Links
Buttons initiate app-specific actions, have customizable backgrounds, and can include a title or an icon. The system provides a number of predefined button styles for most use cases. You can also design fully custom buttons.
For examples, links are provided on the navigation bar Button
TODO: Add shorthands to details, info, cancel and stuff


ZETIA - ezetimibe tablet
Physicians Total Care, Inc.
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use ZETIA safely and effectively. See full prescribing information for ZETIA.
ZETIA (ezetimibe) Tablets
Initial U.S. Approval: 2002
INDICATIONS AND USAGEZETIA® is an inhibitor of intestinal cholesterol (and related phytosterol) absorption indicated as an adjunct to diet to:
Limitations of Use (1.4)
DOSAGE AND ADMINISTRATIONDOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONSWARNINGS AND PRECAUTIONS
ADVERSE REACTIONS
DRUG INTERACTIONS
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 4/2010 |
FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS6 ADVERSE REACTIONS7 DRUG INTERACTIONS8 USE IN SPECIFIC POPULATIONS10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY13 NON CLINICAL TOXICOLOGY14 CLINICAL STUDIES16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION17.1 Muscle Pain17.2 Liver Enzymes17.3 Pregnancy17.4 Breastfeeding17.5 FDA-approved Patient Labeling
|
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.
1.1 Primary HyperlipidemiaMonotherapy
ZETIA1, administered alone, is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B) in patients with primary (heterozygous familial and non-familial) hyperlipidemia.
1COPYRIGHT © 2001, 2002, 2005, 2007, 2008 Merck/Schering-Plough Pharmaceuticals.Combination Therapy with HMG-CoA Reductase Inhibitors (Statins)
ZETIA, administered in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin), is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, and Apo B in patients with primary (heterozygous familial and non-familial) hyperlipidemia.
Combination Therapy with Fenofibrate
ZETIA, administered in combination with fenofibrate, is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-high-density lipoprotein cholesterol (non-HDL-C) in adult patients with mixed hyperlipidemia.
1.2 Homozygous Familial Hypercholesterolemia (HoFH)The combination of ZETIA and atorvastatin or simvastatin is indicated for the reduction of elevated total-C and LDL-C levels in patients with HoFH, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.
1.3 Homozygous SitosterolemiaZETIA is indicated as adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia.
1.4 Limitations of UseThe effect of ZETIA on cardiovascular morbidity and mortality has not been determined.
ZETIA has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.
The recommended dose of ZETIA is 10 mg once daily.
ZETIA can be administered with or without food.
2.2 Concomitant Lipid-Lowering TherapyZETIA may be administered with a statin (in patients with primary hyperlipidemia) or with fenofibrate (in patients with mixed hyperlipidemia) for incremental effect. For convenience, the daily dose of ZETIA may be taken at the same time as the statin or fenofibrate, according to the dosing recommendations for the respective medications.
2.3 Co-Administration with Bile Acid SequestrantsDosing of ZETIA should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant [see Drug Interactions (7.4)].
2.4 Patients with Hepatic ImpairmentNo dosage adjustment is necessary in patients with mild hepatic impairment [see Warnings and Precautions (5.4)].
2.5 Patients with Renal ImpairmentNo dosage adjustment is necessary in patients with renal impairment [see Clinical Pharmacology (12.3)].
2.6 Geriatric PatientsNo dosage adjustment is necessary in geriatric patients [see Clinical Pharmacology (12.3)].
10-mg tablets are white to off-white, capsule-shaped tablets debossed with "414" on one side.
ZETIA is contraindicated in the following conditions:
Concurrent administration of ZETIA with a specific statin or fenofibrate should be in accordance with the product labeling for that medication.
5.2 Liver EnzymesIn controlled clinical monotherapy studies, the incidence of consecutive elevations (≥3 × the upper limit of normal [ULN]) in hepatic transaminase levels was similar between ZETIA (0.5%) and placebo (0.3%).
In controlled clinical combination studies of ZETIA initiated concurrently with a statin, the incidence of consecutive elevations (≥3 × ULN) in hepatic transaminase levels was 1.3% for patients treated with ZETIA administered with statins and 0.4% for patients treated with statins alone. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. When ZETIA is co-administered with a statin, liver tests should be performed at initiation of therapy and according to the recommendations of the statin. Should an increase in ALT or AST ≥3 × ULN persist, consider withdrawal of ZETIA and/or the statin.
5.3 Myopathy/RhabdomyolysisIn clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ZETIA compared with the relevant control arm (placebo or statin alone). However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. In clinical trials, the incidence of creatine phosphokinase (CPK) >10 × ULN was 0.2% for ZETIA vs 0.1% for placebo, and 0.1% for ZETIA co-administered with a statin vs 0.4% for statins alone. Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age (>65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs.
In post-marketing experience with ZETIA, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin prior to initiating ZETIA. However, rhabdomyolysis has been reported with ZETIA monotherapy and with the addition of ZETIA to agents known to be associated with increased risk of rhabdomyolysis, such as fibrates. ZETIA and any statin or fibrate that the patient is taking concomitantly should be immediately discontinued if myopathy is diagnosed or suspected. The presence of muscle symptoms and a CPK level >10 × the ULN indicates myopathy.
5.4 Hepatic ImpairmentDue to the unknown effects of the increased exposure to ezetimibe in patients with moderate to severe hepatic impairment, ZETIA is not recommended in these patients. [See Clinical Pharmacology (12.3).]
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Monotherapy Studies: In the ZETIA controlled clinical trials database (placebo-controlled) of 2396 patients with a median treatment duration of 12 weeks (range 0 to 39 weeks), 3.3% of patients on ZETIA and 2.9% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with ZETIA that led to treatment discontinuation and occurred at a rate greater than placebo were:
The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in the ZETIA monotherapy controlled clinical trial database of 2396 patients were: upper respiratory tract infection (4.3%), diarrhea (4.1%), arthralgia (3.0%), sinusitis (2.8%), and pain in extremity (2.7%).
Statin Co-Administration Studies: In the ZETIA + statin controlled clinical trials database of 11,308 patients with a median treatment duration of 8 weeks (range 0 to 112 weeks), 4.0% of patients on ZETIA + statin and 3.3% of patients on statin alone discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with ZETIA + statin that led to treatment discontinuation and occurred at a rate greater than statin alone were:
The most commonly reported adverse reactions (incidence ≥2% and greater than statin alone) in the ZETIA + statin controlled clinical trial database of 11,308 patients were: nasopharyngitis (3.7%), myalgia (3.2%), upper respiratory tract infection (2.9%), arthralgia (2.6%) and diarrhea (2.5%).
6.1 Clinical Trials ExperienceBecause clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
Monotherapy
In 10 double-blind, placebo-controlled clinical trials, 2396 patients with primary hyperlipidemia (age range 9–86 years, 50% women, 90% Caucasians, 5% Blacks, 3% Hispanics, 2% Asians) and elevated LDL-C were treated with ZETIA 10 mg/day for a median treatment duration of 12 weeks (range 0 to 39 weeks).
Adverse reactions reported in ≥2% of patients treated with ZETIA and at an incidence greater than placebo in placebo-controlled studies of ZETIA, regardless of causality assessment, are shown in Table 1.
| Body System/Organ Class Adverse Reaction |
ZETIA 10 mg (%) n = 2396 |
Placebo (%) n = 1159 |
| Gastrointestinal disorders | ||
| Diarrhea | 4.1 | 3.7 |
| General disorders and administration site conditions | ||
| Fatigue | 2.4 | 1.5 |
| Infections and infestations | ||
| Influenza | 2.0 | 1.5 |
| Sinusitis | 2.8 | 2.2 |
| Upper respiratory tract infection | 4.3 | 2.5 |
| Musculoskeletal and connective tissue disorders | ||
| Arthralgia | 3.0 | 2.2 |
| Pain in extremity | 2.7 | 2.5 |
The frequency of less common adverse reactions was comparable between ZETIA and placebo.
Combination with a Statin
In 28 double-blind, controlled (placebo- or active-controlled) clinical trials, 11,308 patients with primary hyperlipidemia (age range 10–93 years, 48% women, 85% Caucasians, 7% Blacks, 4% Hispanics, 3% Asians) and elevated LDL-C were treated with ZETIA 10 mg/day concurrently with or added to on-going statin therapy for a median treatment duration of 8 weeks (range 0 to 112 weeks).
The incidence of consecutive increased transaminases (≥3 × ULN) was higher in patients receiving ZETIA administered with statins (1.3%) than in patients treated with statins alone (0.4%). [See Warnings and Precautions (5.2).]
Clinical adverse reactions reported in ≥2% of patients treated with ZETIA + statin and at an incidence greater than statin, regardless of causality assessment, are shown in Table 2.
TABLE 2: Clinical Adverse Reactions Occurring in ≥2% of Patients Treated with
ZETIA
Co-Administered with a Statin and at an Incidence Greater than Statin,
Regardless of Causality
Combination with Fenofibrate
This clinical study involving 625 patients with mixed dyslipidemia (age range 20–76 years, 44% women, 79% Caucasians, 0.1% Blacks, 11% Hispanics, 5% Asians) treated for up to 12 weeks and 576 patients treated for up to an additional 48 weeks evaluated co-administration of ZETIA and fenofibrate. This study was not designed to compare treatment groups for infrequent events. Incidence rates (95% CI) for clinically important elevations (≥3 × ULN, consecutive) in hepatic transaminase levels were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for fenofibrate monotherapy (n=188) and ZETIA co-administered with fenofibrate (n=183), respectively, adjusted for treatment exposure. Corresponding incidence rates for cholecystectomy were 0.6% (95% CI: 0.0%, 3.1%) and 1.7% (95% CI: 0.6%, 4.0%) for fenofibrate monotherapy and ZETIA co-administered with fenofibrate, respectively [see Drug Interactions (7.3)]. The numbers of patients exposed to co-administration therapy as well as fenofibrate and ezetimibe monotherapy were inadequate to assess gallbladder disease risk. There were no CPK elevations >10 × ULN in any of the treatment groups.
6.2 Post-Marketing ExperienceBecause the reactions below 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 post-approval use of ZETIA:
Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria; erythema multiforme; arthralgia; myalgia; elevated creatine phosphokinase; myopathy/rhabdomyolysis [see Warnings and Precautions (5.3)]; elevations in liver transaminases; hepatitis; abdominal pain; thrombocytopenia; pancreatitis; nausea; dizziness; paresthesia; depression; headache; cholelithiasis; cholecystitis.
[See Clinical Pharmacology (12.3).]
7.1 CyclosporineCaution should be exercised when using ZETIA and cyclosporine concomitantly due to increased exposure to both ezetimibe and cyclosporine. Cyclosporine concentrations should be monitored in patients receiving ZETIA and cyclosporine.
The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the benefits of alterations in lipid levels provided by ezetimibe.
7.2 FibratesThe efficacy and safety of co-administration of ezetimibe with fibrates other than fenofibrate have not been studied.
Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile [see Nonclinical Toxicology (13.2)]. Co-administration of ZETIA with fibrates other than fenofibrate is not recommended until use in patients is adequately studied.
7.3 FenofibrateIf cholelithiasis is suspected in a patient receiving ZETIA and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered [see Adverse Reactions (6.1) and the product labeling for fenofibrate].
7.4 CholestyramineConcomitant cholestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction.
7.5 Coumarin AnticoagulantsIf ezetimibe is added to warfarin, a coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored.
Pregnancy Category C:
There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus.
In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 × the human exposure at 10 mg daily based on AUC0–24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 × the human exposure at 10 mg daily based on AUC0–24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses.
Multiple-dose studies of ezetimibe given in combination with statins in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy.
