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Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with coronary heart disease (CHD) or at high risk of CHD, Zocor® can be started simultaneously with diet.
Reduce the risk of total mortality by reducing CHD deaths.
Reduce the risk of non-fatal myocardial infarction and stroke.
Reduce the need for coronary and non-coronary revascularization procedures.
Reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb).
Reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type lV hyperlipidemia).
Reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson type lll hyperlipidemia).
Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.
Two or more other CVD risk factors are present in the adolescent patient.
The minimum goal of treatment in pediatric and adolescent patients is to achieve a mean LDL-C <130 mg/dL. The optimal age at which to initiate lipid-lowering therapy to decrease the risk of symptomatic adulthood CAD has not been determined.
Zocor has not been studied in conditions where the major abnormality is elevation of chylomicrons (i.e., hyperlipidemia Fredrickson types I and V).
The usual dosage range is 5 to 40 mg/day. In patients with CHD or at high risk of CHD, Zocor can be started simultaneously with diet. The recommended usual starting dose is 10 or 20 mg once a day in the evening. For patients at high risk for a CHD event due to existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, the recommended starting dose is 40 mg/day. Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter.
Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 80-mg dose of Zocor should be restricted to patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Warnings and Precautions (5.1)].
Patients who are currently tolerating the 80-mg dose of Zocor who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin with less potential for the drug-drug interaction.
Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80-mg dose of Zocor, patients unable to achieve their LDL-C goal utilizing the 40-mg dose of Zocor should not be titrated to the 80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering.
The dose of Zocor should not exceed 10 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)].
The dose of Zocor should not exceed 20 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)].
The recommended dosage is 40 mg/day in the evening [see Dosage and Administration, Restricted Dosing for 80 mg (2.2)]. Zocor should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
Simvastatin exposure is approximately doubled with concomitant use of lomitapide; therefore, the dose of Zocor should be reduced by 50% if initiating lomitapide. Zocor dosage should not exceed 20 mg/day (or 40 mg/day for patients who have previously taken Zocor 80 mg/day chronically, e.g., for 12 months or more, without evidence of muscle toxicity) while taking lomitapide.
The recommended usual starting dose is 10 mg once a day in the evening. The recommended dosing range is 10 to 40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy [see NCEP Pediatric Panel Guidelines1 and Clinical Studies (14.2)]. Adjustments should be made at intervals of 4 weeks or more.
National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 89(3):495-501. 1992.
Because Zocor does not undergo significant renal excretion, modification of dosage should not be necessary in patients with mild to moderate renal impairment. However, caution should be exercised when Zocor is administered to patients with severe renal impairment; such patients should be started at 5 mg/day and be closely monitored [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
Tablets Zocor 5 mg are buff, oval, film-coated tablets, coded MSD 726 on one side and Zocor 5 on the other.
Tablets Zocor 10 mg are peach, oval, film-coated tablets, coded MSD 735 on one side and plain on the other.
Tablets Zocor 20 mg are tan, oval, film-coated tablets, coded MSD 740 on one side and plain on the other.
Tablets Zocor 40 mg are brick red, oval, film-coated tablets, coded MSD 749 on one side and plain on the other.
Tablets Zocor 80 mg are brick red, capsule-shaped, film-coated tablets, coded 543 on one side and 80 on the other.
Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing products) [see Warnings and Precautions (5.1)].
Concomitant administration of gemfibrozil, cyclosporine, or danazol [see Warnings and Precautions (5.1)].
Hypersensitivity to any component of this medication [see Adverse Reactions (6.2)].
Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels [see Warnings and Precautions (5.2)].
Women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins) decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Zocor may cause fetal harm when administered to a pregnant woman. 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. There are no adequate and well-controlled studies of use with Zocor during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. Zocor 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, Zocor should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].
Nursing mothers. It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require treatment with Zocor should not breastfeed their infants [see Use in Specific Populations (8.3)].
Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by elevated plasma levels of simvastatin and simvastatin acid. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment. Chinese patients may be at increased risk for myopathy [see Use in Specific Populations (8.8)].
The risk of myopathy, including rhabdomyolysis, is dose related. In a clinical trial database in which 41,413 patients were treated with Zocor, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.
In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with Zocor (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
All patients starting therapy with Zocor, or whose dose of Zocor is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Zocor. Zocor therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with Zocor or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Zocor therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Zocor therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
The risk of myopathy and rhabdomyolysis is increased by elevated plasma levels of simvastatin and simvastatin acid. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, posaconazole, voriconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, cobicistat-containing products, or grapefruit juice [see Clinical Pharmacology (12.3)]. Combination of these drugs with simvastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with simvastatin must be suspended during the course of treatment [see Contraindications (4) and Drug Interactions (7.1)].
The combined use of simvastatin with gemfibrozil, cyclosporine, or danazol is contraindicated [see Contraindications (4) and Drug Interactions (7.1 and 7.2)].
Caution should be used when prescribing other fibrates with simvastatin, as these agents can cause myopathy when given alone and the risk is increased when they are coadministered [see Drug Interactions (7.2)].
Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine [see Drug Interactions (7.7)].
The benefits of the combined use of simvastatin with the following drugs should be carefully weighed against the potential risks of combinations: other lipid-lowering drugs (fibrates or, for patients with HoFH, lomitapide), amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine [see Dosage and Administration (2.4), Drug Interactions (7.3)].
Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products [see Drug Interactions (7.4)].
Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (2.3, 2.4), Drug Interactions (7), Clinical Pharmacology (12.3)].
For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Persistent increases (to more than 3× the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies. When drug treatment was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity.
In the Scandinavian Simvastatin Survival Study (4S) [see Clinical Studies (14.1)], the number of patients with more than one transaminase elevation to >3× ULN, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 [0.7%] vs. 12 [0.6%]). Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2,221) and 5 in the placebo group (n=2,223). Of the 1,986 simvastatin treated patients in 4S with normal liver function tests (LFTs) at baseline, 8 (0.4%) developed consecutive LFT elevations to >3× ULN and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study. Among these 8 patients, 5 initially developed these abnormalities within the first year. All of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg.
In 2 controlled clinical studies in 1,105 patients, the 12-month incidence of persistent hepatic transaminase elevation without regard to drug relationship was 0.9% and 2.1% at the 40- and 80-mg dose, respectively. No patients developed persistent liver function abnormalities following the initial 6 months of treatment at a given dose.
It is recommended that liver function tests be performed before the initiation of treatment, and thereafter when clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Zocor, promptly interrupt therapy. If an alternate etiology is not found do not restart Zocor. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy [see Warnings and Precautions (5.1)].
The drug 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 transaminase elevations are contraindications to the use of simvastatin.
Moderate (less than 3× ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and did not require interruption of treatment.
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including Zocor.
In the pre-marketing controlled clinical studies and their open extensions (2,423 patients with median duration of follow-up of approximately 18 months), 1.4% of patients were discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: gastrointestinal disorders (0.5%), myalgia (0.1%), and arthralgia (0.1%). The most commonly reported adverse reactions (incidence ≥5%) in simvastatin controlled clinical trials were: upper respiratory infections (9.0%), headache (7.4%), abdominal pain (7.3%), constipation (6.6%), and nausea (5.4%).
In 4S involving 4,444 (age range 35-71 years, 19% women, 100% Caucasians) treated with 20-40 mg/day of Zocor (n=2,221) or placebo (n=2,223) over a median of 5.4 years, adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 2.
In the Heart Protection Study (HPS), involving 20,536 patients (age range 40-80 years, 25% women, 97% Caucasians, 3% other races) treated with Zocor 40 mg/day (n=10,269) or placebo (n=10,267) over a mean of 5 years, only serious adverse reactions and discontinuations due to any adverse reactions were recorded. Discontinuation rates due to adverse reactions were 4.8% in patients treated with Zocor compared with 5.1% in patients treated with placebo. The incidence of myopathy/rhabdomyolysis was <0.1% in patients treated with Zocor.
Other adverse reactions reported in clinical trials were: diarrhea, rash, dyspepsia, flatulence, and asthenia.
In a 48-week, controlled study in adolescent boys and girls who were at least 1 year post-menarche, 10-17 years of age (43.4% female, 97.7% Caucasians, 1.7% Hispanics, 0.6% Multiracial) with heterozygous familial hypercholesterolemia (n=175), treated with placebo or Zocor (10-40 mg daily), the most common adverse reactions observed in both groups were upper respiratory infection, headache, abdominal pain, and nausea [see Use in Specific Populations (8.4) and Clinical Studies (14.2)].
