of total ezetimibe by a factor of 1.7. Ezetimibe (10 mg once daily) did not significantly affect the bioavailability of gemfibrozil.
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 Cmax (112%), possibly due to inhibition of simvastatin acid glucuronidation by gemfibrozil (see WARNINGS, Myopathy/Rhabdomyolysis, PRECAUTIONS, Drug Interactions, DOSAGE AND ADMINISTRATION).
Grapefruit Juice: Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma concentrations of drugs metabolized by CYP3A4. In one study1, 10 subjects consumed 200 mL of double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans of water) three times daily for 2 days and an additional 200 mL double-strength grapefruit juice together with, and 30 and 90 minutes following, a single dose of 60 mg simvastatin on the third day. This regimen of grapefruit juice resulted in mean increases in the concentration (as measured by the area under the concentration-time curve) of active and total HMG-CoA reductase inhibitory activity [measured using a radioenzyme inhibition assay both before (for active inhibitors) and after (for total inhibitors) base hydrolysis] of 2.4-fold and 3.6-fold, respectively, and of simvastatin and its β-hydroxyacid metabolite [measured using a chemical assay — liquid chromatography/tandem mass spectrometry] of 16-fold and 7-fold, respectively. In a second study, 16 subjects consumed one 8 oz glass of single-strength grapefruit juice (one can of frozen concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of 20 mg simvastatin in the evening of the third day. This regimen of grapefruit juice resulted in a mean increase in the plasma concentration (as measured by the area under the concentration-time curve) of active and total HMG-CoA reductase inhibitory activity [using a validated enzyme inhibition assay different from that used in the first1 study, both before (for active inhibitors) and after (for total inhibitors) base hydrolysis] of 1.13-fold and 1.18-fold, respectively, and of simvastatin and its β-hydroxyacid metabolite [measured using a chemical assay — liquid chromatography/tandem mass spectrometry] of 1.88-fold and 1.31-fold, respectively. The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied.
Lilja JJ, Kivisto KT, Neuvonen PJ. Clin Pharmacol Ther 1998;64(5):477-83.
The hypocholesterolemic effect of ezetimibe was evaluated in cholesterol-fed Rhesus monkeys, dogs, rats, and mouse models of human cholesterol metabolism. Ezetimibe was found to have an ED50 value of 0.5 µg/kg/day for inhibiting the rise in plasma cholesterol levels in monkeys. The ED50 values in dogs, rats, and mice were 7, 30, and 700 µg/kg/day, respectively. These results are consistent with ezetimibe being a potent cholesterol absorption inhibitor.
In a rat model, where the glucuronide metabolite of ezetimibe (ezetimibe-glucuronide) was administered intraduodenally, the metabolite was as potent as ezetimibe in inhibiting the absorption of cholesterol, suggesting that the glucuronide metabolite had activity similar to the parent drug.
In 1-month studies in dogs given ezetimibe (0.03 to 300 mg/kg/day), the concentration of cholesterol in gallbladder bile increased ~2- to 4-fold. However, a dose of 300 mg/kg/day administered to dogs for one year did not result in gallstone formation or any other adverse hepatobiliary effects. In a 14-day study in mice given ezetimibe (0.3 to 5 mg/kg/day) and fed a low-fat or cholesterol-rich diet, the concentration of cholesterol in gallbladder bile was either unaffected or reduced to normal levels, respectively.
A series of acute preclinical studies was performed to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of 14C-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins A and D.
In 4- to 12-week toxicity studies in mice, ezetimibe did not induce cytochrome P450 drug metabolizing enzymes. In toxicity studies, a pharmacokinetic interaction of ezetimibe with HMG-CoA reductase inhibitors (parents or their active hydroxy acid metabolites) was seen in rats, dogs, and rabbits.
VYTORIN reduces total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C in patients with hypercholesterolemia. Maximal to near maximal response is generally achieved within 2 weeks and maintained during chronic therapy.
VYTORIN is effective in men and women with hypercholesterolemia. Experience in non-Caucasians is limited and does not permit a precise estimate of the magnitude of the effects of VYTORIN.
Five multicenter, double-blind studies conducted with either VYTORIN or coadministered ezetimibe and simvastatin equivalent to VYTORIN in patients with primary hypercholesterolemia are reported: two were comparisons with simvastatin, two were comparisons with atorvastatin and one was a comparison with rosuvastatin.
In a multicenter, double-blind, placebo-controlled, 12-week trial, 1528 hypercholesterolemic patients were randomized to one of ten treatment groups: placebo, ezetimibe (10 mg), simvastatin (10 mg, 20 mg, 40 mg, or 80 mg), or VYTORIN (10/10, 10/20, 10/40, or 10/80).
When patients receiving VYTORIN were compared to those receiving all doses of simvastatin, VYTORIN significantly lowered total-C, LDL-C, Apo B, TG, and non-HDL-C. The effects of VYTORIN on HDL-C were similar to the effects seen with simvastatin. Further analysis showed VYTORIN significantly increased HDL-C compared with placebo. (See Table 1.) The lipid response to VYTORIN was similar in patients with TG levels greater than or less than 200 mg/dL.
|(Daily Dose)
|Apo B
|Pooled data (All VYTORIN doses)‡
|Pooled data (All simvastatin doses)‡
|Ezetimibe 10 mg
|VYTORIN by dose
|Simvastatin by dose
|10 mg
|20 mg
|40 mg
|80 mg
In a multicenter, double-blind, controlled, 23-week study, 710 patients with known CHD or CHD risk equivalents, as defined by the NCEP ATP III guidelines, and an LDL-C ≥130 mg/dL were randomized to one of four treatment groups: coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/10, 10/20, and 10/40), or simvastatin 20 mg. Patients not reaching an LDL-C <100 mg/dL had their simvastatin dose titrated at 6-week intervals to a maximal dose of 80 mg.
At Week 5, the LDL-C reductions with VYTORIN 10/10, 10/20, or 10/40 were significantly larger than with simvastatin 20 mg (see Table 2).
|20 mg
|Mean baseline LDL-C
|Percent change LDL-C
In a multicenter, double-blind, 6-week study, 1902 patients with primary hypercholesterolemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to one of eight treatment groups: VYTORIN (10/10, 10/20, 10/40, or 10/80) or atorvastatin (10 mg, 20 mg, 40 mg, or 80 mg).
Across the dosage range, when patients receiving VYTORIN were compared to those receiving milligram-equivalent statin doses of atorvastatin, VYTORIN lowered total-C, LDL-C, Apo B, and non-HDL-C significantly more than atorvastatin. Only the 10/40 mg and 10/80 mg VYTORIN doses increased HDL-C significantly more than the corresponding milligram-equivalent statin dose of atorvastatin. The effects of VYTORIN on TG were similar to the effects seen with atorvastatin. (See Table 3.)
|(Daily Dose)
|Apo B‡
|VYTORIN by dose
|Atorvastatin by dose
|10 mg
|20 mg
|40 mg
|80 mg
In a multicenter, double-blind, 24-week, forced titration study, 788 patients with primary hypercholesterolemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to receive coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/10 and 10/20) or atorvastatin 10 mg. For all three treatment groups, the dose of the statin was titrated at 6-week intervals to 80 mg. At each pre-specified dose comparison, VYTORIN lowered LDL-C to a greater degree than atorvastatin (see Table 4).
|Apo B
|Week 6
|Atorvastatin 10 mg‡
|Week 12
|Atorvastatin 20 mg
|Week 18
|Atorvastatin 40 mg
|Week 24
|Atorvastatin 80 mg
In a multicenter, double-blind, 6-week study, 2959 patients with primary hypercholesterolemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to one of six treatment groups: VYTORIN (10/20, 10/40, or 10/80) or rosuvastatin (10 mg, 20 mg, or 40 mg).