All statins are contraindicated in pregnant and nursing women. When ZETIA is administered with a statin in a woman of childbearing potential, refer to the pregnancy category and product labeling for the statin. [See Contraindications (4).]
8.3 Nursing MothersIt is not known whether ezetimibe is excreted into human breast milk. In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. Because many drugs are excreted in human milk, caution should be exercised when ZETIA is administered to a nursing woman. ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.
8.4 Pediatric UseThe effects of ZETIA co-administered with simvastatin (n=126) compared to simvastatin monotherapy (n=122) have been evaluated in adolescent boys and girls with heterozygous familial hypercholesterolemia (HeFH). In a multicenter, double-blind, controlled study followed by an open-label phase, 142 boys and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% multi-racial) with HeFH were randomized to receive either ZETIA co-administered with simvastatin or simvastatin monotherapy. Inclusion in the study required 1) a baseline LDL-C level between 160 and 400 mg/dL and 2) a medical history and clinical presentation consistent with HeFH. The mean baseline LDL-C value was 225 mg/dL (range: 161–351 mg/dL) in the ZETIA co-administered with simvastatin group compared to 219 mg/dL (range: 149–336 mg/dL) in the simvastatin monotherapy group. The patients received co-administered ZETIA and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, co-administered ZETIA and 40 mg simvastatin or 40 mg simvastatin monotherapy for the next 27 weeks, and open-label co-administered ZETIA and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter.
The results of the study at Week 6 are summarized in Table 3. Results at Week 33 were consistent with those at Week 6.
|
Total-C |
LDL-C |
Apo B |
Non-HDL-C |
TG * |
HDL-C |
|
| Mean percent difference between treatment groups | -12% |
-15% |
-12% |
-14% |
-2% |
+0.1% |
| 95% Confidence Interval | (-15%, -9%) |
(-18%, -12%) |
(-15%, -9%) |
(-17%, -11%) |
(-9%, +4%) |
(-3%, +3%) |
From the start of the trial to the end of Week 33, discontinuations due to an adverse reaction occurred in 7 (6%) patients in the ZETIA co-administered with simvastatin group and in 2 (2%) patients in the simvastatin monotherapy group.
During the trial, hepatic transaminase elevations (two consecutive measurements for ALT and/or AST greater than or equal to 3 × ULN) occurred in four (3%) individuals in the ZETIA co-administered with simvastatin group and in two (2%) individuals in the simvastatin monotherapy group. Elevations of CPK (greater than or equal to 10 × ULN) occurred in two (2%) individuals in the ZETIA co-administered with simvastatin group and in zero individuals in the simvastatin monotherapy group.
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.
Co-administration of ZETIA with simvastatin at doses greater than 40 mg/day has not been studied in adolescents. Also, ZETIA has not been studied in patients younger than 10 years of age or in pre-menarchal girls.
Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide), there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population less than 10 years of age are not available.
8.5 Geriatric UseMonotherapy Studies
Of the 2396 patients who received ZETIA in clinical studies, 669 (28%) were 65 and older, and 111 (5%) were 75 and older.
Statin Co-Administration Studies
Of the 11,308 patients who received ZETIA + statin in clinical studies, 3587 (32%) were 65 and older, and 924 (8%) were 75 and older.
No overall differences in safety and effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)].
8.6 Hepatic ImpairmentZETIA is not recommended in patients with moderate to severe hepatic impairment [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].
ZETIA given concomitantly with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations of hepatic transaminase levels [see Contraindications (4); Warnings and Precautions (5.2), and Clinical Pharmacology (12.3)].
In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, or 40 mg/day to 18 patients with primary hyperlipidemia for up to 56 days, was generally well tolerated.
A few cases of overdosage with ZETIA have been reported; most have not been associated with adverse experiences. Reported adverse experiences have not been serious. In the event of an overdose, symptomatic and supportive measures should be employed.
ZETIA (ezetimibe) is in a class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. The chemical name of ezetimibe is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. The empirical formula is C24H21F2NO3. Its molecular weight is 409.4 and its structural formula is:
Ezetimibe is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water. Ezetimibe has a melting point of about 163°C and is stable at ambient temperature. ZETIA is available as a tablet for oral administration containing 10 mg of ezetimibe and the following inactive ingredients: croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, povidone USP, and sodium lauryl sulfate NF.
Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. In a 2-week clinical study in 18 hypercholesterolemic patients, ZETIA inhibited intestinal cholesterol absorption by 54%, compared with placebo. ZETIA had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E (in a study of 113 patients), and did not impair adrenocortical steroid hormone production (in a study of 118 patients).
The cholesterol content of the liver is derived predominantly from three sources. The liver can synthesize cholesterol, take up cholesterol from the blood from circulating lipoproteins, or take up cholesterol absorbed by the small intestine. Intestinal cholesterol is derived primarily from cholesterol secreted in the bile and from dietary cholesterol.
Ezetimibe has a mechanism of action that differs from those of other classes of cholesterol-reducing compounds (statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols). The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols.
Ezetimibe does not inhibit cholesterol synthesis in the liver, or increase bile acid excretion. Instead, ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins and of fenofibrate [see Clinical Studies (14.1)].
12.2 PharmacodynamicsClinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
ZETIA reduces total-C, LDL-C, Apo B, and TG, and increases HDL-C in patients with hyperlipidemia. Administration of ZETIA with a statin is effective in improving serum total-C, LDL-C, Apo B, TG, and HDL-C beyond either treatment alone. Administration of ZETIA with fenofibrate is effective in improving serum total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia as compared to either treatment alone. The effects of ezetimibe given either alone or in addition to a statin or fenofibrate on cardiovascular morbidity and mortality have not been established.
12.3 PharmacokineticsAbsorption
After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of ZETIA to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 and 20 mg. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection.
Effect of Food on Oral Absorption
Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as ZETIA 10-mg tablets. The Cmax value of ezetimibe was increased by 38% with consumption of high-fat meals. ZETIA can be administered with or without food.
Distribution
Ezetimibe and ezetimibe-glucuronide are highly bound (greater than 90%) to human plasma proteins.
Metabolism and Excretion
Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated.
In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.
Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma.
Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose.
Specific Populations
Geriatric Patients: In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2-fold higher in older (greater than or equal to 65 years) healthy subjects compared to younger subjects.
Pediatric Patients: [See Use in Specific Populations (8.4).]
Gender: In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (less than 20%) in women than in men.
Race: Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe were similar to those seen in Caucasian subjects.
Hepatic Impairment: After a single 10-mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe were increased approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic impairment, the mean AUC values for total ezetimibe and ezetimibe were increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, ZETIA is not recommended in these patients [see Warnings and Precautions (5.4)].
Renal Impairment: After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl less than or equal to 30 mL/min/1.73 m2), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n=9).
Drug Interactions [See also Drug Interactions (7)]
ZETIA had no significant effect on a series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a "cocktail" study of twelve healthy adult males. This indicates that ezetimibe is neither an inhibitor nor an inducer of these cytochrome P450 isozymes, and it is unlikely that ezetimibe will affect the metabolism of drugs that are metabolized by these enzymes.
|
Co-Administered Drug and Dosing Regiment |
Total |
Ezetimibe * |
|
Change in AUC |
Change in Cmax | |
| Cyclosporine-stable dose required (75–150 mg BID)†,‡ | ↑240% | ↑290% |
| Fenofibrate, 200 mg QD, 14 days† | ↑48% | ↑64% |
| Gemfibrozil, 600 mg BID, 7 days† | ↑64% | ↑91% |
| Cholestyramine, 4 g BID, 14 days† | ↓55% | ↓4% |
| Aluminum & magnesium hydroxide combination antacid, single dose§ | ↓4% | ↓30% |
| Cimetidine, 400 mg BID, 7 days | ↑6% | ↑22% |
| Glipizide, 10 mg, single dose | ↑4% | ↓8% |
| Statins | ||
| Lovastatin 20 mg QD, 7 days |
↑9% | ↑3% |
| Pravastatin 20 mg QD, 14 days |
↑7% | ↑23% |
| Atorvastatin 10 mg QD, 14 days |
↓2% | ↑12% |
| Rosuvastatin 10 mg QD, 14 days |
↑13% | ↑18% |
| Fluvastatin 20 mg QD, 14 days |
↓19% | ↑7% |
| Co-Administered Drug and its Dosage Regiment |
Ezetimibe Dosage Regiment |
Change in AUC of Co- Administered Drug |
Change in Cmax of Co- Administered Drug |
| Warfarin, 25 mg single dose on day 7 |
10 mg QD, 11 days |
↓2% (R-warfarin) ↓4% (S-warfarin) |
↑3% (R-warfarin) ↑1% (S-warfarin) |
| Digoxin, 0.5 mg single dose |
10 mg QD, 8 days |
↑2% |
↓7% |
| Gemfibrozil, 600 mg BID, 7 days* | 10 mg QD, 7 days |
↓1% | ↓11% |
| Ethinyl estradiol & Levonorgestrel, QD, 21 days |
10 mg QD, days 8-14 of 21d oral contraceptive cycle |
Ethinyl estradiol 0% Levonorgestrel 0% |
Ethinyl estradiol ↓9% Levonorgestrel ↓5% |
| Glipizide, 10 mg on days 1 and 9 |
10 mg QD, days 2-9 |
↓3% | ↓5% |
| Fenofibrate, 200 mg QD, 14 days* | 10 mg QD, 14 days |
↑11% | ↑7% |
| Cyclosporine, 100 mg single dose day 7* | 20 mg QD, 8 days |
↑15% | ↑10% |
|
Statins |
|||
| Lovastatin 20 mg QD, 7 days |
10 mg QD, 7 days |
↑19% | 3 |
| Pravastatin 20 mg QD, 14 days |
10 mg QD, 14 days |
↓20% | ↓24% |
| Atorvastatin 10 mg QD, 14 days |
10 mg QD, 14 days |
↓4% | ↑7% |
| Rosuvastatin 10 mg QD, 14 days |
10 mg QD, 14 days |
↑19% | ↑17% |
| Fluvastatin 20 mg QD, 14 days |
10 mg QD, 14 days |
↓39% | ↓27% |
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 × the human exposure at 10 mg daily based on AUC0–24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 × the human exposure at 10 mg daily based on AUC0–24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice.
No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test.
In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 × the human exposure at 10 mg daily based on AUC0–24hr for total ezetimibe).
13.2 Animal Toxicology and/or PharmacologyThe hypocholesterolemic effect of ezetimibe was evaluated in cholesterol-fed Rhesus monkeys, dogs, rats, and mouse models of human cholesterol metabolism. Ezetimibe was found to have an ED50 value of 0.5 µg/kg/day for inhibiting the rise in plasma cholesterol levels in monkeys. The ED50 values in dogs, rats, and mice were 7, 30, and 700 µg/kg/day, respectively. These results are consistent with ZETIA being a potent cholesterol absorption inhibitor.
In a rat model, where the glucuronide metabolite of ezetimibe (SCH 60663) was administered intraduodenally, the metabolite was as potent as the parent compound (SCH 58235) in inhibiting the absorption of cholesterol, suggesting that the glucuronide metabolite had activity similar to the parent drug.
In 1-month studies in dogs given ezetimibe (0.03 to 300 mg/kg/day), the concentration of cholesterol in gallbladder bile increased ~2- to 4-fold. However, a dose of 300 mg/kg/day administered to dogs for one year did not result in gallstone formation or any other adverse hepatobiliary effects. In a 14-day study in mice given ezetimibe (0.3 to 5 mg/kg/day) and fed a low-fat or cholesterol-rich diet, the concentration of cholesterol in gallbladder bile was either unaffected or reduced to normal levels, respectively.
A series of acute preclinical studies was performed to determine the selectivity of ZETIA for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of 14C-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins A and D.
In 4- to 12-week toxicity studies in mice, ezetimibe did not induce cytochrome P450 drug metabolizing enzymes. In toxicity studies, a pharmacokinetic interaction of ezetimibe with statins (parents or their active hydroxy acid metabolites) was seen in rats, dogs, and rabbits.
