Vytorin

1 INDICATIONS AND USAGE VYTORIN VYTORIN ® is a combination of simvastatin and ezetimibe indicated: As an adjunct to diet to reduce elevated low density lipoprotein cholesterol (LDL-C): In adults with primary hyperlipidemia. In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to other LDL-C-lowering therapies to reduce elevated LDL-C in adults with homozygous familial hypercholesterolemia (HoFH).

Simvastatin Simvastatin, when used as a component of VYTORIN, is indicated to reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events. VYTORIN is a combination of ezetimibe, a dietary cholesterol absorption inhibitor, and simvastatin, an HMG-CoA reductase inhibitor (statin) indicated: As an adjunct to diet to reduce elevated low density lipoprotein cholesterol (LDL-C): In adults with primary hyperlipidemia. In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH).

As an adjunct to other LDL-C lowering therapies to reduce LDL-C in adults with homozygous familial hypercholesterolemia (HoFH). Simvastatin Simvastatin, when used as a component of VYTORIN, is indicated to reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events.

Important Dosage and Administration Information: Take VYTORIN orally once daily in the evening with or without food. Maximum recommended dosage is VYTORIN 10/40 mg once daily. VYTORIN 10/80 mg daily dosage is restricted to patients who have been taking VYTORIN 10/80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity. For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving VYTORIN 10/40 mg daily, prescribe alternative LDL-C-lowering treatment. If as dose is missed, take the missed dose as soon as possible. Do not double the next dose. Assess LDL-C when clinically appropriate, as early as 2 weeks after initiating VYTORIN, and adjust the dosage if necessary. Adults: Recommended dosage range of 10/10 mg to 10/40 mg once daily. See full prescribing information for VYTORIN dosage modifications due to drug interactions. Patients with Renal Impairment: Doses exceeding 10/20 mg should be used with caution and close monitoring in patients with moderate to severe renal impairment.

2.1Important Dosage and Administration Information Take

VYTORIN orally once daily in the evening with or without food. The maximum recommended dosage is VYTORIN 10/40 mg once daily. The VYTORIN 10/80 mg daily dosage is restricted to adult patients who have been taking VYTORIN 10/80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity . For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving VYTORIN 10/40 mg daily, prescribe alternative LDL-C-lowering treatment.

If as dose is missed, take the missed dose as soon as possible. Do not double the next dose. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating VYTORIN, and adjust the dosage if necessary.

2.2Recommended Dosage in Adult Patients The

recommended dosage range of VYTORIN 10/10 mg to 10/40 mg once a day.

2.3Recommended Dosage in Pediatric Patients

10 Years of Age and Older with HeFH The recommended dosage range of VYTORIN 10/10 mg to 10/40 mg once a day.

2.4Recommended Dosage in Patients with Renal Impairment

Renal impairment is a risk factor for statin-associated myopathy. Doses of VYTORIN exceeding 10/20 mg should be used with caution and close monitoring in patients with moderate to severe renal impairment . There are no dosage adjustment recommendations for patients with mild renal impairment.

2.5Dosage Modifications Due to Drug Interactions

Concomitant use of VYTORIN with the following drugs requires dosage modification of VYTORIN . Patients taking Lomitapide Reduce the dosage of VYTORIN by 50%. Do not exceed VYTORIN 10/20 mg once daily (or 10/40 mg once daily for patients who have previously taken VYTORIN 10/80 mg daily chronically while taking lomitapide) . Patients taking Verapamil, Diltiazem, or Dronedarone Do not exceed VYTORIN 10/10 mg once daily. Patients taking Amiodarone, Amlodipine, or Ranolazine Do not exceed VYTORIN 10/20 mg once daily. Patients taking Bile Acid Sequestrants In patients taking a bile acid sequestrant, administer VYTORIN at least 2 hours before or 4 hours after the bile acid sequestrant.

Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher VYTORIN dosage. Chinese patients may be at higher risk for myopathy. Discontinue VYTORIN if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue VYTORIN in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing VYTORIN dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported. Discontinue VYTORIN if IMNM is suspected. Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzyme before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue VYTORIN.