Because the below reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following additional adverse reactions have been identified during postapproval use of simvastatin: pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), dizziness, muscle cramps, myalgia, pancreatitis, paresthesia, peripheral neuropathy, vomiting, anemia, erectile dysfunction, interstitial lung disease, rhabdomyolysis, hepatitis/jaundice, fatal and non-fatal hepatic failure, and depression.
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.1)].
An apparent hypersensitivity syndrome has been reported rarely which has included some 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.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Strong CYP3A4 inhibitors: Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of CYP3A4. Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4.
Elevated plasma levels of HMG-CoA reductase inhibitory activity increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).] Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated [see Contraindications (4)]. If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment.
Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated [see Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
Gemfibrozil: Contraindicated with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1)].
Other fibrates: Caution should be used when prescribing with simvastatin [see Warnings and Precautions (5.1)].
The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amiodarone, dronedarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem, or amlodipine [see Dosage and Administration (2.3) and Warnings and Precautions (5.1), and Table 3 in Clinical Pharmacology (12.3)].
Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. The risk of myopathy is greater in Chinese patients. In a clinical trial (median follow-up 3.9 years) involving patients at high risk of cardiovascular disease and with well-controlled LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg/day, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses (≥1 g/day) of niacin. Coadministration of Zocor with lipid-modifying doses (≥1 g/day) of niacin is not recommended in Chinese patients. It is unknown if this risk applies to other Asian patients [see Warnings and Precautions (5.1) and Use in Specific Populations (8.8)].
In one study, concomitant administration of digoxin with simvastatin resulted in a slight elevation in digoxin concentrations in plasma. Patients taking digoxin should be monitored appropriately when simvastatin is initiated [see Clinical Pharmacology (12.3)].
In two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients, 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 the volunteer and patient studies, 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 simvastatin 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 simvastatin 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.
Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine.
Zocor is contraindicated in women who are or may become pregnant. Lipid lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of use with Zocor during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero. Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Zocor may cause fetal harm when administered to a pregnant woman. If Zocor is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
There are rare reports of congenital anomalies following intrauterine exposure to statins. In a review2 of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related statin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed those expected in the general population. However, the study was only able to exclude a 3- to 4-fold increased risk of congenital anomalies over the background rate. In 89% of these cases, drug treatment was initiated prior to pregnancy and was discontinued during the first trimester when pregnancy was identified.
Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m2 surface area. However, in studies with another structurally-related statin, skeletal malformations were observed in rats and mice.
Women of childbearing potential, who require treatment with Zocor for a lipid disorder, should be advised to use effective contraception. For women trying to conceive, discontinuation of Zocor should be considered. If pregnancy occurs, Zocor should be immediately discontinued.
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.
It is not known whether simvastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not nurse their infants. A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother [see Contraindications (4)].
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 reaction profile 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 significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls. [See Dosage and Administration (2.5), Adverse Reactions (6.1), Clinical Studies (14.2).] Adolescent females should be counseled on appropriate contraceptive methods while on simvastatin therapy [see Contraindications (4) and Use in Specific Populations (8.1)]. Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-menarchal girls.
A pharmacokinetic study with simvastatin showed the mean plasma level of statin activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age. In 4S, 1,021 (23%) of 4,444 patients were 65 or older. Lipid-lowering efficacy was at least as great in elderly patients compared with younger patients, and Zocor significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD. In HPS, 52% of patients were elderly (4,891 patients 65-69 years and 5,806 patients 70 years or older). The relative risk reductions of CHD death, non-fatal MI, coronary and non-coronary revascularization procedures, and stroke were similar in older and younger patients [see Clinical Studies (14.1)]. In HPS, among 32,145 patients entering the active run-in period, there were 2 cases of myopathy/rhabdomyolysis; these patients were aged 67 and 73. Of the 7 cases of myopathy/rhabdomyolysis among 10,269 patients allocated to simvastatin, 4 were aged 65 or more (at baseline), of whom one was over 75. There were no overall differences in safety between older and younger patients in either 4S or HPS.
Zocor is contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels [see Contraindications (4) and Warnings and Precautions (5.2)].
In a clinical trial in which patients at high risk of cardiovascular disease were treated with simvastatin 40 mg/day (median follow-up 3.9 years), the incidence of myopathy was approximately 0.05% for non-Chinese patients (n=7367) compared with 0.24% for Chinese patients (n=5468). The incidence of myopathy for Chinese patients on simvastatin 40 mg/day or ezetimibe/simvastatin 10/40 mg/day coadministered with extended-release niacin 2 g/day was 1.24%.
Chinese patients may be at higher risk for myopathy, monitor patients appropriately. Coadministration of Zocor with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products is not recommended in Chinese patients [see Warnings and Precautions (5.1), Drug Interactions (7.4)].
Significant lethality was observed in mice after a single oral dose of 9 g/m2. No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100 g/m2, respectively. No specific diagnostic signs were observed in rodents. At these doses the only signs seen in dogs were emesis and mucoid stools.
A few cases of overdosage with Zocor have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. Supportive measures should be taken in the event of an overdose. The dialyzability of simvastatin and its metabolites in man is not known at present.
Zocor (simvastatin) is a lipid-lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus. After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol.
Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol.
Tablets Zocor for oral administration contain either 5 mg, 10 mg, 20 mg, 40 mg or 80 mg of simvastatin and the following inactive ingredients: ascorbic acid, citric acid, hydroxypropyl cellulose, hypromellose, iron oxides, lactose, magnesium stearate, microcrystalline cellulose, starch, talc, and titanium dioxide. Butylated hydroxyanisole is added as a preservative.
Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C.
Epidemiological studies have demonstrated that elevated levels of total-C, LDL-C, as well as decreased levels of HDL-C are associated with the development of atherosclerosis and increased cardiovascular risk. Lowering LDL-C decreases this risk. However, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
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 the 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.
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%).
Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Rat studies indicate that when radiolabeled simvastatin was administered, simvastatin-derived radioactivity crossed the blood-brain barrier.
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. Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. While the recommended therapeutic dose range is 5 to 40 mg/day, there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal.
In a study including 16 elderly patients between 70 and 78 years of age who received Zocor 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. Clinical study experience in the elderly (n=1522), suggests that there were no overall differences in safety between elderly and younger patients [see Use in Specific Populations (8.5)].
Kinetic studies with another statin, having a similar principal route of elimination, 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).
Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of medicinal products that are inhibitors of the transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid and an increased risk of myopathy. For example, cyclosporine has been shown to increase the AUC of statins; although the mechanism is not fully understood, the increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1.
The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].
Results based on a chemical assay except results with propranolol as indicated.
Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone.
Simvastatin acid refers to the β-hydroxyacid of simvastatin.
The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied.
Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3.
Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3.
In a study of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4, and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4.
Coadministration of simvastatin (40 mg QD for 10 days) resulted in an increase in the maximum mean levels of cardioactive digoxin (given as a single 0.4 mg dose on day 10) by approximately 0.3 ng/mL.
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 statins. 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.
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).