The effects of VYTORIN and rosuvastatin on total-C, LDL-C, Apo B, TG, non-HDL-C and HDL-C are shown in Table 5.
|(Daily Dose)
|Apo B‡
|VYTORIN by dose
|Rosuvastatin by dose
|10 mg
|20 mg
|40 mg
In a multicenter, double-blind, 24-week trial, 214 patients with type 2 diabetes mellitus treated with thiazolidinediones (rosiglitazone or pioglitazone) for a minimum of 3 months and simvastatin 20 mg for a minimum of 6 weeks, were randomized to receive either simvastatin 40 mg or the coadministered active ingredients equivalent to VYTORIN 10/20. The median LDL-C and HbA1c levels at baseline were 89 mg/dL and 7.1%, respectively.
VYTORIN 10/20 was significantly more effective than doubling the dose of simvastatin to 40 mg. The median percent changes from baseline for VYTORIN vs simvastatin were: LDL-C -25% and -5%; total-C -16% and -5%; Apo B -19% and -5%; and non-HDL-C -23% and -5%. Results for HDL-C and TG between the two treatment groups were not significantly different.
In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary hypercholesterolemia, ezetimibe significantly lowered total-C (‑13%), LDL-C (‑19%), Apo B (‑14%), and TG (‑8%), and increased HDL-C (+3%) compared to placebo. Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.
In two large, placebo-controlled clinical trials, the Scandinavian Simvastatin Survival Study (N=4,444 patients) and the Heart Protection Study (N=20,536 patients), the effects of treatment with simvastatin were assessed in patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease. Simvastatin was proven to reduce: the risk of total mortality by reducing CHD deaths; the risk of non-fatal myocardial infarction and stroke; and the need for coronary and non-coronary revascularization procedures.
No incremental benefit of VYTORIN on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.
A double-blind, randomized, 12-week study was performed in patients with a clinical and/or genotypic diagnosis of HoFH. Data were analyzed from a subgroup of patients (n=14) receiving simvastatin 40 mg at baseline. Increasing the dose of simvastatin from 40 to 80 mg (n=5) produced a reduction of LDL-C of 13% from baseline on simvastatin 40 mg. Coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/40 and 10/80 pooled, n=9), produced a reduction of LDL-C of 23% from baseline on simvastatin 40 mg. In those patients coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/80, n=5), a reduction of LDL-C of 29% from baseline on simvastatin 40 mg was produced.
VYTORIN is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and to increase HDL-C in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia.
VYTORIN is indicated for the reduction of elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.
Therapy with lipid-altering agents should be a component of multiple risk-factor intervention in individuals at increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Lipid-altering agents should be used in addition to an appropriate diet (including restriction of saturated fat and cholesterol) and when the response to diet and other non-pharmacological measures has been inadequate. (See NCEP Adult Treatment Panel (ATP) III Guidelines, summarized in Table 6.)
|Risk Category
LDL Goal
|LDL Level at Which to Initiate Therapeutic Lifestyle Changes*
|LDL Level at Which to Consider Drug Therapy
|CHD or CHD risk equivalents†
(10-year risk >20%)‡
(100-129: drug optional)§
|2+ Risk factors¶
(10-year risk ≤20%)‡
|10-year risk 10-20%: ≥130‡
10-year risk <10%: ≥160‡
|0-1 Risk factor#
(160-189: LDL-lowering drug optional)
Prior to initiating therapy with VYTORIN, secondary causes for dyslipidemia (i.e., diabetes, hypothyroidism, obstructive liver disease, chronic renal failure, and drugs that increase LDL-C and decrease HDL-C [progestins, anabolic steroids, and corticosteroids]), should be excluded or, if appropriate, treated. A lipid profile should be performed to measure total-C, LDL-C, HDL-C and TG. For TG levels >400 mg/dL (>4.5 mmol/L), LDL-C concentrations should be determined by ultracentrifugation.
At the time of hospitalization for an acute coronary event, lipid measures should be taken on admission or within 24 hours. These values can guide the physician on initiation of LDL-lowering therapy before or at discharge.
Hypersensitivity to any component of this medication.
Active liver disease or unexplained persistent elevations in serum transaminases (see WARNINGS, Liver Enzymes).
Pregnancy and lactation. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Moreover, cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Because of the ability of inhibitors of HMG-CoA reductase such as simvastatin to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway, VYTORIN is contraindicated during pregnancy and in nursing mothers. VYTORIN should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, VYTORIN should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus (see PRECAUTIONS, Pregnancy).
In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ezetimibe compared with the relevant control arm (placebo or HMG-CoA reductase inhibitor alone). However, myopathy and rhabdomyolysis are known adverse reactions to HMG-CoA reductase inhibitors and other lipid-lowering drugs. In clinical trials, the incidence of CK >10 X the upper limit of normal [ULN] was 0.2% for VYTORIN. (See PRECAUTIONS, Skeletal Muscle.)
Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase above 10 X 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.
All patients starting therapy with VYTORIN or whose dose of VYTORIN is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. VYTORIN therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when simvastatin treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with simvastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients taking VYTORIN merit closer monitoring. Therapy with VYTORIN should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.
Potent inhibitors of CYP3A4: Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of cytochrome P450 3A4 (CYP3A4). 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.
The use of VYTORIN concomitantly with the potent CYP3A4 inhibitors itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 quart daily) should be avoided. Concomitant use of other medicines labeled as having a potent inhibitory effect on 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 VYTORIN should be suspended during the course of treatment.
Other drugs:
Gemfibrozil, particularly with higher doses of VYTORIN: There is an increased risk of myopathy when simvastatin is used concomitantly with fibrates (especially gemfibrozil). The combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination. The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with gemfibrozil. Therefore, although not recommended, if VYTORIN is used in combination with gemfibrozil, the dose should not exceed 10/10 mg daily. (See CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions, Interactions with lipid-lowering drugs that can cause myopathy when given alone, Other drug interactions, and DOSAGE AND ADMINISTRATION.)
Other lipid-lowering drugs (other fibrates or ≥1 g/day of niacin): Caution should be used when prescribing other fibrates or lipid-lowering doses (≥1 g/day) of niacin with VYTORIN, as these agents can cause myopathy when given alone. The safety and effectiveness of VYTORIN administered with other fibrates or (≥1 g/day) of niacin have not been established. Therefore, the benefit of further alterations in lipid levels by the combined use of VYTORIN with other fibrates or niacin should be carefully weighed against the potential risks of these drug combinations. (See CLINICAL PHARMACOLOGY, Pharmacokinetics, PRECAUTIONS, Drug Interactions, Interactions with lipid-lowering drugs that can cause myopathy when given alone, Other drug interactions, and DOSAGE AND ADMINISTRATION.)
Cyclosporine or danazol with higher doses of VYTORIN: The dose of VYTORIN should not exceed 10/10 mg daily in patients receiving concomitant medication with cyclosporine or danazol. The benefits of the use of VYTORIN in patients receiving cyclosporine or danazol should be carefully weighed against the risks of these combinations. (See CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions, Other drug interactions.)