ZETIA reduces total-C, LDL-C, Apo B, and TG, and increases HDL-C in patients with hyperlipidemia. Maximal to near maximal response is generally achieved within 2 weeks and maintained during chronic therapy.
Monotherapy
In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary hyperlipidemia, ZETIA significantly lowered total-C, LDL-C, Apo B, and TG, and increased HDL-C compared to placebo (see Table 6). Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.
| Treatment Group |
N |
Total-C |
LDL-C |
Apo B |
TG* |
HDL-C |
|
| Study 1‡ |
Placebo Ezetimibe |
205 622 |
+1 -12 |
+1 -18 |
-1 -15 |
-1 -7 |
-1 +1 |
| Study 2‡ | Placebo Ezetimibe |
226 666 |
+1 -12 |
+1 -18 |
-1 -16 |
+2 -9 |
-2 +1 |
| Pooled Data‡ (Studies 1 & 2) |
Placebo Ezetimibe |
431 1288 |
0 -13 |
+1 -18 |
-2 -16 |
0 -8 |
-2 +1 |
Combination with Statins
ZETIA Added to On-going Statin Therapy
In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients with primary hyperlipidemia, known coronary heart disease or multiple cardiovascular risk factors who were already receiving statin monotherapy, but who had not met their NCEP ATP II target LDL-C goal were randomized to receive either ZETIA or placebo in addition to their on-going statin.
ZETIA, added to on-going statin therapy, significantly lowered total-C, LDL-C, Apo B, and TG, and increased HDL-C compared with a statin administered alone (see Table 7). LDL-C reductions induced by ZETIA were generally consistent across all statins.
| Treatment (Daily Dose) |
N |
Total-C |
LDL-C |
Apo B |
TG† |
HDL-C |
| On-going Statin + Placebo§ |
390 |
-2 |
-4 |
-3 |
-3 |
+1 |
| On-going Statin + ZETIA§ |
379 |
-17 |
-25 |
-19 |
-14 |
+3 |
ZETIA Initiated Concurrently with a Statin
In four multicenter, double-blind, placebo-controlled, 12-week trials, in 2382 hyperlipidemic patients, ZETIA or placebo was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin.
When all patients receiving ZETIA with a statin were compared to all those receiving the corresponding statin alone, ZETIA significantly lowered total-C, LDL-C, Apo B, and TG, and, with the exception of pravastatin, increased HDL-C compared to the statin administered alone. LDL-C reductions induced by ZETIA were generally consistent across all statins. (See footnote ‡, Tables 8 to 11.)
| Treatment (Daily Dose) |
N |
Total-C |
LDL-C |
Apo B |
TG* |
HDL-C |
| Placebo |
60 |
+4 |
+4 |
+3 |
-6 |
+4 |
| ZETIA |
65 |
-14 |
-20 |
-15 |
-5 |
+4 |
| Atorvastatin 10 mg |
60 |
-26 |
-37 |
-28 |
-21 |
+6 |
| ZETIA + Atorvastatin 10 mg |
65 |
-38 |
-53 |
-43 |
-31 |
+9 |
| Atorvastatin 20 mg |
60 |
-30 |
-42 |
-34 |
-23 |
+4 |
| ZETIA + Atorvastatin 20 mg | 62 |
-39 |
-54 |
-44 |
-30 |
+9 |
| Atorvastatin 40 mg |
66 |
-32 |
-45 |
-37 |
-24 |
+4 |
| ZETIA + Atorvastatin 40 mg | 65 |
-42 |
-56 |
-45 |
-34 |
+5 |
| Atorvastatin 80 mg |
62 |
-40 |
-54 |
-46 |
-31 |
+3 |
| ZETIA + Atorvastatin 80 mg | 63 |
-46 |
-61 |
-50 |
-40 |
+7 |
| Pooled data (All Atorvastatin Doses)‡ | 248 |
-32 |
-44 |
-36 |
-24 |
+4 |
| Pooled data (All ZETIA + Atorvastatin Doses)‡ |
255 |
-41 |
-56 |
-45 |
-33 |
+7 |
| Treatment (Daily Dose) |
N |
Total-C |
LDL-C |
Apo B |
TG* | HDL-C |
| Placebo |
70 |
-1 |
-1 |
0 |
+2 |
+1 |
| ZETIA |
61 |
-13 |
-19 |
-14 |
-11 |
+5 |
| Simvastatin 10 mg |
70 |
-18 |
-27 |
-21 |
-14 |
+8 |
| ZETIA + Simvastatin 10 mg |
67 |
-32 |
-46 |
-35 |
-26 |
+9 |
| Simvastatin 20 mg | 61 |
-26 |
-36 |
-29 |
-18 |
+6 |
| ZETIA + Simvastatin 20 mg | 69 |
-33 |
-46 |
-36 |
-25 |
+9 |
| Simvastatin 40 mg | 65 |
-27 |
-38 |
-32 |
-24 |
+6 |
| ZETIA + Simvastatin 40 mg | 73 |
-40 |
-56 |
-45 |
-32 |
+11 |
| Simvastatin 80 mg | 67 |
-32 |
-45 |
-37 |
-23 |
+8 |
| ZETIA + Simvastatin 80 mg | 65 |
-41 |
-58 |
-47 |
-31 |
+8 |
| Pooled data (All Simvastatin Doses)‡ | 263 |
-26 |
-36 |
-30 |
-20 |
+7 |
| Pooled data (All ZETIA + Simvastatin Doses)‡ |
274 |
-37 |
-51 |
-41 |
-29 |
+9 |
| Treatment (Daily Dose) |
N |
Total-C |
LDL-C |
Apo B |
TG* |
HDL-C |
| Placebo |
65 |
0 |
-1 |
-2 |
-1 |
+2 |
| ZETIA |
64 |
-13 |
-20 |
-15 |
-5 |
+4 |
| Pravastatin 10 mg |
66 |
-15 |
-21 |
-16 |
-14 |
+6 |
| ZETIA + Pravastatin 10 mg |
71 |
-24 |
-34 |
-27 |
-23 |
+8 |
| Pravastatin 20 mg | 69 |
-15 |
-23 |
-18 |
-8 |
+8 |
| ZETIA + Pravastatin 20 mg | 66 |
-27 |
-40 |
-31 |
-21 |
+8 |
| Pravastatin 40 mg | 70 |
-22 |
-31 |
-26 |
-19 |
+6 |
| ZETIA + Pravastatin 40 mg | 67 |
-30 |
-42 |
-32 |
-21 |
+8 |
| Pooled data (All Pravastatin Doses)‡ | 205 |
-17 |
-25 |
-20 |
-14 |
+7 |
| Pooled data (All ZETIA + Pravastatin Doses)‡ |
204 |
-27 |
-39 |
-30 |
-21 |
+8 |
| Treatment (Daily Dose) |
N |
Total-C |
LDL-C |
Apo B |
TG* |
HDL-C |
| Placebo |
64 |
+1 |
0 |
+1 |
+6 |
0 |
| ZETIA |
72 |
-13 |
-19 |
-14 |
-5 |
+3 |
| Lovastatin 10 mg |
73 |
-15 |
-20 |
-17 |
-11 |
+5 |
| ZETIA + Lovastatin 10 mg | 65 |
-24 |
-34 |
-27 |
-19 |
+8 |
| Lovastatin 20 mg |
74 |
-19 |
-26 |
-21 |
-12 |
+3 |
| ZETIA + Lovastatin 20 mg | 62 |
-29 |
-41 |
-34 |
-27 |
+9 |
| Lovastatin 40 mg |
73 |
-21 |
-30 |
-25 |
-15 |
+5 |
| ZETIA + Lovastatin 40 mg |
65 |
-33 |
-46 |
-38 |
-27 |
+9 |
| Pooled data (All Lovastatin Doses)‡ | 220 |
-18 |
-25 |
-21 |
-12 |
+4 |
| Pooled data (All ZETIA + Lovastatin Doses)‡ |
192 |
-29 |
-40 |
-33 |
-25 |
+9 |
Combination with Fenofibrate
In a multicenter, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidemia, 625 patients were treated for up to 12 weeks and 576 for up to an additional 48 weeks. Patients were randomized to receive placebo, ZETIA alone, 160 mg fenofibrate alone, or ZETIA and 160 mg fenofibrate in the 12-week study. After completing the 12-week study, eligible patients were assigned to ZETIA co-administered with fenofibrate or fenofibrate monotherapy for an additional 48 weeks.
ZETIA co-administered with fenofibrate significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to fenofibrate administered alone. The percent decrease in TG and percent increase in HDL-C for ZETIA co-administered with fenofibrate were comparable to those for fenofibrate administered alone (see Table 12).
| Treatment (Daily Dose) |
N |
Total-C |
LDL-C |
Apo B |
TG* |
HDL-C |
Non-HDL-C |
| Placebo |
63 |
0 |
0 |
-1 |
-9 |
+3 |
0 |
| ZETIA |
185 |
-12 |
-13 |
-11 |
-11 |
+4 |
-15 |
| Fenofibrate 160 mg |
188 |
-11 |
-6 |
-15 |
-43 |
+19 |
-16 |
| ZETIA + Fenofibrate 160 mg |
183 |
-22 |
-20 |
-26 |
-44 |
+19 |
-30 |
A study was conducted to assess the efficacy of ZETIA in the treatment of HoFH. This double-blind, randomized, 12-week study enrolled 50 patients with a clinical and/or genotypic diagnosis of HoFH, with or without concomitant LDL apheresis, already receiving atorvastatin or simvastatin (40 mg). Patients were randomized to one of three treatment groups, atorvastatin or simvastatin (80 mg), ZETIA administered with atorvastatin or simvastatin (40 mg), or ZETIA administered with atorvastatin or simvastatin (80 mg). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine [see Drug Interactions (7.1)], ezetimibe was dosed at least 4 hours before or after administration of resins. Mean baseline LDL-C was 341 mg/dL in those patients randomized to atorvastatin 80 mg or simvastatin 80 mg alone and 316 mg/dL in the group randomized to ZETIA plus atorvastatin 40 or 80 mg or simvastatin 40 or 80 mg. ZETIA, administered with atorvastatin or simvastatin (40 and 80 mg statin groups, pooled), significantly reduced LDL-C (21%) compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to 80 mg (7%). In those treated with ZETIA plus 80 mg atorvastatin or with ZETIA plus 80 mg simvastatin, LDL-C was reduced by 27%.
14.3 Homozygous Sitosterolemia (Phytosterolemia)A study was conducted to assess the efficacy of ZETIA in the treatment of homozygous sitosterolemia. In this multicenter, double-blind, placebo-controlled, 8-week trial, 37 patients with homozygous sitosterolemia with elevated plasma sitosterol levels (greater than 5 mg/dL) on their current therapeutic regimen (diet, bile-acid-binding resins, statins, ileal bypass surgery and/or LDL apheresis), were randomized to receive ZETIA (n=30) or placebo (n=7). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine [see Drug Interactions (7.1)], ezetimibe was dosed at least 2 hours before or 4 hours after resins were administered. Excluding the one subject receiving LDL apheresis, ZETIA significantly lowered plasma sitosterol and campesterol, by 21% and 24% from baseline, respectively. In contrast, patients who received placebo had increases in sitosterol and campesterol of 4% and 3% from baseline, respectively. For patients treated with ZETIA, mean plasma levels of plant sterols were reduced progressively over the course of the study. The effects of reducing plasma sitosterol and campesterol on reducing the risks of cardiovascular morbidity and mortality have not been established.
Reductions in sitosterol and campesterol were consistent between patients taking ZETIA concomitantly with bile acid sequestrants (n=8) and patients not on concomitant bile acid sequestrant therapy (n=21).
Limitations of Use
The effect of ZETIA on cardiovascular morbidity and mortality has not been determined.
No. 3861 — Tablets ZETIA, 10 mg, are white to off-white, capsule-shaped tablets debossed with "414" on one side. They are supplied as follows:
NDC 54868-4719-1 bottles of 30
NDC 54868-4719-0 bottles of 90.
Storage
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). [See USP Controlled Room Temperature.] Protect from moisture.
[See FDA-approved Patient Labeling (17.5).]
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.
All patients starting therapy with ezetimibe should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. The risk of this occurring is increased when taking certain types of medication. Patients should discuss all medication, both prescription and over-the-counter, with their physician.
Liver tests should be performed when ZETIA is added to statin therapy and according to statin recommendations.
Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using ZETIA added to statin therapy. Discuss future pregnancy plans with your patients, and discuss when to stop combination ZETIA and statin therapy if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking combination ZETIA and statin therapy and call their healthcare professional.
ZETIA® (ezetimibe) Tablets
Patient Information about ZETIA (zĕt´-ē-ă)
Generic name: ezetimibe (ĕ-zĕt´-ĕ-mīb)
Read this information carefully before you start taking ZETIA and each time you get more ZETIA. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about ZETIA, ask your doctor. Only your doctor can determine if ZETIA is right for you.
What is ZETIA?
ZETIA is a medicine used to lower levels of total cholesterol and LDL (bad) cholesterol in the blood. ZETIA is for patients who cannot control their cholesterol levels by diet and exercise alone. It can be used by itself or with other medicines to treat high cholesterol. You should stay on a cholesterol-lowering diet while taking this medicine.
ZETIA works to reduce the amount of cholesterol your body absorbs. ZETIA does not help you lose weight. ZETIA has not been shown to prevent heart disease or heart attacks.
For more information about cholesterol, see the "What should I know about high cholesterol?" section that follows.
Who should not take ZETIA?
ZETIA has not been studied in children under age 10.
What should I tell my doctor before and while taking ZETIA?
Tell your doctor about any prescription and non-prescription medicines you are taking or plan to take, including natural or herbal remedies.
Tell your doctor about all your medical conditions including allergies.
Tell your doctor if you:
How should I take ZETIA?
See your doctor regularly to check your cholesterol level and to check for side effects. Your doctor may do blood tests to check your liver before you start taking ZETIA with a statin and during treatment.
What are the possible side effects of ZETIA?
In clinical studies patients reported few side effects while taking ZETIA. These included diarrhea, joint pains, and feeling tired.
Patients have experienced severe muscle problems while taking ZETIA, usually when ZETIA was added to a statin drug. If you experience unexplained muscle pain, tenderness, or weakness while taking ZETIA, contact your doctor immediately. You need to do this promptly, because on rare occasions, these muscle problems can be serious, with muscle breakdown resulting in kidney damage.
Additionally, the following side effects have been reported in general use: allergic reactions (which may require treatment right away) including swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing, rash, and hives; raised red rash, sometimes with target-shaped lesions; joint pain; muscle aches; alterations in some laboratory blood tests; liver problems; stomach pain; inflammation of the pancreas; nausea; dizziness; tingling sensation; depression; headache; gallstones; inflammation of the gallbladder.
Tell your doctor if you are having these or any other medical problems while on ZETIA. For a complete list of side effects, ask your doctor or pharmacist.
What should I know about high cholesterol?