In 4S, the effect of therapy with Zocor on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L). In this multicenter, randomized, double-blind, placebo-controlled study, patients were treated with standard care, including diet, and either Zocor 20-40 mg/day (n=2,221) or placebo (n=2,223) for a median duration of 5.4 years. Over the course of the study, treatment with Zocor led to mean reductions in total-C, LDL-C and TG of 25%, 35%, and 10%, respectively, and a mean increase in HDL-C of 8%. Zocor significantly reduced the risk of mortality by 30% (p=0.0003, 182 deaths in the Zocor group vs 256 deaths in the placebo group). The risk of CHD mortality was significantly reduced by 42% (p=0.00001, 111 vs 189 deaths). There was no statistically significant difference between groups in non-cardiovascular mortality. Zocor significantly decreased the risk of having major coronary events (CHD mortality plus hospital-verified and silent non-fatal myocardial infarction [MI]) by 34% (p<0.00001, 431 vs 622 patients with one or more events). The risk of having a hospital-verified non-fatal MI was reduced by 37%. Zocor significantly reduced the risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37% (p<0.00001, 252 vs 383 patients). Zocor significantly reduced the risk of fatal plus non-fatal cerebrovascular events (combined stroke and transient ischemic attacks) by 28% (p=0.033, 75 vs 102 patients). Zocor reduced the risk of major coronary events to a similar extent across the range of baseline total and LDL cholesterol levels. Because there were only 53 female deaths, the effect of Zocor on mortality in women could not be adequately assessed. However, Zocor significantly lessened the risk of having major coronary events by 34% (60 vs 91 women with one or more event). The randomization was stratified by angina alone (21% of each treatment group) or a previous MI. Because there were only 57 deaths among the patients with angina alone at baseline, the effect of Zocor on mortality in this subgroup could not be adequately assessed. However, trends in reduced coronary mortality, major coronary events and revascularization procedures were consistent between this group and the total study cohort. Additionally, Zocor resulted in similar decreases in relative risk for total mortality, CHD mortality, and major coronary events in elderly patients (≥65 years), compared with younger patients.
The Heart Protection Study (HPS) was a large, multi-center, placebo-controlled, double-blind study with a mean duration of 5 years conducted in 20,536 patients (10,269 on Zocor 40 mg and 10,267 on placebo). Patients were allocated to treatment using a covariate adaptive method3 which took into account the distribution of 10 important baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients had a mean age of 64 years (range 40-80 years), were 97% Caucasian and were at high risk of developing a major coronary event because of existing CHD (65%), diabetes (Type 2, 26%; Type 1, 3%), history of stroke or other cerebrovascular disease (16%), peripheral vessel disease (33%), or hypertension in males ≥65 years (6%). At baseline, 3,421 patients (17%) had LDL-C levels below 100 mg/dL, of whom 953 (5%) had LDL-C levels below 80 mg/dL; 7,068 patients (34%) had levels between 100 and 130 mg/dL; and 10,047 patients (49%) had levels greater than 130 mg/dL.
The HPS results showed that Zocor 40 mg/day significantly reduced: total and CHD mortality; non-fatal MI, stroke, and revascularization procedures (coronary and non-coronary) (see Table 4).
Two composite endpoints were defined in order to have sufficient events to assess relative risk reductions across a range of baseline characteristics (see Figure 1). A composite of major coronary events (MCE) was comprised of CHD mortality and non-fatal MI (analyzed by time-to-first event; 898 patients treated with Zocor had events and 1,212 patients on placebo had events). A composite of major vascular events (MVE) was comprised of MCE, stroke and revascularization procedures including coronary, peripheral and other non-coronary procedures (analyzed by time-to-first event; 2,033 patients treated with Zocor had events and 2,585 patients on placebo had events). Significant relative risk reductions were observed for both composite endpoints (27% for MCE and 24% for MVE, p<0.0001). Treatment with Zocor produced significant relative risk reductions for all components of the composite endpoints. The risk reductions produced by Zocor in both MCE and MVE were evident and consistent regardless of cardiovascular disease related medical history at study entry (i.e., CHD alone; or peripheral vascular disease, cerebrovascular disease, diabetes or treated hypertension, with or without CHD), gender, age, creatinine levels up to the entry limit of 2.3 mg/dL, baseline levels of LDL-C, HDL-C, apolipoprotein B and A-1, baseline concomitant cardiovascular medications (i.e., aspirin, beta blockers, or calcium channel blockers), smoking status, alcohol intake, or obesity. Diabetics showed risk reductions for MCE and MVE due to Zocor treatment regardless of baseline HbA1c levels or obesity with the greatest effects seen for diabetics without CHD.
N = number of patients in each subgroup. The inverted triangles are point estimates of the relative risk, with their 95% confidence intervals represented as a line. The area of a triangle is proportional to the number of patients with MVE or MCE in the subgroup relative to the number with MVE or MCE, respectively, in the entire study population. The vertical solid line represents a relative risk of one. The vertical dashed line represents the point estimate of relative risk in the entire study population.
In the Multicenter Anti-Atheroma Study, the effect of simvastatin on atherosclerosis was assessed by quantitative coronary angiography in hypercholesterolemic patients with CHD. In this randomized, double-blind, controlled study, patients were treated with simvastatin 20 mg/day or placebo. Angiograms were evaluated at baseline, two and four years. The co-primary study endpoints were mean change per-patient in minimum and mean lumen diameters, indicating focal and diffuse disease, respectively. Zocor significantly slowed the progression of lesions as measured in the Year 4 angiogram by both parameters, as well as by change in percent diameter stenosis. In addition, simvastatin significantly decreased the proportion of patients with new lesions and with new total occlusions.
Zocor has been shown to be effective in reducing total-C and LDL-C in heterozygous familial and non-familial forms of hyperlipidemia and in mixed hyperlipidemia. Maximal to near maximal response is generally achieved within 4-6 weeks and maintained during chronic therapy. Zocor significantly decreased total-C, LDL-C, total-C/HDL-C ratio, and LDL-C/HDL-C ratio; Zocor also decreased TG and increased HDL-C (see Table 5).
mean baseline LDL-C 156 mg/dL and median baseline TG 391 mg/dL.
The results of a subgroup analysis in 74 patients with type lV hyperlipidemia from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 6.
The median baseline values (mg/dL) for the patients in this study were: total-C = 254, LDL-C = 135, HDL-C = 36, TG = 404, VLDL-C = 83, and non-HDL-C = 215.
The results of a subgroup analysis in 7 patients with type lll hyperlipidemia (dysbetalipoproteinemia) (apo E2/2) (VLDL-C/TG>0.25) from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 7.
The median baseline values (mg/dL) were: total-C = 324, LDL-C = 121, HDL-C = 31, TG = 411, VLDL-C = 170, and non-HDL-C = 291.
In a controlled clinical study, 12 patients 15-39 years of age with homozygous familial hypercholesterolemia received simvastatin 40 mg/day in a single dose or in 3 divided doses, or 80 mg/day in 3 divided doses. In 11 patients with reductions in LDL-C, the mean LDL-C changes for the 40- and 80-mg doses were 14% (range 8% to 23%, median 12%) and 30% (range 14% to 46%, median 29%), respectively. One patient had an increase of 15% in LDL-C. Another patient with absent LDL-C receptor function had an LDL-C reduction of 41% with the 80-mg dose.
In clinical studies, simvastatin did not impair adrenal reserve or significantly reduce basal plasma cortisol concentration. Small reductions from baseline in basal plasma testosterone in men were observed in clinical studies with simvastatin, an effect also observed with other statins and the bile acid sequestrant cholestyramine. There was no effect on plasma gonadotropin levels. In a placebo-controlled, 12-week study there was no significant effect of simvastatin 80 mg on the plasma testosterone response to human chorionic gonadotropin. In another 24-week study, simvastatin 20-40 mg had no detectable effect on spermatogenesis. In 4S, in which 4,444 patients were randomized to simvastatin 20-40 mg/day or placebo for a median duration of 5.4 years, the incidence of male sexual adverse events in the two treatment groups was not significantly different. Because of these factors, the small changes in plasma testosterone are unlikely to be clinically significant. The effects, if any, on the pituitary-gonadal axis in pre-menopausal women are unknown.
In a double-blind, placebo-controlled study, 175 patients (99 adolescent boys and 76 post-menarchal girls) 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (HeFH) were randomized to simvastatin (n=106) or placebo (n=67) for 24 weeks (base study). Inclusion in the study required a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with an LDL-C level >189 mg/dL. The dosage of simvastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24-week extension, 144 patients elected to continue therapy with simvastatin 40 mg or placebo.
Zocor significantly decreased plasma levels of total-C, LDL-C, and Apo B (see Table 8). Results from the extension at 48 weeks were comparable to those observed in the base study.
After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64.0-289.0 mg/dL) in the Zocor 40 mg group compared to 207.8 mg/dL (range: 128.0-334.0 mg/dL) in the placebo group.
The safety and efficacy of doses above 40 mg daily have not been studied in children with HeFH. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
NDC 0006-0726-31 unit of use bottles of 30.
NDC 0006-0735-54 unit of use bottles of 90.
NDC 0006-0740-54 unit of use bottles of 90.
NDC 0006-0749-54 unit of use bottles of 90.
NDC 0006-0543-54 unit of use bottles of 90.
Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel.
Patients should be advised about substances they should not take concomitantly with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1)]. Patients should also be advised to inform other healthcare professionals prescribing a new medication or increasing the dose of an existing medication that they are taking Zocor.
All patients starting therapy with Zocor should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing Zocor. Patients using the 80-mg dose should be informed that the risk of myopathy, including rhabdomyolysis, is increased with use of the 80-mg dose. The risk of myopathy, including rhabdomyolysis, occurring with use of Zocor is increased when taking certain types of medication or consuming grapefruit juice. Patients should discuss all medication, both prescription and over the counter, with their healthcare professional.
It is recommended that liver function tests be performed before the initiation of Zocor, and thereafter when clinically indicated. All patients treated with Zocor should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.
Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using Zocor. Discuss future pregnancy plans with your patients, and discuss when to stop taking Zocor if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking Zocor and call their healthcare professional.
Women who are breastfeeding should not use Zocor. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professional.
Copyright © 1999-2019 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
Each tablet contains 5 mg of simvastatin.
Each tablet contains 10 mg of simvastatin.
Each tablet contains 20 mg of simvastatin.
Each tablet contains 40 mg of simvastatin.
Each tablet contains 80 mg of simvastatin.
What are the side effects of statins?