Amiodarone or verapamil with higher doses of VYTORIN: The dose of VYTORIN should not exceed 10/20 mg daily in patients receiving concomitant medication with amiodarone or verapamil. The combined use of VYTORIN at doses higher than 10/20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy. (See PRECAUTIONS, Drug Interactions, Other drug interactions.) In an ongoing clinical trial, myopathy has been reported in 6% of patients receiving simvastatin 80 mg and amiodarone. In an analysis of clinical trials involving 25,248 patients treated with simvastatin 20 to 80 mg, the incidence of myopathy was higher in patients receiving verapamil and simvastatin (4/635; 0.63%) than in patients taking simvastatin without a calcium channel blocker (13/21,224; 0.061%).
Prescribing recommendations for interacting agents are summarized in Table 7 (see also CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions; DOSAGE AND ADMINISTRATION).
|Interacting Agents
|Prescribing Recommendations
HIV protease inhibitors
|Avoid VYTORIN
|Do not exceed 10/10 mg VYTORIN daily
|Do not exceed 10/20 mg VYTORIN daily
|Grapefruit juice
|Avoid large quantities of grapefruit juice (>1 quart daily)
In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (≥3 X ULN) in serum transaminases was 1.7% overall for patients treated with VYTORIN and appeared to be dose-related with an incidence of 2.6% for patients treated with VYTORIN 10/80. In controlled long-term (48-week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations (≥3 X ULN) in serum transaminases was 1.8% overall and 3.6% for patients treated with VYTORIN 10/80. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment.
It is recommended that liver function tests be performed before the initiation of treatment with VYTORIN, and thereafter when clinically indicated. Patients titrated to the 10/80-mg dose should receive an additional test prior to titration, 3 months after titration to the 10/80-mg dose, and periodically thereafter (e.g., semiannually) for the first year of treatment. 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(ies) return to normal. Should an increase in AST or ALT of 3 X ULN or greater persist, withdrawal of therapy with VYTORIN is recommended.
VYTORIN should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained persistent transaminase elevations are contraindications to the use of VYTORIN.
Patients should be advised about substances they should not take concomitantly with VYTORIN and be advised to report promptly unexplained muscle pain, tenderness, or weakness (see list below and WARNINGS, Myopathy/Rhabdomyolysis). Patients should also be advised to inform other physicians prescribing a new medication that they are taking VYTORIN.
In post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported regardless of causality. Most patients who developed rhabdomyolysis were taking a statin prior to initiating ezetimibe. However, rhabdomyolysis has been reported very rarely with ezetimibe monotherapy and very rarely with the addition of ezetimibe to agents known to be associated with increased risk of rhabdomyolysis, such as fibrates.
Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, VYTORIN is not recommended in these patients. (See CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations.)
(See also CLINICAL PHARMACOLOGY, Drug Interactions)
Potent inhibitors of CYP3A4 (below) increase the risk of myopathy by reducing the elimination of the simvastatin component of VYTORIN.
See WARNINGS, Myopathy/Rhabdomyolysis, and CLINICAL PHARMACOLOGY, Pharmacokinetics, Drug Interactions.
HIV protease inhibitors
Large quantities of grapefruit juice (>1 quart daily)
See WARNINGS, Myopathy/Rhabdomyolysis.
The risk of myopathy is increased by gemfibrozil and to a lesser extent by other fibrates and niacin (nicotinic acid) (≥1 g/day).
Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil with higher doses of VYTORIN (see WARNINGS, Myopathy/Rhabdomyolysis).
Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding VYTORIN to cholestyramine may be reduced by this interaction.
Cyclosporine or Danazol: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol particularly with higher doses of VYTORIN (see CLINICAL PHARMACOLOGY, Pharmacokinetics and WARNINGS, Myopathy/Rhabdomyolysis).
Caution should be exercised when using VYTORIN and cyclosporine concomitantly due to increased exposure to both ezetimibe and cyclosporine (see DOSAGE AND ADMINISTRATION, Patients taking Cyclosporine or Danazol). Cyclosporine concentrations should be monitored in patients receiving VYTORIN and cyclosporine (see CLINICAL PHARMACOLOGY, Drug Interactions).
The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the benefits of alterations in lipid levels provided by ezetimibe. In a pharmacokinetic study in post-renal transplant patients with mildly impaired or normal renal function (creatinine clearance of >50 mL/min), concomitant cyclosporine administration increased the mean AUC and Cmax of total ezetimibe 3.4-fold (range 2.3- to 7.9-fold) and 3.9-fold (range 3.0- to 4.4-fold), respectively. In a separate study, the total ezetimibe exposure increased 12-fold in one renal transplant patient with severe renal insufficiency receiving multiple medications, including cyclosporine. (See CLINICAL PHARMACOLOGY, Drug Interactions and WARNINGS, Myopathy/Rhabdomyolysis.)
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 plasma digoxin concentrations compared to concomitant administration of placebo and digoxin. Patients taking digoxin should be monitored appropriately when VYTORIN is initiated.
Fibrates: The safety and effectiveness of VYTORIN administered with fibrates have not been established.
Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile (see ANIMAL PHARMACOLOGY). Coadministration of VYTORIN with fibrates is not recommended until use in patients is studied. (See WARNINGS, Myopathy/Rhabdomyolysis.)
Warfarin: Simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: 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 a normal volunteer study and in a hypercholesterolemic patient study, respectively. With other statins, 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 VYTORIN 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 VYTORIN is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. There have been post-marketing reports of increased International Normalized Ratio (INR) in patients who had ezetimibe added to warfarin. Most of these patients were also on other medications.
The effect of VYTORIN on the prothrombin time has not been studied.
Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold.
Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold.
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.
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.
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 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).
No animal carcinogenicity or fertility studies have been conducted with the combination of ezetimibe and simvastatin. The combination of ezetimibe with simvastatin did not show evidence of mutagenicity in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with ezetimibe and simvastatin with or without metabolic activation. There was no evidence of genotoxicity at doses up to 600 mg/kg with the combination of ezetimibe and simvastatin (1:1) in the in vivo mouse micronucleus test.
A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice.
No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test.
In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).
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.
See CONTRAINDICATIONS.
As safety in pregnant women has not been established, treatment should be immediately discontinued as soon as pregnancy is recognized. VYTORIN should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards.
In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses.
Multiple-dose studies of ezetimibe coadministered with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in coadministration therapy compared to monotherapy.
Simvastatin was not teratogenic in rats at doses of 25 mg/kg/day or in rabbits at doses up to 10 mg/kg daily. 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.
Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA reductase inhibitors. In a review2 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 what would be expected in the general population. The number of cases is adequate only to exclude a 3- to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.
Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy, Reproductive Toxicology, 10(6):439-446, 1996.
The effects of VYTORIN on labor and delivery in pregnant women are unknown.
In rat studies, exposure to ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe or simvastatin are excreted into human breast milk. Because a small amount of another drug in the same class as simvastatin is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women who are nursing should not take VYTORIN (see CONTRAINDICATIONS).
There are insufficient data for the safe and effective use of VYTORIN in pediatric patients. (See Ezetimibe and Simvastatin below.)
The pharmacokinetics of ezetimibe in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ezetimibe in the pediatric population is limited to 4 patients (9 to 17 years) with homozygous sitosterolemia and 5 patients (11 to 17 years) with HoFH. Treatment with ezetimibe in children (<10 years) is not recommended.
Safety and effectiveness of simvastatin in patients 10-17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys and in girls who were at least 1 year post-menarche. Patients treated with simvastatin had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In this limited controlled study, there was no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. Adolescent females should be counseled on appropriate contraceptive methods while on therapy with simvastatin (see CONTRAINDICATIONS and PRECAUTIONS, Pregnancy). Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-menarchal girls.