5.1Myopathy and Rhabdomyolysis

VYTORIN may cause myopathy and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including VYTORIN. In clinical trials of 24,747 simvastatin-treated patients with a median follow-up of 4 years, the incidence of myopathy, defined as unexplained muscle weakness, pain, or tenderness accompanied by creatinine kinase (CK) increases greater than ten times the upper limit of normal (10 X ULN), were approximately 0.03%, 0.08%, and 0.61% in patients treated with simvastatin 20 mg, 40 mg, and 80 mg daily, respectively. In another clinical trial of 12,064 simvastatin-treated patients (with a history of myocardial infarction) with a mean follow-up of 6.7 years, the incidences of myopathy in patients taking simvastatin 20 mg and 80 mg daily were approximately 0.02% and 0.9%, respectively.

The incidences of rhabdomyolysis (defined as myopathy with a CK >40 X ULN) in patients taking simvastatin 20 mg and 80 mg daily were approximately 0% and 0.4%, respectively . In the Trial of Heart and Renal Protection (SHARP), 9270 patients with chronic kidney disease were allocated to receive VYTORIN 10/20 mg daily (n=4650) or placebo (n=4620). During a median follow-up period of 4.9 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]) was 0.2% for VYTORIN and 0.1% for placebo: the incidence of rhabdomyolysis (defined as myopathy with a CK > 40 times ULN) was 0.09% for VYTORIN and 0.02% for placebo. In postmarketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported.

Most patients who developed rhabdomyolysis were taking a statin prior to initiating ezetimibe. However, rhabdomyolysis has been reported with ezetimibe monotherapy and with the addition of ezetimibe to agents known to be associated with increased risk of rhabdomyolysis, such as fibric acid derivatives. VYTORIN and a fenofibrate, if taking concomitantly, should both be immediately discontinued if myopathy is diagnosed or suspected.

Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher VYTORIN dosage; Chinese patients on VYTORIN may be at higher risk for myopathy . The risk of myopathy is increased by elevated plasma levels of simvastatin and simvastatin acid. The risk is also greater in patients taking VYTORIN 80 mg daily compared with patients taking lower VYTORIN dosages and compared with patients using other statins with similar or greater LDL-C-lowering efficacy . Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis The concomitant use of strong CYP3A4 inhibitors with VYTORIN is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is required, temporarily suspend VYTORIN during the duration of strong CYP3A4 inhibitor treatment.

The concomitant use of VYTORIN with gemfibrozil, cyclosporine, or danazol is also contraindicated . VYTORIN dosage modifications are recommended for patients taking lomitapide, verapamil, diltiazem, dronedarone, amiodarone, amlodipine or ranolazine . VYTORIN use should be temporarily suspended in patients taking daptomycin. Lipid modifying doses (≥1 gram/day) of niacin, fibrates, colchicine, and grapefruit juice may also increase the risk of myopathy and rhabdomyolysis . Use the 80 mg daily dosage of VYTORIN only in patients who have been taking simvastatin 80 mg daily chronically without evidence of muscle toxicity . If patients treated with VYTORIN 80 mg are prescribed an interacting drug that increases the risk for myopathy and rhabdomyolysis, switch to an alternate statin . Discontinue VYTORIN if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK increases may resolve if VYTORIN is discontinued.

Temporarily discontinue VYTORIN in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis, e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the VYTORIN dosage and advise patients receiving VYTORIN 80 mg of the increased risk of myopathy and rhabdomyolysis. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

5.2Immune-Mediated Necrotizing Myopathy There

have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy without significant inflammation; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary.

Treatment with immunosuppressive agents may be required. Discontinue VYTORIN if IMNM is suspected.

5.3Hepatic Dysfunction Increases in

serum transaminases have been reported with use of VYTORIN . In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Marked persistent increases of hepatic transaminases have also occurred with VYTORIN. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including VYTORIN. In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (≥3 X ULN) in serum transaminases was 1.7% overall for patients treated with VYTORIN and appeared to be dose-related with an incidence of 2.6% for patients treated with VYTORIN 10/80. In controlled long-term (48-week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations (≥3 X ULN) in serum transaminases was 1.8% overall and 3.6% for patients treated with VYTORIN 10/80.

These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. In SHARP, 9270 patients with chronic kidney disease were allocated to receive VYTORIN 10/20 mg daily (n=4650), or placebo (n=4620). During a median follow-up period of 4.9 years, the incidence of consecutive elevations of transaminases (>3 X ULN) was 0.7% for VYTORIN and 0.6% for placebo.

Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. Consider liver enzyme testing before VYTORIN initiation and when clinically indicated thereafter. VYTORIN is contraindicated in patients with acute liver failure or decompensated cirrhosis . If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue VYTORIN.

5.4Increases in HbA1c and Fasting Serum Glucose

Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including VYTORIN. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

4 CONTRAINDICATIONS VYTORIN is contraindicated in the following conditions: Concomitant use of strong CYP3A4 inhibitors (select azole anti-fungals, macrolide antibiotics, anti-viral medications, and nefazodone) . Concomitant use of cyclosporine, danazol, or danazol . Acute liver failure or decompensated cirrhosis . Hypersensitivity to simvastatin, ezetimibe, or any excipients in VYTORIN. Hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson syndrome, have been reported . Concomitant use of strong CYP3A4 inhibitors (select azole anti-fungals, macrolide antibiotics, anti-viral medications and nefazodone). Concomitant use of cyclosporine, danazol or gemfibrozil. Acute liver failure or decompensated cirrhosis.

Hypersensitivity to simvastatin, ezetimibe or any excipient of VYTORIN.

8.1Pregnancy

VYTORIN Risk Summary Discontinue VYTORIN when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. VYTORIN decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, VYTORIN may cause fetal harm when administered to pregnant patients based on the mechanism of action . In addition, treatment of hyperlipidemia is not generally necessary during pregnancy.

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 hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with VYTORIN use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage . In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered simvastatin during the period of organogenesis at doses that resulted in 2.5 and 2 times, respectively, the human exposure at the maximum recommended human dosage of 80 mg/day, based on body surface area (mg/m 2 ).

In animal reproduction studies, no adverse developmental effects were observed in pregnant rats and rabbits orally administered ezetimibe during the period of organogenesis at doses that resulted in up to 10 and 150 times, respectively, the human exposure at the MRHD, based on AUC . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data Ezetimibe There are insufficient data on ezetimibe use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Simvastatin A Medicaid cohort linkage trial of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders.

In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Trial limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data Ezetimibe In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats (gestation days 6-15) and rabbits (gestation days 7-19), there was no evidence of maternal toxicity or embryolethality at any dose tested (250, 500, 1000 mg/kg/day) at exposure equivalent to 10 to 150 times the clinical exposure, based on AUC, in rats and rabbits.

In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). The animal-to-human exposure multiple for total ezetimibe at the no-observed effect level was 6 times for rat and 134 times for rabbit.

Fetal exposure to ezetimibe (conjugated and unconjugated) was confirmed in subsequent placental transfer studies conducted using a maternal dose of 1000 mg/kg/day. The fetal maternal plasma exposure ratio (total ezetimibe) was 1.5 for rats on gestation day 20 and 0.03 for rabbits on gestation day 22. The effect of ezetimibe on prenatal and postnatal development and maternal function was evaluated in pregnant rats at doses of 100, 300 or 1000 mg/kg/day (gestation day 6 through lactation day 21).

No maternal toxicity or adverse developmental outcomes were observed up to and including the highest dose tested (17 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). Multiple-dose studies of ezetimibe given in combination with statins in rats and rabbits during organogenesis resulted in higher ezetimibe and statin exposures. Reproductive findings occurred at lower doses in combination therapy compared to monotherapy.

Simvastatin Simvastatin was given to pregnant rats at doses of 6.25, 12.5 and 25 mg/kg/day (0.6 times, 1.3 times, and 2.5 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area) from gestation days 6-17 and to pregnant rabbits from gestation days 6-18 at doses of 2.5, 5, and 10 mg/kg/day (0.5 times, 1 times, and 2 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area). For both species, there was no evidence of maternal toxicity, or embryolethality. In rats, mean fetal body weights in the 25 mg/kg/day group were decreased 5.4%. Similar fetal body weight effects were not observed in rabbits.

Simvastatin doses of 6.25, 12.5 and 25 mg/kg/day (0.6 times, 1.3 times, and 2.5 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area) were given to pregnant rats from gestation day 15 to lactation day 21. Slight decreases in maternal body weight gain and pup postnatal day 0 weight were observed in the 25 mg/kg/day dose group. Mean body weight gain of pups during lactation was slightly decreased at doses ≥12.5 mg/kg/day.