LDL cholesterol is called "bad" cholesterol because it can build up in the wall of your arteries and form plaque. Over time, plaque build-up can cause a narrowing of the arteries. This narrowing can slow or block blood flow to your heart, brain, and other organs. High LDL cholesterol is a major cause of heart disease and one of the causes for stroke.
HDL cholesterol is called "good" cholesterol because it keeps the bad cholesterol from building up in the arteries.
Triglycerides also are fats found in your blood.
General information about ZETIA
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use ZETIA for a condition for which it was not prescribed. Do not give ZETIA to other people, even if they have the same condition you have. It may harm them.
This summarizes the most important information about ZETIA. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about ZETIA that is written for health professionals.
Croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate.
29480885T
REV 21
Issued July 2009
U.S. Patent Nos. 5,846,966; 7,030,106 and RE37,721.
Manufactured for:
Merck/Schering-Plough Pharmaceuticals
North Wales, PA
19454, USA
By:
Schering Corporation
Kenilworth, NJ 07033,
USA
or
Merck & Co., Inc.
Whitehouse Station, NJ 08889, USA
COPYRIGHT © 2001, 2002, 2007, 2008, 2009 Merck/Schering-Plough
Pharmaceuticals.
All rights reserved.
|
ZETIA
ezetimibe tablet | ||||||||||||||||||||
| ||||||||||||||||||||
| ||||||||||||||||||||
| ||||||||||||||||||||
| ||||||||||||||||||||
| ||||||||||||||||||||
|
| Labeler - Physicians Total Care, Inc. (194123980) |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| Physicians Total Care, Inc. | 194123980 | repack, relabel |