Of the patients who received VYTORIN in clinical studies, 792 were 65 and older (this included 176 who were 75 and older). The safety of VYTORIN was similar between these patients and younger patients. Greater sensitivity of some older individuals cannot be ruled out. (See CLINICAL PHARMACOLOGY, Special Populations and ADVERSE REACTIONS.)
VYTORIN has been evaluated for safety in more than 3800 patients in clinical trials. VYTORIN was generally well tolerated.
Table 8 summarizes the frequency of clinical adverse experiences reported in ≥2% of patients treated with VYTORIN (n=1236) and at an incidence greater than placebo regardless of causality assessment from three similarly designed, placebo-controlled trials.
|Body System/Organ Class
|10 mg
|Adverse Event
|Body as a whole – general disorders
|Infection and infestations
|Upper respiratory tract infection
|Musculoskeletal and connective tissue disorders
|Pain in extremity
The adverse reactions reported for VYTORIN are consistent with those previously reported with ezetimibe and/or simvastatin.
Other adverse experiences reported with ezetimibe in placebo-controlled studies, regardless of causality assessment: Body as a whole – general disorders: fatigue; Gastrointestinal system disorders: abdominal pain, diarrhea; Infection and infestations: infection viral, pharyngitis, sinusitis; Musculoskeletal system disorders: arthralgia, back pain; Respiratory system disorders: coughing.
The following adverse reactions have been reported in post-marketing experience, regardless of causality assessment:
Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria; arthralgia; myalgia; elevations in liver transaminases; hepatitis; thrombocytopenia; pancreatitis; nausea; dizziness; paresthesia; depression; cholelithiasis; cholecystitis; elevated creatine phosphokinase; and, very rarely, myopathy/rhabdomyolysis (see WARNINGS, Myopathy/Rhabdomyolysis).
Other adverse experiences reported with simvastatin in placebo-controlled clinical studies, regardless of causality assessment: Body as a whole – general disorders: asthenia; Eye disorders: cataract; Gastrointestinal system disorders: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, nausea; Skin and subcutaneous tissue disorders: eczema, pruritus, rash.
The following effects have been reported with other HMG-CoA reductase inhibitors. Not all the effects listed below have necessarily been associated with simvastatin therapy.
Musculoskeletal system disorders: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.
Nervous system disorders: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, memory loss, paresthesia, peripheral neuropathy, peripheral nerve palsy, psychic disturbances.
Ear and labyrinth disorders: vertigo.
Psychiatric disorders: anxiety, insomnia, depression, loss of libido.
Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.
Gastrointestinal system disorders: pancreatitis, vomiting.
Hepatobiliary disorders: hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver, and, rarely, cirrhosis, fulminant hepatic necrosis, hepatic failure, and hepatoma.
Metabolism and nutrition disorders: anorexia.
Skin and subcutaneous tissue disorders: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails) have been reported.
Reproductive system and breast disorders: gynecomastia, erectile dysfunction.
Eye disorders: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, γ-glutamyl transpeptidase, and bilirubin; thyroid function abnormalities.
Marked persistent increases of serum transaminases have been noted (see WARNINGS, Liver Enzymes). About 5% of patients taking simvastatin had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK. Muscle pain or dysfunction usually was not reported (see WARNINGS, Myopathy/Rhabdomyolysis).
In controlled clinical studies in which simvastatin was administered concomitantly with cholestyramine, no adverse reactions peculiar to this concomitant treatment were observed. The adverse reactions that occurred were limited to those reported previously with simvastatin or cholestyramine.
In a 48-week controlled study in adolescent boys and girls who were at least 1 year post-menarche, 10-17 years of age with heterozygous familial hypercholesterolemia (n=175), the safety and tolerability profile of the group treated with simvastatin (10-40 mg daily) was generally similar to that of the group treated with placebo, with the most common adverse experiences observed in both groups being upper respiratory infection, headache, abdominal pain, and nausea (see CLINICAL PHARMACOLOGY, Special Populations and PRECAUTIONS, Pediatric Use).
No specific treatment of overdosage with VYTORIN can be recommended. In the event of an overdose, symptomatic and supportive measures should be employed.
In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, or 40 mg/day to 18 patients with primary hypercholesterolemia for up to 56 days, was generally well tolerated.
A few cases of overdosage have been reported; most have not been associated with adverse experiences. Reported adverse experiences have not been serious.
A few cases of overdosage with simvastatin have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae.
The dialyzability of simvastatin and its metabolites in man is not known at present.
The patient should be placed on a standard cholesterol-lowering diet before receiving VYTORIN and should continue on this diet during treatment with VYTORIN. The dosage should be individualized according to the baseline LDL-C level, the recommended goal of therapy, and the patient's response. (See NCEP Adult Treatment Panel (ATP) III Guidelines, summarized in Table 6.) VYTORIN should be taken as a single daily dose in the evening, with or without food.
The dosage range is 10/10 mg/day through 10/80 mg/day. The recommended usual starting dose is 10/20 mg/day. Initiation of therapy with 10/10 mg/day may be considered for patients requiring less aggressive LDL-C reductions. Patients who require a larger reduction in LDL-C (greater than 55%) may be started at 10/40 mg/day. After initiation or titration of VYTORIN, lipid levels may be analyzed after 2 or more weeks and dosage adjusted, if needed. See below for dosage recommendations for patients receiving certain concomitant therapies and for those with renal insufficiency.
The recommended dosage for patients with homozygous familial hypercholesterolemia is VYTORIN 10/40 mg/day or 10/80 mg/day in the evening. VYTORIN should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
No dosage adjustment is necessary in patients with mild hepatic insufficiency (see PRECAUTIONS, Hepatic Insufficiency).
No dosage adjustment is necessary in patients with mild or moderate renal insufficiency. However, for patients with severe renal insufficiency, VYTORIN should not be started unless the patient has already tolerated treatment with simvastatin at a dose of 5 mg or higher. Caution should be exercised when VYTORIN is administered to these patients and they should be closely monitored (see CLINICAL PHARMACOLOGY, Pharmacokinetics and WARNINGS, Myopathy/Rhabdomyolysis).
No dosage adjustment is necessary in geriatric patients (see CLINICAL PHARMACOLOGY, Special Populations).
Dosing of VYTORIN should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant (see PRECAUTIONS, Drug Interactions).
Caution should be exercised when initiating VYTORIN in the setting of cyclosporine. In patients taking cyclosporine or danazol, VYTORIN should not be started unless the patient has already tolerated treatment with simvastatin at a dose of 5 mg or higher. The dose of VYTORIN should not exceed 10/10 mg/day.
In patients taking amiodarone or verapamil concomitantly with VYTORIN, the dose should not exceed 10/20 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions, Other drug interactions).
The safety and effectiveness of VYTORIN administered with fibrates have not been established. Therefore, the combination of VYTORIN and fibrates should be avoided (see WARNINGS, Myopathy/Rhabdomyolysis, and PRECAUTIONS, Drug Interactions, Other drug interactions).
There is an increased risk of myopathy when simvastatin is used concomitantly with fibrates (especially gemfibrozil). Therefore, although not recommended, if VYTORIN is used in combination with gemfibrozil, the dose should not exceed 10/10 mg daily (see WARNINGS, Myopathy/Rhabdomyolysis, and PRECAUTIONS, Drug Interactions, Other drug interactions).
No. 3873 — Tablets VYTORIN 10/10 are white to off-white capsule-shaped tablets with code "311" on one side.
They are supplied as follows:
NDC 66582-311-31 bottles of 30
NDC 66582-311-54 bottles of 90
NDC 66582-311-82 bottles of 1000 (If repackaged in blisters, then opaque or light-resistant blisters should be used.)