text:
Edward Chafizadeh, MD, has practiced cardiology in Austin since 1997. He received a bachelor degree in molecular biochemistry from Yale University in 1985 and went on to earn his medical degree with high honors from Baylor College of Medicine in 1989. He subsequently completed an internal medicine residency at Baylor and served as Chief Medical Resident at Baylor/St.Luke's Episcopal Hospital. Dr. Chafizadeh then completed fellowship in cardiology and interventional cardiology at Harvard Beth Israel from 1993-1997. He is board certified by the American Board of Internal Medicine in cardiovascular disease.
Dr. Chafizadeh currently practices general and interventional cardiology at St. David's Medical Center in Austin. He is on the Bylaws Committee, the Quality Assurance Committee, and is the Medical Director for STEMI care at St. David's. His clinical interests include preventive cardiology, lipid disorders, interventional cardiology (including both cardiac and peripheral vascular disease) and non-invasive imaging of the heart and blood vessels.
Dr. Chafizadeh is a past president of the Capitol Area Division of the American Heart Association and has served on the Texas Board of Directors of the American Heart Association.
In his spare time, Dr. Chafizadeh enjoys spending time with his wife and four kids, running, playing basketball, flag football and golf, and working the Sunday Times crossword puzzle.
Board certified in Cardiovascular Disease by the American Board of Internal Medicine.