WONDER BOYS (2000) / *** 1/2
Directed by Curtis Hanson. Screenplay by Steve Kloves, based on the novel by Michael Chabon. Starring Michael Douglas, Tobey Maguire, Robert Downey Jr. Running time: 114 minutes. Rated AA. Reviewed on March 19th, 2000.
By SHANNON PATRICK SULLIVAN
A quiet, understated character piece, "Wonder Boys" is the sort of movie which, when recalled afterward, seems more like a dream than something actually experienced. Slow-moving but never plodding, funny and original without being absurd, it is a pleasurable journey through one man's personal struggles.
Grady Tripp (Michael Douglas) is a University of Pittsburgh English professor who wrote a critically-acclaimed novel seven years ago and hasn't published anything since. Most people think Tripp is washed up, but the truth is that his new novel just isn't finished yet; it is now two thousand single-spaced pages long and counting. Tripp, whose wife has just left him, is having an affair with the university chancellor, Sara Gaskell (Frances McDormand). Sara's husband Walter (Richard Thomas) is the head of the English department and hence Grady's boss. Tripp's most promising student is James Leer (Tobey Maguire), a dour and eccentric youth held in disdain by most of his classmates. The lone exception is Hannah Green (Katie Holmes), who is also boarding with Grady and is clearly interested in taking their relationship beyond the academic.
The movie takes place during WordFest, a weekend-long writers' convention. The Gaskells host a party to kick off WordFest, during which Sara reveals to Grady that she is pregnant. Going outside for a draw, Tripp (aptly named, given that he spends most of the movie under the influence of drugs, both prescription and otherwise) encounters James, standing in the backyard with a gun he insists is just a fake. The two sneak upstairs to have a look at Walter's collection of memorabilia. When Grady is attacked by the Gaskells' dog, James shoots it dead. At a loss, Tripp ends up lugging the canine corpse around in his trunk until he can figure out what to do about it.
All this is just set-up for a sometimes harrowing, always amusing odyssey through the streets of Pittsburgh and the problems which plague Grady's life. He finds himself having to deal not just with the end of his marriage and the complication of his affair, not just with the dead dog and a stolen piece of Walter's collection, not just with editor Terry Crabtree (Robert Downey Jr) whose own job is riding on the publication of Tripp's new novel, but with the enigma that is James Leer. James isn't just a writer; the entirety of his behavior is one big creative process (at one point, intoxicated, he begins narrating out loud) and it is impossible to take anything he says or does at face value: the fake-gun-that-isn't is just the tip of the iceberg of James' fantasies and deceptions.
"Wonder Boys" is a smart movie that understands its characters and takes the time to develop and explore them fully. Written by Steve Kloves from the novel by Michael Chabon, it is populated by believable individuals who make believable choices, not ones dictated by stereotypical Hollywood expectations. For example, both Terry and James are clearly not strictly heterosexual, but when they finally do end up in bed together, it is dealt with almost offhandedly. The event is just a natural development of both characters, and the script does not grind to a halt to exploit it. Nothing in "Wonder Boys" feels staged or melodramatic; realism seethes from its characters, their relationships with each other, and the decisions they make.
But perhaps this is all to be expected. "Wonder Boys" is a movie all about making choices and the consequences of avoiding them, and a film with such a theme lives and dies on the conviction of its characters. Grady has spent the past half-decade evading decisions, and it has cost him his marriage. Here, then, is the story of how he comes to rise above his personal apathy and seize control of his life. Nowhere is this theme of making choices more clearly illustrated than with Grady's epic novel. Even Hannah, Grady's potential new love interest, finds it impossible to finish, but not because it is poorly written. On the other hand, Hannah thinks it is beautiful, but she tells Grady, "you didn't make any choices": Grady has not found the will to leave anything out of the text, and as a result it has ballooned to mammoth proportions. The manuscript's final fate depicts another important fact about decisions: that sometimes they're made for you, not by you.
The movie's dialogue is sparkling throughout, and there are plenty of laughs, many of them derived from the film's frank view of reality. Surprisingly for a movie which muses on so deep a theme, "Wonder Boys" has many of the elements of a screwball comedy, complete with mistaken identities and misplaced valuables. But the screwball elements are always in service to the overall plot, complementing it rather than fragmenting the film. As a result, "Wonder Boys" is appealing and enjoyable on a number of different levels.
The acting is uniformly excellent. Douglas finds just the right note as the harried Grady, portraying him as confused and aimless without making him seem weak. Maguire, always a quiet, reserved actor, is a perfect fit as James -- he is quirky, inspired and fragile, all at the same time. Amongst the supporting cast, Richard Knox gives a hilarious performance as a man who claims to be the real owner of Grady's battered car.
For a movie about choices, "Wonder Boys" makes all the right ones. It is smart and well-acted, and the top-notch script finds a good balance between drama and comedy. Although its sheer placidness may work against it in such a crowded box office, it should not be overlooked. This may be one of the first Oscar contenders of the year 2000.
Copyright © 2000 Shannon Patrick Sullivan. Archived at http://www.physics.mun.ca/~sps/movies/WonderBoys.html
-- _______________________________________________________________________ / Shannon Patrick Sullivan | "We are all in the gutter, but some of us \ | | are looking at the stars." | \<EMAIL_ADDRESS>| -- Oscar Wilde /
The review above was posted to the
rec.arts.movies.reviews newsgroup (de.rec.film.kritiken for German reviews).
The Internet Movie Database accepts no responsibility for the contents of the
review and has no editorial control. Unless stated otherwise, the copyright
belongs to the author.
Please direct comments/criticisms of the review to relevant newsgroups.
Broken URLs inthe reviews are the responsibility of the author.
The formatting of the review is likely to differ from the original due
to ASCII to HTML conversion.
Related links: index of all rec.arts.movies.reviews reviews