NDC 66582-311-87 bottles of 10,000 (If repackaged in blisters, then opaque or light-resistant blisters should be used.)
NDC 66582-311-28 unit dose packages of 100.
No. 3874 — Tablets VYTORIN 10/20 are white to off-white capsule-shaped tablets with code "312" on one side.
They are supplied as follows:
NDC 66582-312-31 bottles of 30
NDC 66582-312-54 bottles of 90
NDC 66582-312-82 bottles of 1000 (If repackaged in blisters, then opaque or light-resistant blisters should be used.)
NDC 66582-312-87 bottles of 10,000 (If repackaged in blisters, then opaque or light-resistant blisters should be used.)
NDC 66582-312-28 unit dose packages of 100.
No. 3875 — Tablets VYTORIN 10/40 are white to off-white capsule-shaped tablets with code "313" on one side.
They are supplied as follows:
NDC 66582-313-31 bottles of 30
NDC 66582-313-54 bottles of 90
NDC 66582-313-74 bottles of 500 (If repackaged in blisters, then opaque or light-resistant blisters should be used.)
NDC 66582-313-86 bottles of 5000 (If repackaged in blisters, then opaque or light-resistant blisters should be used.)
NDC 66582-313-52 unit dose packages of 50.
No. 3876 — Tablets VYTORIN 10/80 are white to off-white capsule-shaped tablets with code "315" on one side.
They are supplied as follows:
NDC 66582-315-31 bottles of 30
NDC 66582-315-54 bottles of 90
NDC 66582-315-74 bottles of 500 (If repackaged in blisters, then opaque or light-resistant blisters should be used.)
NDC 66582-315-66 bottles of 2500 (If repackaged in blisters, then opaque or light-resistant blisters should be used.)
NDC 66582-315-52 unit dose packages of 50.
Store at 20-25°C (68-77°F). [See USP Controlled Room Temperature.] Keep container tightly closed.
Store bottle of 10,000 VYTORIN 10/10 and 10/20, 5000 VYTORIN 10/40, and 2500 VYTORIN 10/80 capsule-shaped tablets at 20-25°C (68-77°F). [See USP Controlled Room Temperature.] Store in original container until time of use. When product container is subdivided, repackage into a tightly-closed, light-resistant container. Entire contents must be repackaged immediately upon opening.
Issued January 2008
Printed in USA
Manufactured for:
MERCK/Schering-Plough Pharmaceuticals
North Wales, PA 19454, USA
MSD Technology Singapore Pte. Ltd.
Singapore 637766
Merck Sharp & Dohme (Italia) S.p.A.
Via Emilia, 21
27100 – Pavia
Merck Sharp & Dohme Ltd.
Northumberland, UK NE23 3JU
VYTORIN® (ezetimibe/simvastatin) Tablets
Patient Information about VYTORIN (VI-tor-in)
Generic name: ezetimibe/simvastatin tablets
Read this information carefully before you start taking VYTORIN. Review this information each time you refill your prescription for VYTORIN as there may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about VYTORIN, ask your doctor. Only your doctor can determine if VYTORIN is right for you.
VYTORIN contains two cholesterol-lowering medications, ezetimibe and simvastatin, available as a tablet in four strengths:
− VYTORIN 10/10 (ezetimibe 10 mg/simvastatin 10 mg)
− VYTORIN 10/20 (ezetimibe 10 mg/simvastatin 20 mg)
− VYTORIN 10/40 (ezetimibe 10 mg/simvastatin 40 mg)
− VYTORIN 10/80 (ezetimibe 10 mg/simvastatin 80 mg)
VYTORIN is a medicine used to lower levels of total cholesterol, LDL (bad) cholesterol, and fatty substances called triglycerides in the blood. In addition, VYTORIN raises levels of HDL (good) cholesterol. It is used for patients who cannot control their cholesterol levels by diet alone. You should stay on a cholesterol-lowering diet while taking this medicine.
VYTORIN works to reduce your cholesterol in two ways. It reduces the cholesterol absorbed in your digestive tract, as well as the cholesterol your body makes by itself. VYTORIN does not help you lose weight.
For more information about cholesterol, see the section called " What should I know about high cholesterol?"
Do not take VYTORIN:
VYTORIN is not recommended for use in children under 10 years of age.
Tell your doctor right away if you experience unexplained muscle pain, tenderness, or weakness. This is because on rare occasions, muscle problems can be serious, including muscle breakdown resulting in kidney damage.
The risk of muscle breakdown is greater at higher doses of VYTORIN.
The risk of muscle breakdown is greater in patients with kidney problems.
Taking VYTORIN with certain substances can increase the risk of muscle problems. It is particularly important to tell your doctor if you are taking any of the following:
It is also important to tell your doctor if you are taking coumarin anticoagulants (drugs that prevent blood clots, such as warfarin).
Tell your doctor about any prescription and nonprescription medicines you are taking or plan to take, including natural or herbal remedies.
Tell your doctor about all your medical conditions including allergies.
Tell your doctor if you:
Tell other doctors prescribing a new medication that you are taking VYTORIN.
Your doctor has prescribed your dose of VYTORIN. The available doses of VYTORIN are 10/10, 10/20, 10/40, and 10/80. The usual daily starting dose is VYTORIN 10/20.
Contact your doctor immediately.
See your doctor regularly to check your cholesterol level and to check for side effects. Your doctor may do blood tests to check your liver before you start taking VYTORIN and during treatment.
In clinical studies patients reported the following common side effects while taking VYTORIN: headache and muscle pain (see What should I tell my doctor before and while taking VYTORIN?).
The following side effects have been reported in general use with either ezetimibe or simvastatin tablets (tablets that contain the active ingredients of VYTORIN):
Tell your doctor if you are having these or any other medical problems while on VYTORIN. This is not a complete list of side effects. For a complete list, ask your doctor or pharmacist.
Cholesterol is a type of fat found in your blood. Cholesterol comes from two sources. It is produced by your body and it comes from the food you eat. Your total cholesterol is made up of both LDL and HDL cholesterol.
LDL cholesterol is called "bad" cholesterol because it can build up in the wall of your arteries and form plaque. Over time, plaque build-up can cause a narrowing of the arteries. This narrowing can slow or block blood flow to your heart, brain, and other organs. High LDL cholesterol is a major cause of heart disease and stroke.
HDL cholesterol is called "good" cholesterol because it keeps the bad cholesterol from building up in the arteries.
Triglycerides also are fats found in your body.
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use VYTORIN for a condition for which it was not prescribed. Do not give VYTORIN to other people, even if they have the same condition you have. It may harm them.
This summarizes the most important information about VYTORIN. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about VYTORIN that is written for health professionals. For additional information, visit the following web site: vytorin.com.
Butylated hydroxyanisole NF, citric acid monohydrate USP, croscarmellose sodium NF, hydroxypropyl methylcellulose USP, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, and propyl gallate NF.
Issued January 2008
Manufactured for:
Merck/Schering-Plough Pharmaceuticals
North Wales, PA 19454, USA
MSD Technology Singapore Pte. Ltd.
Singapore, 637766
Merck Sharp & Dohme (Italia) S.p.A.
Via Emilia, 21
27100 – Pavia
Merck Sharp & Dohme Ltd.
Northumberland, UK NE23 3JU
|VYTORIN (ezetimibe and simvastatin)
|VYTORIN (ezetimibe and simvastatin)
|VYTORIN (ezetimibe and simvastatin)
|VYTORIN (ezetimibe and simvastatin)
Data are from FDA and U.S. National Library of Medicine.