industry_corpus2: Health & Medicine


text:
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industry_corpus2: Real Estate & Construction


text:
You want to obtain a spontaneous mutant for Ampicillin resistance in a sample of E. coli. Of the strategies listed below, which is most likely to yield a result the fastest?
Plate the E coli on a linear gradient medium from a concentration of 1μg/L to a 1 g/mL.

industry_corpus2: Biopharmaceuticals


text: One of the best movies I've seen in a while, so so so good! You completely forget it's Scarlett, she's phenomenal. Who else has seen it? I liked it so much, I want to see it again.

industry_corpus2: Film & Entertainment


text:
Back when I played good basketball, I really played good basketball. I remember those times when I would be the one to shoot winning shots. Those times when I would get to play with the pros. Not that it’s a big deal. You just go to Green Meadows, or Valle Verde I, or White Plains at the right time and you might be able to play with PBA pros and actors for that matter. But I do realize that there must be millions of pinoys who would grab that chance in a heartbeat.
I was once asked by the highschool coach if I wanted to try out for the team. Back in those days, that was equivalent to an assurance that you would indeed make it to the team. I had my backing… there were four boys in the family and at that point, everyone of my brothers were in the varsity. My kuya (Michael) played PAYA and PRADA, my younger brother (Carlo) played for the Father Martin’s, and the youngest in the family (Francis) played with the SBP (he was in the same team as Macky Escalona back when he was still in LSGH, yes peepz he was Green before he was Blue). All my brothers played guard. The coach that approached me must’ve seen me play with my Kuya one afternoon.
But I guess it was the feeling that I had to separate myself from my brothers that I chose a different path – the chess team. The chess team did not get that much attention. In fact, it hardly got any attention at all. That was my cross-over to the unnoticed world. It was an odd mix when everyone of my brothers were almost known for their skills and here I came… and I was part of the family. Hahaha.
This entry was posted in Life, Personal and tagged Ball, Basketball, Sports by Jack Ross Aethen. Bookmark the permalink.
saan kaya merong mabibiling shougi (japanese chess) set dito sa Pinas?

industry_corpus2: Sports


text:
Are you looking for a special present for your husband for his birthday, wedding day, or to celebrate an anniversary? How about giving your husband an adventure through ‘time’? Our clockmaking kits and watchmaking seminars give men the chance to discover time and experience the traditional craft of watchmaking.
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is delivered in a precious package.
Ready to make a present!

industry_corpus2: Manufacturing


text:
Through the Tenth Malaysia Plan (RM-10), the government has identified the need for the establishment of the Malaysia Board of Technologist (MBOT) in order to recognize graduates of relevant skills and technology. This recognition will encourage institutions of higher learning (IPT), including educational institutions and technical and vocational training (TVET-Technical Vocational Education and Training) offers courses and programs in line with the needs of technology-based economy towards a high-income country.
This exposition is proposed in response to the call by the government in promoting TVET as well as the interests of technologists and technicians, especially graduates of institutions of higher learning (IPT), educational institutions and technical and vocational training and the industry together to showcase the innovation and research related to TVET and subsequently registered with MBOT for recognition of their profession.
This exposition is also seen as capable of affirming promote related activities at the TVET East Coast Zone in addition to generating revenue for the university.
To display the innovations achieved through research and development activities by all institutions in Malaysia and demonstrate the strength of researchers which are fundamental to a university.
To Increase the confidence of the industry and outside of the expertise and research capabilities available so that the exposition can be used as a channel for business matching both parties.
To promote networking and strategic cooperation between higher education institutions and other players such as entrepreneurs, private companies and individuals.
To open up opportunities for higher education institutions and to strengthen the joint ventures with other institutions in related fields.

industry_corpus2: Subject Education


text:
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text: Find a great sale price on this 2019 Nissan Titan PRO-4X at Pocatello Nissan in Pocatello ID. This 2019 Nissan Titan PRO-4X is located at our Nissan dealership in Pocatello. We also serve the cities of Idaho Falls and Blackfoot. So if you're looking for a great price on this 2019 Nissan Titan PRO-4X or just looking to get an auto loan for the vehicle you want... you've come to the right place! Pocatello Nissan.

industry_corpus2: Automobiles


text:
I was diagnosed positive in January 2015, and suffered a lot in the first two months after the diagnosis.
I read a lot about my alleged illness as well as a lot of material on the internet written by dissidents, whose theoretical and practical reasoning convinced me about the inaccurate facts underlying the theories of HIV and AIDS.
I have never taken treatment, so I cannot believe what I recently read, that the “worst” phase of the disease is in the first year, which is why we are told it is important to take medication from the beginning.
I’m perfectly fine, the only consequence of my diagnosis is brief episodes of depression, because of all this social campaign of fear. I have managed to reduce my stress through meditation and reading.
When they tested my viral load and CD4 counts, they were perfect, however the doctor recommended that I start treatment, recommending even a new medication, which is more expensive, but which he told me was the best, after he checked that I could afford it.


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All our villas resale in the town of Cabo Roig, as well as in other localities in which ES for Sale in Spain Property has properties feature the latest designs, avant-garde and stylish. If you are a fan of the best design and the latest architectural trends, we offer what you want.
Similarly, customers can view our catalog of properties or our buying guide to see how most of our properties have several added extras such as garden, pool, BBQ and terraces. Similarly, properties, whether new or second hand ES Property for Sale in Spain are very well positioned within their locality and very close to major attractions and basic services for major purchases or spend good times in the best environments.
The situation in which we find the area of Cabo Roig is renowned for its beauty and recognized quality of its beaches. Points to Cala Capitan, La Caleta or Playa de Cabo Roig itself are genuine locations in which to make the most of nature and the crystal waters of the Mediterranean Sea. You should know that buying property in Cabo Roig are taking the opportunity to live in a surrounded by the best climate in the world, established by the World Health Organization as one of the most beneficial health idyllic setting. You can enjoy the beautiful sunsets and sunsets on the Costa Blanca have place leaving an image that only those can enjoy having a home such as those within your reach from ES Property for Sale in Spain.
If you are considering buying a resale villa in Cabo Roig, Orihuela Costa, know that we are very possibly going through the best time to do it. Note that the latest figures released by the National Statistics Institute (INE) show a slight increase in quarterly house prices of 0.8% over the previous year. Many experts are already talking about a certain stabilization of the market, so it is quite possible that prices are reaching their lowest point. This means we are quite possibly the perfect time to be encouraged to buy a home in Spain. So you should not wait to contact us if you want to buy a new villa in Cabo Roig, Orihuela Costa.
Take advantage of the opportunity to make an inspection trip to see first hand the feelings it provokes in you climate and atmosphere of the Mediterranean.


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There are a few ways on BigMarker to share with and invite people to your event or webinar.
At the most basic, you can copy and paste the webinar page link (URL) into an email, social media page, newsletter, website or blog. Understand when copy and paste the URL and use your own email system or email account, people will not receive reminders via BigMarker until they sign up. Also, only share the link from the webinar page, not your personal link in the confirmation email. Make sure to send our attendee guide and system requirements with any email sent.
There are a couple of ways to invite using BigMarker's system. Including inviting those that have subscribed to your channel and your personal contacts. Using our system insures they will also receive reminder emails and personalized links to your event.
3. Choose to type emails, upload and invite contacts, and invite channel subscribers.
4. You can also click Promote & Manage and Send Email Contacts.
5. After you have clicked Send, you can visit the Invite List to see who was invited, opened & clicked the invitation and who has registered.

industry_corpus2: Computing & Telecommunications


text: Born in our home juli 30 2009. A carefull little man, very gentle and always sweet. Loves to play, specially in our catproof garden. He understands we humans are very fragile, but he doesn't really get why. He may look elegant, but his behaviour is not always very elegant. When it is a little bit busy in the house he has no time at all to cuddle, even if he loves his cuddles. No time, he needs to play! He loves to play with Cad, just running and running. And Elmira, playing hide and seek. But when things quiet down, he comes to get his cuddles, loves to be with you. Stands right next to you and starts purring when you look at him. Pick him up en put him on your lap, he will stay with you for a while. Unless of course he didn't mean to sit on your lap. Then he leaves as soon as possible! Purring all the way of course.Velvet is a bit of a pushover, but o so sweet. My beautifull special man.