{% extends 'base_generic.html' %} {% block content %}
| File Information | |
|---|---|
| Uploaded by | {{ evidence.uploaded_by }} |
| Upload Date | {{ evidence.upload_date }} |
| Description | {{ evidence.description }} |
| Report Caption | {{ evidence.caption }} |
{{ line }}
{% endfor %} {% endif %} {% else %}Evidence file type cannot be displayed.
{% endif %} {% endblock %}


|
Please select grant type
Please enter the funding body and scheme
Please enter the first year funded, ensure this value is greater than or equal to 1970.
Please enter the grant duration (1 to 1000 Months).
Please enter the total amount of funding
|


--- layout: post title: VIM - Select the word under the cursor categories: - VIM tags: - vim status: publish type: post published: true meta: _edit_last: '1' _headspace_page_title: VIM - Select the word under the cursor _headspace_description: VIM - Select the word under the cursor author: login: maxcnunes email<EMAIL_ADDRESS>display_name: maxcnunes first_name: '' last_name: '' ---
Type in normal mode:
{% gist maxcnunes/7284424 select-the-word-under-the-cursor %}


Click on the button below to launch a signed WebStart application that shows the available Substance features.
The test application is structured in the following way:
You can switch Substance skins via the "Skin" or "Look & feel" menu items. In addition, you can test the support for high-resolution monitors via "Sizes" tab or the font size slider in the application status bar.
The left side of the application status bar shows the build stamp and the version of Substance.
The test application requires a number of jar files. These are bundled in the WebStart application, and can be downloaded separately from the "Documents & Files" section of the project site.
substance-tst.jar
- contains
the test application and its resources. The main class is
test.Check
and most of the
tabs are implemented in the test.check
package.substance.jar
- the Substance
look-and-feel itself.trident.jar
- the
Trident animation
library. Is used for the animation effects.forms-1.2.0.jar
-
FormLayout from JGoodies. Is used
to layout most of the panels.swingx.jar
-
SwingX. Is used for the status
bar and the control panel task pane container.substance-swingx.jar
-
Substance plugin
for SwingX. Is used to provide consistent appearance for SwingX controls.