text:
You Will Be Missed, GameTrailers February 10, 2016Posted by Maniac in Editorials, You Will Be Missed.
In 2006, my Sony PSP received a software update which gave it the ability to play pretty decent quality video files I could store on a Memory Stick. While I had the ability to convert most of the video files I wanted to the PSP's new video format, some websites wanted to be at the cutting edge of technology and offered plenty of their site's video content available to download in that format. I downloaded a review of the game Dead Rising for the Xbox 360 to my PSP and watched it. I thought the video was well written, with some great editing, and I agreed with its conclusions.
That was the first time I came across content produced by the website GameTrailers. Yesterday, in an announcement I'm still trying to believe, the people who were employed by the site have announced they were all let go.
I've been following gaming news for over fifteen years and I've been involved in the industry for over ten years as a staff writer on various sites. I understand that not all companies last forever, but there comes a time when you are so caught up in the activities of an organization that when it shuts down, a part of you goes with it. It's happened to me more times than I can remember, and here's a story about another one. It is a sad story to see such great potential end abruptly, but we have to move on, and we will never forget.
In Summer 2007 I was working a college job and I became obsessed with a game called The Darkness. When I first saw a commercial for it air on TV, I immediately became interested in obtaining it. Usually games rarely released during the summer, but this game has been developed by the studio who made Escape from Butcher Bay, and was based on a comic series with a cult following. Unable to buy the game yet, I decided to look for all the information I could about it, and that brought me to GameTrailers. They had just recently reviewed the game and had a lot of other videos about it ready to download. For two weeks I visited that site daily to try and get the latest information I could about games like Metal Gear Solid 4: Guns of The Patriots, Halo 3, and Bioshock.
While the site would mirror most of the popular game trailers, it was top notch at their editing quality when it came to producing exclusive previews and reviews of new games. Also, GameTrailers had a lot of amazing and unique content creators. I'm sure everyone will remember ScrewAttack's partnership with the site, which brought in series like The Angry Video Game Nerd, but if there was any reason to watch GameTrailer's content, it was for their Retrospectives. Seriously, if you ever have a few free hours try checking out their retrospectives on Final Fantasy, Metroid, Metal Gear, or Star Wars. You won't be disappointed.
Farewell, GameTrailers, you will be missed!
No comments yet — be the first.

subset: commoncrawl


text:
The Vampire Diaries S03E20: "Do Not Go Gentle"
Let's be real, the Mystic Falls High School dance calendar has become one of the most trustworthy predictors of disaster since Nostradamus first said "Whoa I got a bad feeling about this, guys." The Decade Dance in particular has turned into an almost poignant exercise wherein all the town's teenagers get dolled up in earnest when they know FULL WELL the night will end in tears and bloodshed. Like, what is even going through their minds as they look through their vast theatrical wardrobes? "I guess I'll wear this top hat. And maybe college is overrated anyway. [Sadface.]" But then again this is Mystic Falls, where brutal murder has been so normalized that most surviving citizens are probably just plum looking forward to dying. "Just following in my parents' footsteps!"
"Do Not Go Gentle" was a good episode, but you knew that! It mostly served to set up the season's grand finale, and grand finales are what The Vampire Diaries does best. Like, duh. Saying this episode was good is like saying "She ordered a pizza really well." That's fine but STAY TUNED.
But I do have one quibble and it's that Esther sort of sucks? Hear me out. Okay, that was basically it. Does Esther suck, you guys? Maybe she doesn't, I don't know. I mean, the character is fine, and her story was fine when it first played out. But that's the problem: To me it played out already! But she keeps coming back! I guess the thing that bugs me about her the most is that her grimoire isn't even a book, it's just a napkin with the word "ANYTHING" scrawled on it. Because that's what she's able to do: Anything. She's invincible. She can create vampires from scratch. She can swap bodies like it ain't even a thing. She can possess (allegedly) powerful witches to do whatever. This show has taken pains to write out a supposedly strict set of rules the vampires must live by, but then some viking witch ghost strolls in and does tons of crazy powerful stuff without precedent. And her motives don't even make a ton of sense. Has she been preying on ring-wearing citizens of Mystic Falls this whole time, even when her children weren't living there? And if she can possess Bonnie to overtake Damon like that, why did she even need an Alaric vampire? Can't Esther just pick up the dang stake on her own?
So to me a lot of this endgame stuff just seems a bit random now, which is fine if we're going by dream logic. I like dream logic! I still remember last year when TVD was like, "Oh, that Sun & Moon curse we were yammering on about for half the season? That was sort of fake, forget about it." Cool, thanks! Look, it's all good, really. I'm not Joyce Carol Oates over here trying to pretend I have high standards in writing. Ultimately this episode was super entertaining and its sense of dread was palpable. Bad times are coming for our characters, and it doesn't really matter what the threat is.
Had enough rambling yet? (I can't actually hear you because this is a written piece and you're probably at a computer, but I'm just going to assume you nodded or gave a thumbs-up.) Let's talk about this episode!
So first off, Klaus was sick of charcoals and had moved onto mixed media. What exactly this medium was I'm not sure. Shoe polish on drywall?
The Rebekah/Esther arrived with a fake stake and they threw it in the fire together. She'd apparently been out all night chillin' with Evil Alaric or something. Because seriously didn't they go to the cave the night before? Anyway, that's when Klaus informed his sister-mother that it was time to bounce.
Luckily Esther knew JUST the way to get him to stay another night. Like most everyone else alive, Klaus was a sucker for some Caroline.
Elsewhere, Evil Alaric was using up tons of daytime minutes trying to get Damon off his back.
Yeah, it was weird. It made me laugh that it would be reasonable to allow a known split-personality murderer to roam free in the area. That definitely keeps everybody safe!
But it turned out Evil Alaric was all up in Klaus's mansion, chillin' in the coffin parlor. Klaus must've run out to 7-11 or something because Rebekah/Esther and Evil Alaric were just freely discussing their plans at normal volume. (P.S. didn't those coffins look so clean and inviting? I honestly wouldn't mind curling up in one for an afternoon.)
Anyway, Esther wanted her real body back. Why, you ask? Wouldn't remaining undercover be the better plan? I don't know. She probably needed her old body back in order to do mega magic. Except then at the end of the episode her ghost was plenty magical? Honestly, most of the witchcraft in this show just confused me. Anyway, this happened:
Okay, so Esther was back to being Esther. That's definitely a bit more straightforward at least.
Back at the school, the kids had hung their elaborately painted backdrop and were now hanging Christmas lights and glittery stars, just like they had in the 1920s!
Meanwhile, Caroline took Elena aside for some unsolicited love triangle advice:
That's right, it's as though this season only had three episodes left to deal with its central love triangle! Because out of the blue, Caroline was now insisting that Elena give Stefan another chance by inviting him to the dance. And you know Elena, don't have to tell her twice to forgive a minimally apologetic mass murderer!
As suggested last episode, Stefan was more than ready to get back with Elena, so he practically lit up when she invited him to the school dance. Not as thrilled about this turn of events was a certain eaves-droppy older bro:
Meanwhile at the Salvatore crypt, Esther and Evil Alaric were getting down to business:
The first part of her plan involved melting down Alaric's ring so as to make the last remaining wooden stake re-usable. Which, if you think about it, is just a good example of Esther going green.
See that? That's the instrument with which she wants to stab each of her children to death! Or, more specifically, she wants a vampire version of Alaric to do it. Because, I guess, if he turns into a vampire his evil personal will take over permanently. According to her. Because fine. Esther's the boss, not me.