industry_corpus2: Others


text:
At Waterproof Flooring Guys, we offer you with the most reliable professional installation of Waterproof Flooring in Rock Rapids, IA. We have been offering our services to the residential as well as commercial premises in this city for the last three decades during which we have managed to scale the heights to become among the top service providers. We have installer who are equally skilled and are well trained in all aspects of waterproof installation. With our services therefore, you will have peace of mind with the full knowledge that the real experts are the ones who did your flooring hence you dont have to worry about any mishaps thereafter. Give us a call today at 888-383-3443 for Waterproof Flooring services in Rock Rapids, IA.
Due to the fact that we have skilled technicians and we also deal with high quality waterproof laminate flooring products, we give warranties for both the flooring materials and the labor we offer during installation. Under such arrangements, we will undertake to do a new installation if by any chance the flooring materials showed defects before the warranty period is over. Additionally, if we offer our services and you feel that they are not up to standard or you notice certain flaws after we leave, we will redo the work at no additional cost. For more information, call us today at 888-383-3443 for guaranteed Waterproof Flooring in Rock Rapids, IA.
The Waterproof Flooring you get from Waterproof Flooring Guys at Rock Rapids, IA will not just prevent water from getting into your floors but also ensure that your floors retain their original aesthetics and beauty. This is simply due to the fact the materials we use have been designed to resist any form of wearing. With a surface density of over 3000kg/m3, the floor can withstand pressure even from sharp pointed objects such as ladies heels. With this type of resilience, you can safely install the flooring in high traffic areas such as alleys and corridors yet they will retain their luster without ever showing signs of wear or tear.
One thing you will love about waterproof laminate flooring is the fact that they are very easy to clean and maintain. They dont require expensive detergents or polishes to make look nice. In addition to this, these types of floors are compatible with under floor heating hence they will be crucial in adding warmth and a little bit of luxury to the rooms. Allow us to offer you the best waterproof laminate flooring in Rock Rapids, IA and tap on all the benefits it brings to you. Call us at 888-383-3443 for more information.


text: Phone Number in Elbe. Find a Phone Number, Address or other Contact Detail, like Email Address and Profiles of people or friends who live in Elbe, Washington, USA. Results of Phone Numbers and Addresses in any Street.


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Hygge is the new cool. Sooo, obvs you’re doing it too, aren’t you? Here’s my post on enjoying hygge in…. Carlow. If hygge is life’s simple pleasures; good food, appreciating nature and indulging in plenty of what makes you happy, and you can do all of this just under two hours from Dublin, Why is everyone not doing it? Read on and I’ll fill you in!
Carlow may not seem like the most obvious destination for a weekend retreat when everyone raves about the breath taking scenery of the Wild Atlantic Way and the raw, beauty of the Northern coastline but hear me out. Carlow is a gem all on its own.
In all my years of living in this country I had never been to Carlow until 2016 and now I have been three times in the space of 12 months! Partly because of a certain delicious tapas restaurant, ok mainly because of that tapas restaurant but this past weekend, my ‘explore Carlow’ hat was on and it was such a fun trip I couldn’t wait to share it with you.
Please give a round of applause for our Airbnb host, Breda. Her keen interior designer eye and attention to detail made this beautifully converted stone barn a home from home option. Sold. I couldn’t wait to book our Carlow barn conversion for a chilled weekend of food, wine, walks, wine and photos. Oh and the rugby match, so more wine.
Carlow is a handy 1hr and 40 mins or so from Dublin and if you take the ‘sneaky, scenic N81 via Blessington route’ you are rewarded with stunning sunsets as you drive south. Our weekend was off to a great start. Hygge begins now!
Absolute sky goals. Thanks Stephen!
Our host met us in the village of Ballon because where we were actually staying was a further 10 minutes drive out into the dark wilderness of the countryside.
Check out the photos below of this gorgeous, cosy, converted barn on a working farm. Complete with bunnies in the field next door. The fire was lighting and freshly made warm scones were waiting. The freezing cold temperatures outside were not going to dampen our spirits.
Up early on Saturday morning to explore what Carlow has to offer. A short drive to Altamont Gardens for a stroll around the landscaped gardens, riverside walks and along the snowdrop lined lanes. Breathe in that fresh air and if you want to warm up there is even a little café tucked into the garden centre area. With heaters. Much needed heaters.
The house wasn’t open for visitors and looked pretty delapitated, to be honest but that certainly didn’t detract from its haunting beauty.
So many little bird houses dotted around the outbuildings and tree lined avenues encouraged a flurry of winged activity as you passed by.
Knock, knock open wide, see what’s on the other side.
Stephen’s pretty amazing fauxtography skills at work again helped to capture these manicured gardens.
I’m not in the slightest bit green fingered. I did not inherit that gene from my father, unfortunately, but I can appreciate a beautifully cared for garden. The many varieties of mature trees really help you to feel insignificant and the babbling little river, complete with diving ducks, evokes nothing but inner peace. At only €2 for the carpark fee, it’s a small price to pay for mindfulness.
We then checked out Trip Advisor’s ‘top 10 things to do in Carlow’ and, little-known fact, the area has a high density of prehistoric remains. Who knew? We drove past Brownshill Dolmen and stopped off for a lookie. I always think the capstones on large dolmens are pretty darn impressive. How the devil did they lift these 100 ton capstones up onto the tomb? How? No cranes, no nothin’. Mad engineering skills! This portal dolmen is the largest of its kind in Europe. And I read somewhere that they think human sacrifices took place there. Grim.
Rightio, off we go, after all that history a lunch stop at The Forge restaurant is in order. Our afternoon was then spent watching the first match of the Six Nations rugby tournament. You may choose to spend your Saturday exploring some of the other top 10 locations on the Trip Advisor list. I, unfortunately, cannot help you there because we were in the pub watching the game for the afternoon. Bad blogger move, I know. But this was my hygge so you can’t judge!
So, enough faffing, let me tell you about the capital reason I have returned to Carlow three times in the past twelve months. Mimosa Tapas Bar, Carlow Town.
This spot is rated the #1 restaurant in Carlow on Trip Advisor. I hip, hip, hurray heartily agree. The chilled, Mediterranean vibe and décor are complimented by the soothing tones of Latin strings.
Perfect for chats and Saturday night dates. I do dislike, however, that you can’t book for tables of two. That, Mimosa, is a complete downer. It means you can’t really tell at what time you’ll be eating. We arrived about 7:45pm to be told we would be called around 9:30pm and we headed to The Med Bar around the corner to wine, I mean while away the time. I was fully prepared since this wasn’t my first rodeo here, but my boyfriend was not expecting the delay. Around 9:40pm I reckoned that it was time to check out the table situation and since our stomachs were practically eating themselves we popped back in and were seated by 10pm.
It was a little late to be eating by Irish standards, to be fair. BUT, the food is delish and worth the wait! We ordered 3 tapas plates each and a portion of patatas bravas and tapenade to share. So. Much. Food!
They have a fish, meat and veggie menu with at least five plates on each. Perfect for sharing or, inhaling all by yourself. NO judgement from me. The wine selection in Mimosa is good and a Malbec always goes down well. I do love the food here and would highly, HIGHLY recommend it to any visitors to Carlow.
Tummies full we rolled out the door and off to our barn in the wilderness.
Slivers of pale, winter sunshine filtered through the skylight in the barn when we woke on a frosty Sunday morning and we availed of the breakfast treats our host had left for us. She thought of everything!
Sundays are made for road trips and we headed to Mount Leinster. Cautious on the icy morning roads we found a convenient viewpoint half way up the hillside at Nine Stones and on such a clear, sunny day we were rewarded with a view of the patchwork quilt style landscape rolling out below the Blackstairs Mountains. AND it would also seem that this area is perfect for hang gliders to launch from. I have never seen a glider close up and now I have such conflicting FOMO!
Stephen’s eagle eye photography skills again.
I am envious that the glider guy is able to soar, birdlike in the air and sweep along the air currents far above this stunning countryside. However, I am also terrified at the very thought of hurtling down a hillside hoping the updraft takes me and I don’t snot myself. And then, once up there, that a strong gust of wind doesn’t decide to dash my helpless body against a local tree or mountain top. Divided!
I was also pretty jealous that the glider guy (What is the proper word for people who hand glide? Because I am sure glider guy is not it!) looked like a human butterfly with his body tucked into the chrysalis-like body stocking. Amazing.
The fun wasn’t over. We took a drive along Ireland’s version of Death Road up to the foot of Mount Leinster. Seriously, the drop was a little harrowing.
Here is where the plans for the day differed slightly. I thought we were going to take a few photos, wander up to one of the foothills before heading off to find somewhere that served scones and tea or some sort of cake. I was wrong.
There I am, thinking we are going to pop to the top of this hill and then it’s scone time. Nope.
We instead trekked up to the summit of Mount Leinster. Just, casually ambling up all 794 metres of it. No sporty, outdoor gear on apart from the ever ready hiking boots, which I was very glad of.
To be honest it was a rewarding 50 minute climb to the summit. With the bonus of getting to experience all the weathers in one afternoon. All of them. Sun and wind at the bottom of the climb, foggy drifts of cloud as we reached the top. Freezing, falling shards of ice and snow and hailstones on our descent. Ah, Ireland. You have it all!
Yip, we’re heading up there.
Spooky looking as the mental structures disappeared into the clouds at the summit.
I can blame my lack of fitness on the fact that I hadn’t done any form of exercise in the week prior to this, or that the climb was ‘quite steep’ towards the end. When I say ‘quite steep’, I mean, you know steepish. I needed a few breath breaks disguised as photo opportunities. I ignored the many families with small kids gallivanting up and down the route and also the woman who was CARRYING her small child. I could just about get myself up there, let alone be responsible for a small child. Respect to that woman. I’m sure, locals run up and down this in no time but this was, and correct me if I’m wrong friends, the highest peak I have climbed. So I was a little slow. ‘Unimpressive’ I hear you scoff. Hush up. I already mentioned in my Wicklow post that I am no hiker, so the fact that so many of my weekends seem to include traipsing up and down some hill or mountain or other should not fool you. I have no idea what I’m doing!
Finally, upon making it down to the waiting car park and blasting the heat to defrost our soaked jeans we decided to get some comfort food in the Step House Hotel in Borris.
Creamy, piping hot tomato soup was just what my chilly body needed. If you recall, I thought we were going for scones a good two hours earlier. So this was a good compromise. Climb every mountain first, then eat all the culinary treats.
So much to pack into a weekend and plenty more we didn’t get to do, I can certainly suggest you put Carlow on your weekend escapes list. Don’t forget to follow the link above for a discount onyour own airbnb weekend and let me know in the comments what your hygge getaway is!