The HTML Popup is a tall skinny on-screen quick reference showing all HTML tags and attributes in use or universal. It includes color-coded indications of support by Netscape®, Microsoft® Internet Explorer and W3C®, plus style sheet alternatives, and bug and clash icons with details online. It is taken from a page of the VisiBone HTML Card (September 2000 edition).
The Color Popups show all 216 web-safe colors in a wheel, the same arrangement as the VisiBone2 swatch libraries shipped in Adobe® Photoshop® and Illustrator®, BBEdit® and The Gimp. The same arrangement is used in the VisiBone Color Card.
© 2000 VisiBone Popups home: http://www.visibone.com/popups/ Revision history: revision.txt
Terms Of Use: By activating a VisiBone Popup you agree to the following: 1. To get a lot of use out of it. 2. To distribute it anywhere you please. 3. To create web sites that are (select all that apply): useful, entertaining, lucrative, inspiring, cool, joyful, righteous, gorgeous, hilarious, hideous, reverent, irreverent, sinful, sublime, profound, frivolous, radical, seductive, erudite, pioneering. 4. To ask before modifying a popup.


{{selected_month}}
Mon
Tue
Wed
Thu
Fri
Sat
Sun
{% for week in cal %}
{% for day in week %}
{% if day.script %}
{{day.day}}
{% else %}{{day.day}}{% endif %}
{% endfor %}
{% endfor %}
Time frames noted are for delivery only and are in addition to the time needed for your order
${{OverNightShipping}} Overnight Shipping
${{SecondDayShipping}} Second Day Delivery
${{GroundShipping}} Ground Shipping(Estimated 3-5 Days)
${{SaturdayDelivey}} Saturday Delivery
Delivery Not Available
Selected Estimated Delivery Date:
Shipping Price for option Selected:
Upgrade to priority shipping Delivery (by10am) $10.00


Vedant wants to buy some Somaiya sheets but he is short of pocket money! The
Somaiya sheets costs C Rupees.
Vedant has a magical piggy bank. He soon discovered that he could put some money
into it each morning and in the dark of the night the money contained in the piggy bank
would become X times. He could deposit any amount of money on any day. He might
not deposit any money on some days. Regardless of all this the money in the piggy bank
would become X times every night.
Now Vedant wants to deposit the least possible total sum of money into the piggy bank
and obtain C Rupees. Being the good boy Vedant is, he doesn't aspire for anything more
and hence needs exactly C Rupees when he breaks the piggy bank on some afternoon.
Note that the number of days he puts money or when he breaks the piggy bank is not
required to be minimised.


[Originally posted to
Shaman Australis Web Forums. Thanks to SA and gomaos for this report.]
I had to give it a shot, especially after touching alcohol again after having been off it for 6 months completely.
At the beginning of December, say around the 10th , I had bought a bottle of scotch and drank it. Nothing bad had happened, nothing depressing, life was being pretty gradual... i just was bored BECAUSE nothing ever happened.
For about 4 weeks, I drank almost every day. Perhaps twice a week, I'd drink a bottle of whiskey/day, other times a sixpack of beer a day or equivalent.
On weekends with friends perhaps 2 bottles of whiskey or equivalent/day.
Then I traded some kratom leaves with a friend, 25 nice and big ones, and made an extract, using water, citric acid and vinegar.
I simmered until a black paste was left.
I took half of that paste.
Approx 4-6 hours later I felt no need to drink anymore and switched from homebrew to coffee.
The next day I had the other half of the extractand stayed of the alc.
I have to mention the the extract also gives you a slight tryptaminy tingle in the brain, quite pleasant and perhaps a little similar to mdma.
If the dose was upped say, four times, this would be quite spectacular.
I stayed off the booze four five days and probably would have stayed off it further, but we went to the Coast stayed in a motel, and since my mate was shouting there was all this free bourbon, just too good an oppurtunity to say no.
So I spent 2 and a half days on the grog again.
Quite heavily, but my, I paid for it dearly with horrible hangovers. On monday morning I made a second extraction of the kratom leaves, as well as adding some shiva stalks and leaves, calea leaves, my last mexican poppy leaves and some brahmi.
It helped me again to stay off it for 3 days now and I think I'm gonna make until the next good oppurtunity comes along.

I'm now toally out of kratom, but will get some most likely in another 2 weeks... In meanwhile I suppose me old mate san pedro and a few off his mates will have to help out.
I give kratom 10 out of 10 as an ethnobotanical miracle plant.
Experience Reports are the writings and opinions of the individual authors who submit them.
Some of the activities described are dangerous and/or illegal and none are recommended by Erowid.


|
Elaboration enhances the imagined contact effect Husnu, S. & Crisp, R.J. (2010, Journal of Experimental Social Psychology, doi: 10.1016/j.jesp.2010.05.014) |
Recent studies have shown that imagining intergroup contact can improve attitudes held toward a range of social groups. We extended research on imagined contact by testing an elaborated task variant designed speci?cally to enhance future contact intentions. In three experiments imagined contact heightened intentions, elaborated imagery enhanced this effect, and these enhancements were attributable to both reduced intergroup anxiety and an increase in the reported vividness of the imagined scenario. Furthermore, prior contact enhanced the vividness with which imagined scenarios were envisaged, with concurrent bene?ts for future contact intentions. Results also supported the notion that elaboration creates a more accessible contact script upon which to base future judgments of intention. We discuss the implications of these ?ndings for a developing model of imagined contact effects.
Keywords: Intergroup contact, Imagined contact, Prejudice, Intergroup bias,
| Of Study 1: | |||||
| SP | Nosek & Schmidt | Very Close | N = 1329 | power = 99% | d = 0.15 |
| SP | Klein et al. | Very Close | N = 1000 | power = 99% | d = 0.26 |
| SP | Kappes | Very Close | N = 277 | power = 99% | d = 0.18 |
| SP | Davis & Hicks | Very Close | N = 225 | power = 99% | d = 0.32 |
| SP | Devos | Very Close | N = 162 | power = 99% | d = 0.3 |


{{ year.key }} -1 }" (click)="selectQuarters(quarter)"> {{ quarter.name }} calendar_today Apply close Last 30 days Apply


I'm Roger Steve Ruiz. I am a L4 Senior Engineer at TrussWorks building user-centered digital services.
Pertinent links
Currently working with


Unlike Inline example, <%= _.camelize(moduleName) %> is not globally available, as expected, because it is namespaced in the require() block.