Elena and Stefan both looked quite dapper, and it was just like olden times! In both senses. Costume-wise and romance-wise. (Aside: Elena looked real good, but I still think maybe Detective Katherine rocked the '20s garb better back in the day. Personal preference!)
No offense to Caroline, but maybe Rebekah might've done a better job at putting this room together. I mean, what am I even looking at here? A bunch of teenagers in feather boas throwing elbows around. The '20s!
Obviously Caroline looked awesome, but it was great when she immediately took Matt aside and warned him about getting too close to Elena. Elena's human friends tend to die!
Some may call this a tiny character moment, but I took it as foreshadowing. Be careful, Matt!
Meanwhile Elena was tearin' it up:
Fortunately she waited for a slow-dance to bring up the most awkward topic possible.
Stefan DID NOT want to know what happened in Denver. Which means he totally knew right? Why else would he have said that? I actually liked this moment because he finally admitted that it'll be a while before Elena could possibly come close to hurting him the way he'd hurt her. So yeah, Stefan was pretty cool about the whole thing. As he should be! If these two are gonna get back together, Elena's got A LOT of free f*ck-up tickets she'll get to redeem. He'll be like, "Did you dent my fender?" and she'll be like "Did you eat a family in Tennessee? That's what I thought."
Anyway, because this was a high school dance, any old grown man could walk in off the street and attend. So Damon showed up with some bad news about Alaric: He was gonna have to die.
But Jeremy was NOT okay with that plan. To his credit he was still pretty out of the loop, but still.
Then Esther showed up at the front of the high school and whisked Elena away.
But not before exacting one of the more hilarious boundary spells this show's ever seen:
Haha, did Esther arrive in a DUMP TRUCK? Did she seriously dump a trail of salt around the entirety of the high school? And nobody noticed? That was one clever witch. Anyway, all vampires were now locked in.
Meanwhile in Alaric's classroom Bonnie and Jamie were enjoying some quality time.
Unfortunately for Bonnie, the vampires were in trouble so she would be expected to drop everything and help them at all costs! Ugh, back to the grindstone for our resident deus ex machina.
Back at the Salvatore mausoleum, Esther and Evil Alaric laid out their whole plan for Elena.
Esther wanted to turn Alaric into a vampire to match the strength of the Originals. Even though he'd be a NEW vampire. He'd still be as strong as them. Because why? Because doppelganger blood. What? No idea. Oh, and for kicks Esther elaborated that the ring had turned Alaric evil because every time he died she threw a surprise party for him in the afterlife and I guess talked him into developing a split personality. If you're curious about whether she'd done the same thing for Samantha Gilbert, stay curious because that was never explained. BUT Esther did admit to turning her husband Mikael into a bloodthirsty vampire-hunter, so there's that. Honestly, the more she opened her mouth the more I got confused.
Then Klaus arrived at the high school, apparently after not having seen his sister all day nor noticing the enormous ring of salt around the campus. Why should he worry about those things when he had an unrequited love to pursue?
Tyler had been acting sort of jackassy all night (might've just been the hat) and he had to swallow his jealousy over Klaus by pretending to still be sired. So then Caroline HAD to dance with Klaus and he pitched his best offer right up front:
We could tell Caroline was definitely listening to his eloquent plea to become his cultural protege, but at the last second huffed incredulously.
So then he got all butt hurt, told her that someday she'd realize she was too good for Mystic Falls, and THEN she'd be sorry. Or something. Klaus was definitely acting a jerk but I felt real bad for him. Sometimes even the alpha male doesn't get his way.
That's when he finally noticed the salt ring.
So yeah. Now Klaus was involved and it wasn't long before he was hassling Bonnie to break the boundary spell also.
Although, and this might be my screengrab-damaged brain speaking, but did it seem like Klaus totally lit up when Jeremy offered to help?
'Sup Klaremy?
Back at the Salvatore Badtimes Bounce House, the conversion ceremony was underway:
And just like that, Alaric's conversion to vampire had begun!
Aside: Did you guys like the original song that this gentleman wrote?
If there's one thing we can all agree on, The Vampire Diaries needs more R&B; slow jams called "Love Triangle." Great job, Backwards James!
Back in the gymnasium, Tyler was stressin' about the fact that everybody wanted to kill Klaus even though it would probably kill him also (bloodline drama). Caroline did her best to cheer him up, but he was being real mopey about it.
Wuh-oh. This relationship has been real front-and-center these past few episodes. That can't bode well for the future, right?
So then a couple of mortals came at a one thousand-year-old witch with sporting equipment.
And get this: She STILL had the upper hand! She tried to make Jeremy and Matt shoot each other!
Phew! Luckily Original Recipe Alaric woke up and stabbed Esther so bad.
Just so we're clear, THIS type of murder was cool. So this was definitely the Good Alaric. Not the Evil one who sought to murder other murderers. (Someone keepin' a flowchart, btw?)
Back at the salt line, Klaus was caught up in a romantic mood evidently brought on by nostalgia for the 1920s. He even referred to Stefan as a bedfellow! You know, I'm starting to suspect that the subtext of their relationship is just plain old text now. Pretty sure they shirtless-hugged at least once back in the '20s.
Oh, Klaus. At least he tries, you know? Hang in there, kitten.
But then it was time for tearful goodbyes. Deciding that he would definitely NOT complete the transition into evil vampire and bringer of nightmares, Alaric started getting closure from Jeremy and Elena. Elena was especially guilt-ridden over all that had happened.
Then in the real gut-puncher of the episode, Alaric walked outside to see all his friends standing in teary-eyed tableau.
It was sad! All I ever want on ensemble dramas is for all the characters to stand in tableau, united for some emotional purpose. This scene was tableau porno basically. All the greats just assemblin' to say goodbye to their history teacher from thirty feet away.
Do you think he ever asked why they were all in costume? Probably he was just distracted.
At some point someone dragged Esther's dead body back to Klaus's house where he gingerly placed her back in a coffin for some reason. (Try a woodchipper next time?) Despite opting to preserve her body, Klaus was still NOT happy with his mum.
He shouted at her corpse a ton, threatening to build an army to protect himself. I definitely expected someone to jump out and stab him at that very moment, but WHEW! Didn't happen.
So then Bonnie and Jamie went somewhere truly fantastical.
Yeah. Bonnie was emotional about, I guess, Alaric? But let's be real, her three minutes of screentime in this episode didn't necessarily deserve the emotional pay-off it was now getting. Unless this was just a cumulative effect type thing. Either way, her sadness was clearly appealing enough for Jamie to want to stay the night.
Matt and Jeremy decided to remember Alaric the best way they saw fit:
Aw, at least they got each other, you know? (Question: Jett or Maremy?)
Back at high school (man these kids were really all over town tonight, weren't they?), Stefan decided to make a move on Elena by, I guess, bragging about how healed he was now.
It was especially cool how he took advantage of Elena's lowest emotional moment to swoop in and be the hero again.
Welcome back, Normal Stefan! Honestly you guys, I'm happy for them, but I could not be more bored by this love triangle. Sorry. Sue me in a court of law if you must, but it's getting to the point where my eyes just glaze over every time Elena so much as looks at a Salvatore.
This was nice: Damon and Alaric had a funny, touching, and slightly devastating final scene together. Laughin' and cryin' and apologizin' and drinking tons of brown liquid together.
Okay, technically he'd only fallen asleep here... Which, hey brilliant plan, Dr. Fell! Give sleeping pills to a man whose alter ego emerges whenever he sleeps? What could go wrong?? (Either way, this was definitely the end for Original Recipe Alaric. Bye, you handsome weirdo!)