industry_corpus2: Travel & Geography


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Guatemala is a very traditional market when it comes to grocery retailing. The most important channels are traditional retailers like independent small grocers, with almost 116,000 stores across the country. The success of these stores come mainly from their location (which are at a walking distance from consumers’ homes and working areas), their strong penetration in rural areas of the country and the sales of small pack sizes that make products more affordable for consumers, especially those on the lower end of the market that have tight budgets and do their grocery shopping on a daily-need basis. However, urbanisation is allowing modern grocery retailers like supermarkets to have strong growth in the country, mainly in Guatemala City but also expanding to the suburbs. In 2016, for example, Unisuper opened seven new stores, five La Torre outlets and two Econosuper outlets. Modern channel retailers appeal mainly to middle- to upper-class consumers that prefer to shop with access to a wider selection of products and pack sizes and to do their shopping on a weekly or monthly basis.
Wal-Mart Centroamérica is the leading grocery retailer with a retail value share of 15% in 2016. The company has strong presence in Guatemala with over 300 stores across the country. The company operates the only discounter chains, Maxi Despensa and Despensa Familiar, Paiz supermarkets and Wal-Mart hypermarkets. The company is constantly opening new stores to reach more consumers through good-quality products at low prices. The mix of grocery and non-grocery items that these stores offer are more convenient for consumers that do not have time to visit several stores for what they need to purchase. For example, open markets offer better prices, but they mainly sell fresh produce. In December 2015, the company closed its warehouse club format store ClubCo.
Urbanisation and population growth are expected to be the main growth drivers for grocery retailers over the forecast period in Guatemala. Urbanisation is mainly allowing growth of modern channels like supermarkets, whilst population growth continues to support growth for traditional channels like independent small grocers.
Discover the latest market trends and uncover sources of future market growth in the Grocery Retailers industry in Guatemala with research from Euromonitor's team of in-country analysts.
If you're in the Grocery Retailers industry in Guatemala, our research will save you time and money while empowering you to make informed, profitable decisions.
How is grocery and non-grocery performing in Guatemala?
Are independent and family run stores coming under pressure in Guatemala?

industry_corpus2: Hospitality & Catering


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im hardworker and simple leaving and high thinking.
I consider myself as a smart boy from a middle class family. Full of cultural value and looking for same in my partner.
iam tall handsome intelligent ,want to have good life partner to enjoy lovelife and to fullfil my darlings ambitions.


text: Ubisoft and the Ubisoft logo are trademarks of UbisoftEntertainment in the US and/or other countries. Nadeo and Trackmania logo are trademarks of Nadeo in the USand/or other countries. Nadeo is a Ubisoft Entertainment company.