Repos for getting hired
I’m often involved in hiring. When GitHub links are on a resume, I look at pinned repos and source repos. Here’s a checklist of important items to have in a GitHub public repository to catch the eye of reviewers. Or at least my eye when hiring, and why it’s important. Your goal, my goal Yours: get hired. Mine: make an informed decision about hiring someone who can do the job.
Postgres over TLS with postgres and r2d2_postgres
“Dance like nobody’s watching. Encrypt like everybody is.” In this post we’ll go over how to get the postgres crate and r2d2_postgres working with openssl for connection pooling with TLS. Source code is available. Goal Modern web applications are built with resiliency and fault tolerance in mind. For our example, we’ll be examining parts of a web application backed by a Postgres database. When services launch, their database won’t always be available.
CI/CD Pipeline
Previously, we defined Continuous Integration (CI), Continuous Deployment (CD) and build servers. Now we’ll see how combining these concepts creates something greater than its parts: a true CI/CD pipeline. Continuous Integration and Continuous Delivery are processes that tell humans what techniques to use with source control. Build server is a server, servers or a system that automatically builds and tests code. Putting these concepts together require people following processes so automated tasks execute well.
Build servers, Continuous Integration, Continuous Delivery
Ever hear someone say “CI/CD build pipeline” and weren’t sure that that means, exactly? Let’s define and explore the concepts of: Build server Continuous Integration (CI) Continous Delivery (CD) Three separate ideas Build server is a server, servers or a system that automatically builds and tests code. Continuous Integration and Continuous Delivery are both processes, guiding humans on what to do. Build server (or build service) Whenever code is pushed to the repository, the build server checks out that commit or branch and tries to build the code and run tests.
Taking a break
After three years maintaining an open source project, it’s time to take a few months of me time. TL;DR I’m taking a break to do things I’ve been missing. I will be back, no later than September 1st, 2018. Rusoto history and running an open source project Back in early 2015, Anthony DiMarco and I started Rusoto. Rust’s promises of performance and correctness looked like a perfect match for cloud computing.
Curated list of resources for software engineering
List of links for topics including: Git Branching strategies Ruby Go Testing Cloud and AWS Git Think like a Git Pro Git Branching strategies GitHub flow Trunk based Development Ruby Learn Ruby the Hard Way Go Effective Go Golang Tripping Hazards Testing Practical Test Pyramid https://en.wikipedia.org/wiki/Test-driven_development Red Green Refactor Repeat Cucumber general reference Cloud and AWS Getting Started on AWS This Is My Architecture A Cloud Guru Linux Academy
Rust 2018
Per the call for blog posts, I’ve got thoughts and ideas on where Rust can go in the upcoming year. My wants haven’t changed much over the last year or so: give me non-embarassing compilation speed! 😁 Before getting started, I’m very appreciative of the hard work put into the overall Rust community and ecosystem, including the behind-the-scenes work. It’s difficult to understate just how much time and energy people volunteer in pursuit of a better, Rust-ier world.
Rusoto: 2017 in review
Rusoto, an unofficial SDK for Amazon Web Services, had a wonderful year! We made great strides in improving functionality, increasing the number of services covered and making various ergonomic changes. Improved functionality Added all publicly available AWS regions Custom endpoint support HTTP connection pools for connecting to services S3 supports streaming responses: no more loading the entire file to download into a Vector More supported services A non-exhaustive list:
Test driven development with Rust
Test Driven Development (TDD) encourages better software design. When the desired behavior is known and expressible, it’s highly effective to make modular and easily tested code. Let’s take a look at using TDD with Rust, using release-party as an example. What we’re changing Release-party is a command line tool I made for my day job. We’ve got a fair amount of repositories on GitHub: one for each microservice. Our deployments are automated through TravisCI: the master branch is deployed to our testing environment and the release branch is deployed to production.
Software development force multipliers
While a software enginerd/pixie wrangler at heart, I’ve discovered the stereotypical developer path of grabbing a ticket from Jira, working on it, shoving the results to QA and repeat isn’t for me. The biggest reason is how this leaves a tremendous amount of efficiency on the table. This inefficient approach is difficult to reconcile with empathy for the customer buying and using the product. My code writing speed has peaked: I can’t write code any faster.


References
The orthogonal kernels and its fractional form are based on the follwoing papers:
Hadian Rasanan, A. H., Rahmati, D., Gorgin, S., & Parand, K.: A single layer fractional orthogonal neural network for solving various types of Lane–Emden equation. New Astron. 75, 101307 (2020).
Ozer, S., Chen, C. H., & Cirpan, H. A.: A set of new Chebyshev kernel functions for support vector machine pattern classification. Pattern Recognit 44, 1435–1447 (2011).
Dunkl, C. F., & Yuan X.: Orthogonal polynomials of several variables. Cambridge University Press 155, (2014)
Pan, Z. B., Chen, H., & You, X. H.: Support vector machine with orthogonal Legendre kernel.International Conference on Wavelet Analysis and Pattern Recognition. IEEE, 125–130 (2012).
Padierna, L. C, et al.: A novel formulation of orthogonal polynomial kernel functions for SVM classifiers: the Gegenbauer family. Pattern Recognition 84, 211–225 (2018).
A comprehensive guide on Fractional Orthogonal Kernels for SVM classification is available in the following book, which is set to be available online soon on February 2023:
Jamal Amani Rad, Kourosh Parand, Snehashish Chakraverty: Learning with Fractional Orthogonal Kernel Classifiers in Support Vector Machines ,Theory, Algorithms and Applications


The Trends Report
A Case Study in Automated Analysis
Matt Frost, CSRA • Aaron Hula, EPA OTAQ
About the Trends Report
"Light-Duty Automotive Technology, Carbon Dioxide Emissions, and Fuel Economy Trends: 1975–2015."
Pre-R Workflow
Circa 2008
Text files → Access → FORTRAN* script → Text files → Access → Excel or other graphing tool
* Yes, really!
Two Tracks: Data Preparation and Report Production
Cleaning the data and producing the report are interrelated.
Data Preparation
The incoming data requires extensive processing, not all of which can be automated.
Each distinct vehicle record might have several rows in the source data:
- Fuel type
- Test group
- Motor KW rating
Initial R Workflow
Circa 2009
Access → R → Text files → Excel or Adobe Illustrator
Figure Production
Old production method, final version:
Figure Production
New production method, draft straight from R:
Figure Production Source Code
ggplot(mpg.percentile , aes(x=MODEL_YEAR)) +
facet_wrap(~ CarOrTruck , ncol=2 ) +
geom_ribbon(aes(ymin=worst, ymax=best), fill="#FCF9CE", color="darkgray") +
geom_ribbon(aes(ymin=pct05, ymax=pct95), fill="#A3D6B3", color="darkgray") +
geom_ribbon(aes(ymin=pct25, ymax=pct75), fill="#2C7FB9", color="darkgray") +
scale_y_continuous(name='Adjusted Composite MPG', limits=c(0, 70),breaks=seq(0,80,10)) +
scale_x_continuous(name='Model Year', limits=c(1975, 2020),breaks=seq(1975,2020,5))
Figure Production
Final version, edited in Illustrator:
RMarkdown & knitr
Version Control
Operational Constraints: CBI
The CAFE and label databases contain confidential business information (CBI), which must be stored and handled securely.
- The database is stored on an encrypted network share.
- All communication with the database happens via VPN.
- No raw database records are written to any local drives or to the version control system.
Other Potential Applications
- Business intelligence "dashboards"
- Daily, weekly, or monthly reporting
- Interactive reporting via Shiny


Add Your Business
Delhi/NCR
Login
or
Register
Delhi
Mumbai
Chennai
Hydrabad
Jaipur
Rajsthan
Kolkata
Surat
Food & Drinks
Restaurants
Places
Shopping & Store
Hotels
Art & History
My Profile
My Listing
Favorite Listing
Add Listing
Logout
Search
Search
Popular Categories
Home& Office
Home Improvement
Properties & Rentasl
Education & Training
Professional Services
Travel & Transport
Home& Office
Home Improvement
Properties & Rentasl
Education & Training
Professional Services
Travel & Transport
Home& Office
Home Improvement
Properties & Rentasl
Education & Training
Professional Services
Travel & Transport
Sign In
×
Keep me signed in
Sign In
Not a member?
Sign up
Recover Password
Or connect with
Facebook
Google
Sign Up
×
Sign Up
Already a member?
Sign In
Recover Password
Or Signup with
Facebook
Google


Breakpoint ID
Function
File
Line
Variable Name
Type
Value
Thread ID
Name
Stack Frames
Next(n)
Step(s)
Continue(c)
Interrupt
Exit
Show Variables
Show Breakpoints


Contact
Site Map
Privacy Policy
Terms of Use
Copyright © 2011, Cargo Chief, All rights reserved.
Home
Shippers
Truckers
About
Contact
Luke makes this hierarchical chart