Back at Bonnie's HOUSE (I know, I'm still getting over it too!) her slumber was interrupted by a VERY persistent viking witch ghost.
Then there was this completely useless "it was only a nightmare" fakeout. Why did they even do that? Only minutes later Bonnie was definitely possessed and on a mission:
AND BAM! Endgame time.
So Universal Soldier Alaric is now awake and on the move, and he'll be stabbin' EVERYBODY! Fingers crossed that they go full Jason Voorhees with this thing, because man, this guy is scary looking!
All in all, an emotional and tense episode. I will not pretend to understand all the witch stuff, but that could just be a personal problem on my part. Or maybe Esther's storyline was written quickly in a notebook during a very bumpy commute? Either way, I am able to look past the particulars and enjoy "Do Not Go Gentle" for what it was: Entertaining! Can't wait for next week when the pizza party REALLY starts.
... Who WON'T survive Alaric's rampage?
... Which romance is circling the drain?
... Foxiest flapper: Elena, Caroline, or Katherine?
... No seriously, where is Jeremy's dog?


text:
Improving Global Public Health Through Knowledge Application, Continuous Learning, and Adaptation
From June 19-21, 2018, K4Health Director Tara Sullivan and USAID LEARN Chief of Party Piers Bocock will once again offer their course, "Improving Global Public Health Through Knowledge Application, Continuous Learning, and Adaptation."
Register by May 15 for this and other courses on the JHSPH website, or download the course flyer.
This acclaimed three-day introductory course has earned "Excellence in Teaching" awards for both instructors. It is offered through the Summer Institute of the Health, Behavior, and Society Department of the Johns Hopkins Bloomberg School of Public Health (JHSPH).
The course uses intensive participatory approaches to:
- Define knowledge management (KM) and related principles,
- Explain the challenges to implementing KM programs, and
- Help determine the best KM approaches for real-life public health programs.
For more information, download the course flyer.
Filed Under: Training
June 19, 2018 - June 21, 2018
8:30 am - 4:30 pm EST
Washington, United States
May 15, 2018
Event Host
Johns Hopkins Center for Communication Programs
Event Link
Please join Learning Lab or Log In to comment.


text:
Why the Dow is Heading to 30,000 Under Trump EconomyJan_Januar_abbreviation 22nd, 2018 | Mit brinvest | Kategorie: AaronsBlog
Even a partial government shutdown in the U.S. over the weekend could not stop the markets from rising Monday. Last Tuesday saw the Dow trade above 26,000 for the first time. While new records are nothing new for the Dow, especially since Trump took office, the rate of its ascension is worth noting. It took just six trading days to soar from 25,000 to above 26,000. That is the fastest 1,000 point move in the Dow's history; while, from a ... [mehr]


text:
Restaurants can extend the use of their patios!
Control the amount of sun, shade or light into your patio.
- Protect your customers from the rain.
- Protect your patio furniture.
- Louvers open or close with the touch of a button.
- Motorized operation is via handheld remote.
- Lowers summer patio temperatures by 15-20 degrees.
- Create a beautiful patio oasis of shade for customers to enjoy.
Above is an explanation of how Louvered Patio Roofs Work!
Add value and aesthetic appeal to your patio!
- Custom designed and manufactured for each installation.
- Aluminum construction designed to withstand high winds, rain, hail snow, sleet and the hot scorching sun.
- All parts are electrostatically powder coated.
- Optional infrared heat for the ultimate in outdoor comfort in the fall and winter months.


text:
Day 22
As men, we have a tendency to isolate ourselves when stressed, confused, embarrassed, or ashamed. Especially in American culture, we tend to go into our "cave" to think things through. Some of this is okay, as it allows us time to process the events of our lives, but problems arise when we stay in those caves and stay in isolation. No one is meant to stay isolated from their family, friends, and children. We are meant to be in vibrant, meaningful relationships.
When a predator is hunting its prey, it will seek to isolate the weak, sick, or smaller ones from the rest of the herd, then attack, and kill. The devil operates the same way. He seeks to isolate men from relationships, especially with Jesus and family. He wants to keep them weak and bound to the fear, shame, or rejection that drove them into isolation, and then move in for the kill.
Even Jesus got away to meditate and pray. This in itself is not a bad thing at all. Jesus drew away for the purpose of connecting with the Father.
"But Jesus often withdrew to lonely places and prayed." - Luke 5:16 (NIV)Jesus left this as a tremendous example for us today.
There have been many examples in the media that have portrayed men as isolated and disconnected in need of no one. This is selfishness. At its root, pornography is about self and pleasing one's self. Isolation is really about self as well. Often with good excuses, hurts or private passions cause men to distance themselves from the people and things that are very important to them.
"A man who isolates himself seeks his own desire; He rages against all wise judgment." - Proverbs 18:1 (NKJV)Recognize What's Driving Isolation
We all have a sphere of influence. As men, we are called to be leaders, but first we must lead ourselves well. Think of the people you are pouring yourself into. Think of how your actions will influence those around you.


text:
A SERIAL sex offender who raped a woman and sexually assaulted four young girls over a 40-year period has been released from prison to be cared for at a hospice in the Capital.
Robert Clyde, 73, is being guarded round the clock as he receives the same level of care for a "brain illness" as members of the public would at the Marie Curie Hospice in Frogston.
A whistleblower contacted the Evening News to say some staff were refusing to enter the predator's room and nurses are angry that they have been put in a position where they have to treat him to maintain the integrity of their profession.
Housekeeping staff who were told his name were warned "not to Google him" and to treat him with "respect" when he arrived with G4S security guards on August 23 from Saughton Prison. However, the nurses weren't told anything.
Clyde is originally from Ireland but was living in Niddrie when he was caught by police in 2013 after repeatedly raping a woman over two days at his home.
Police delved into the Irishman's past and uncovered evidence that he began molesting the youngsters in 1970. They also discovered he assaulted two boys – one who was aged just four when the attacks began – for a period of 16 years.
Clyde wept in the dock after he was convicted of 13 charges and was jailed for nine years.
Politicians and campaigners have questioned whether it is right that a serving prisoner who committed such crimes over 40 years should be let out of prison to die in a hospice.
The source said: "He came in on August 23 and none of the staff knew about his past. What happened was obviously when he came in with the 24-hour G4S security guards it gave the staff a bit of a clue and alarm bells started to go off.
"He's got security guards and he's now been given a private room on the ground floor with two guards doing 12-hour shifts, then another two come, six till six.
"Now, somebody is paying for that and it's a hell of a lot of money apart from anything else. All the staff have been told is that he's got a problem with his brain.
"The horrible thing is he's sharp and alert and he doesn't seem to be at end of life."
Marie Curie said that for reasons of patient confidentiality they were unable to confirm any details of individuals in their care and would not be drawn on their policy with regard to refusing to accept certain offenders.
At present the hospice in Frogston receives 40 per cent funding from NHS Lothian.
Margaret Watt, of Scotland Patients Association, attacked the decision to release Clyde for care.
She said: "He should still be in jail and he should die in jail.
"He shouldn't be allowed back into the public domain. You draw the line in that you don't put him into a place where he has the potential to offend again – that is obscene.
"I wouldn't expect the nurses to have to deal with someone like that – to put him in the hospice is totally unacceptable."
Scottish Conservative shadow justice secretary Liam Kerr said: "It's a difficult situation for Marie Curie to deal with.
"However, this is a vile, depraved individual who ruined the lives of many.
"As such, people will clearly be angry that he is being given access to this type of facility and some may wonder why he should be given access to the first-class services Marie Curie specialise in."