industry_corpus2: Gaming


text:
Butternut squash is easier to peel if it's first cut into smaller sections.
Spicy butternut squash soup is a delicious appetizer for a holiday meal or party.
Butternut squash is a vine crop that needs about 100 days to mature before cutting and curing. It can be stored for several months.
When the organic winter squash went on sale at the market, I decided to stock up on these versatile vegetables. While weighing the difference between two butternut squash, another customer stopped and watched. She said, "I'd love to get some of those, too, but they're just too hard to peel."
After I showed her how to cut the squash for easy peeling, she smiled and placed a few in her cart.
The secret to preparing a butternut squash is to 1) slice through the squash at the narrow neck to separate it from the bottom section 2) cut the bottom portion into rings for easier peeling and 3) scoop out the seeds and stringy pulp.
If you think the squash will still be too hard to cut, simply use a fork to poke holes over the surface of the squash (to allow steam to escape) and microwave on high for 3-4 minutes or just until the squash starts to soften. Let cool slightly before slicing and peeling.
Once the squash is peeled, you can cut it into cubes for sautéing, pureeing, roasting, baking, steaming, or blanching for freezing.
Besides being so adaptable to different recipes, butternut squash (Cucurbita moschata) is an excellent source of vitamins A, B6 and C. It's one of those vegetables that's high in fiber, low in calories and its orange color means it's rich with beta-carotene.
Butternut Squash with Cheddar Cheese and Sage requires cutting the squash in half lengthwise and scooping out the seeds. Use the technique for microwaving the squash for a few minutes to make cutting easier.
Squash, Apple and Onion pizza uses 1 cup of cooked, pureed butternut squash in place of tomato sauce for a perfect fall combination of flavors.
Squash is filled with tomatoes, Feta cheese and sage before it's baked in this simple twist on stuffed vegetables.
Spicy Butternut Squash Soup can be served at any temperature from steaming hot to soothing cool. It makes a nice home-cooked dinner with a salad and warm rolls or it can be served as an appetizer in shot glasses for a party. Garnish with your favorite fresh herbs. One ingredient that helps flavor this butternut squash soup is turmeric, a spice containing curcumin, an antioxidant that has anti-inflammatory properties.
Mince shallots and garlic and set aside.
Wash and peel squash; cut into ¾-inch cubes.
Add shallots and garlic; cook for several minutes.
Add curry powder; stir well.
Add squash and cover the pan.
Cook squash over medium-low heat for 20 minutes.
Add stock, cover and simmer until squash is very tender.
Puree small batches of squash and liquid in a blender or food processor until smooth.
Do you have a favorite way to prepare butternut squash? Please share it here.
WesternGardener writes: Thanks for the comments--especially the tip for adding an apple to the butternut squash soup recipe.
Josefly writes: teeth810, turmeric is one of the spices in curry powder.
Cleis writes: Love Butternut Squash soup but also add one tasty apple to the recipe. My friends love it.
teeth810 writes: Where is the tumeric in the Spicy Butternut Squash Soup Recipe?

industry_corpus2: Agriculture & Fisheries


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7th grade girls basketball will be dismissed at 2:20. Wrestlers and wrestling crew will be dismissed at 2:50.
There will be a 7th and 8th grade alto sax and flute sectional today after SSR.
2 teacher teams have signed up for the book battle The Misfits with Ms. Gacke, Ms. Blanchard, Mr. Hurlburt, and Ms. Christenson and the LEADers with Ms. Coffman, Mrs. Mrosko, Ms. Alons, and Mrs. Ness. Which student teams will face their teachers?
Books on hold for Diego Carranza, Jocelyn Torres, Anthony Brugman, Arianna Aguilar, Adam LaGrange, Jared Castro Rivera, Kendall Burger and Allyson Franke.


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I found this page and want to share it with all of you, basically the first one on the list and one of the best is ImDisk & ImDisk Tool kit, congratulations to Olof Lagerkvist and v77, two of the valuable members of this forum.
As we mentioned earlier, the results can be split into two distinct categories, 4K scores and Sequential (Seq) scores. The Q32T1 scores for both sequential and 4K are how well the RAM disk handles multiple file transfer requests at once, so they represent a heavier workload.
Bond Disc was the fastest for both sets of 4K scores. The problem is it’s an old and not very user friendly tool focusing more on encryption. The 640MB size limit could also present a problem. More user-friendly and less restrictive tools that did well with 4K were IMDisk, ROG RAMDisk, Ultra RAMDisk Lite, SoftPerfect RAM Disk, OSFMount and Gizmo Drive.
It might come as no surprise the software that did well in the 4K scores also mostly did well in the sequential read and write scores. Ultra RAM Disk Lite and SoftPerfect RAM Disk got the highest sequential scores while Gizmo Drive, IMDisk, and Asus ROG RAMDisk were better when the number of simultaneous file requests was increased with the Q32T1 score.
For generally faster across the board performance, IMDisk, Asus ROG RAMDisk, Ultra RAMDisk Lite, OSFMount, Gizmo Drive, and SoftPerfect RAMDisk are all good choices. Bond Disc is very fast but may be incompatible or too restrictive for your requirements. What RAM disk you prefer may be down to what other features each software offers that helps you decide which is best for you.
Although you can use the original ImDisk driver and Control Panel applet , the ImDisk Toolkit is easier to use. It also includes options to mount floppy, CD-ROM and hard disk image files (ISO, BIN, VFD and etc) as virtual drives. RAM disk size is not limited and there are options to load content from an image file or folder, synchronize at shutdown, enable compression, auto add temporary folders, and allocate memory for the RAM disk dynamically.


text: Preheat oven to 425 degrees F. Cut 1 to 2 medium sweet potatoes (3/4 pound) lengthwise into 8 wedges each. On a large parchment-lined rimmed baking sheet, toss potatoes with 1 tablespoon extra-virgin olive oil, 1 1/2 teaspoon sugar, 1/2 teaspoon chili powder, 1/2 teaspoon coarse salt, and 1/8 teaspoon freshly ground pepper until coated. Arrange wedges cut-sides down. Roast sweet potatoes until browned and tender, 15 to 20 minutes. Season with additional salt, if desired, and serve.


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Birchwood at Spring Lake is located in Middle Island Long Island. The Spring Lake community has 624 units. The community has two club houses, both with indoor and outdoor pools, tennis courts, and a 9 hole golf course.
Plus… Indoor and outdoor pools, Fully equipped exercise rooms, Racquetball courts, Fireplace lounges with wet bar and large screen projection television, Card and meeting rooms, Full size all-weather tennis courts, jogging and biking trails, guard-gatehouse, and landscaped common areas professionally maintained by community’s homeowners association.
If you would like to view any unit available in this lovely community, or any other home or condo for sale on The North Shore of Long Island, please contact Realtors Lawrence and Sheila at 631-805-4400 (c) .


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Preston decided to head up to Hoodsport for the long weekend (we made our own long weekend by taking Friday off) and my mom and I decided to steal Maya and head down to meet my dad in Sun River. It was a lot of driving BUT a lot of relaxing - although one of us decided they didn't really want to sleep there - which then, of course, caused the other not to sleep.
Callie had an amazing time with Grandma and Grandpa's undivided attention and LOVED having Maya with her. It was so much fun to watch Maya interact with Callie - she is an amazing, caring, and silly little girl. One of my favorite parts of the weekend happened when Callie and Maya were eating dinner. Maya was a little distracted from eating (I know, big surprise!) and was playing with Grandma's phone case. She was driving it around the table like a car, and I am not sure why, but Callie found it SO funny! Every time it came close to her, she would giggle, which would cause Maya to giggle and then the cycle continued. It was so cute.
Callie didn't really dig the snow too much (probably because she couldn't move with all her layers of clothes) but sat and watched us make a snow turtle (with a horn in the middle of its head - Maya's idea to add another rock). She loved swimming in the pool though - I can't wait to take her this summer. Both of the girls were troopers in the car (I think Callie just liked having someone in the back seat with her) - and even though I was exhausted on Monday, it was a great weekend!
First time in swings and she is crammed in it with all her layers of clothes! Poor girl!
Thanks again for taking her... she had so much fun! Wish we all could have joined.