Post weaning weight, behavior, reproductive performance and fertility of the offspring were not affected at any dose tested. Placental transfer of simvastatin was not evaluated in rats or rabbits. However, it has been shown that other drugs in this class cross the placenta.

The following serious adverse reactions are discussed in greater detail in other sections of the label: Myopathy and Rhabdomyolysis Immune-Mediated Necrotizing Myopathy Hepatic Dysfunction Increases in HbA1c and Fasting Serum Glucose Levels Common (incidence ≥2% and greater than placebo) adverse reactions in clinical trials: headache, increased ALT, myalgia, upper respiratory tract infection, and diarrhea. To report SUSPECTED ADVERSE REACTIONS, contact Organon LLC, a subsidiary of Organon & Co., at 1-844-674-3200 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience Because

clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. VYTORIN In the VYTORIN (ezetimibe and simvastatin) placebo-controlled clinical trials database of 1420 patients (age range 20-83 years, 52% female, 87% White, 3% Black or African American, 3% Asians, 5% other races identified as Hispanic or Latino ethnicity) with a median treatment duration of 27 weeks, 5% of patients on VYTORIN and 2.2% of patients on placebo discontinued due to adverse reactions. The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in controlled clinical trials were: headache (5.8%), increased ALT (3.7%), myalgia (3.6%), upper respiratory tract infection (3.6%), and diarrhea (2.8%).

The most common adverse reactions in the group treated with VYTORIN that led to treatment discontinuation and occurred at a rate greater than placebo were: increased ALT (0.9%), myalgia (0.6%), increased AST (0.4%), and back pain (0.4%). VYTORIN has been evaluated for safety in more than 10,189 patients in clinical trials. Table 1 summarizes the frequency of clinical adverse reactions reported in ≥2% of patients treated with VYTORIN (n=1420) and at an incidence greater than placebo from four placebo-controlled trials.

Table 1 Includes two placebo-controlled combination studies in which the active ingredients equivalent to VYTORIN were coadministered and two placebo-controlled studies in which VYTORIN was administered. : Adverse Reactions Reported ≥2% of Patients Treated with VYTORIN at an Incidence Greater than Placebo Regardless of Causality % Placebo N = 371 % Ezetimibe 10 mg N = 302 % Simvastatin All doses. N = 1234 % VYTORIN N = 1420 Headache 5.4 6.0 5.9

5.8Upper

respiratory tract infection 2.7 5.0 5.0

3.6Myalgia

2.4 2.3 2.6

3.6Diarrhea

2.2 5.0 3.7

2.8Pain in

extremity 1.3 3.0 2.0

2.3Influenza

0.8 1.0 1.9

2.3Study of Heart and Renal Protection In

SHARP , 9270 patients were allocated to VYTORIN 10/20 mg daily (n=4650) or placebo (n=4620) for a median follow-up period of 4.9 years. The proportion of patients who permanently discontinued trial treatment as a result of either an adverse event or abnormal safety blood result was 10.4% vs. 9.8% among patients allocated to VYTORIN and placebo, respectively. Comparing those allocated to VYTORIN vs. placebo, the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum CK >10 times ULN) was 0.2% vs. 0.1% and the incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) was 0.09% vs. 0.02%, respectively.

Consecutive elevations of transaminases (>3 X ULN) occurred in 0.7% vs. 0.6%, respectively. Patients were asked about the occurrence of unexplained muscle pain or weakness at each trial visit: 21.5% vs. 20.9% patients ever reported muscle symptoms in the VYTORIN and placebo groups, respectively. Cancer was diagnosed during the trial in 9.4% vs. 9.5% of patients assigned to VYTORIN and placebo, respectively.

Ezetimibe Other adverse reactions reported with ezetimibe in placebo-controlled studies, regardless of causality assessment: Musculoskeletal system disorders: arthralgia; Infections and infestations: sinusitis; Body as a whole – general disorders: fatigue. Simvastatin In a clinical outcome trial in which 12,064 adult patients with a history of myocardial infarction were treated with simvastatin (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 (1200 U/L) upper limit of normal [ULN]) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0.02% and 0.9% respectively. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0% and 0.4%. The incidence of myopathy and 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. Other adverse reactions reported with simvastatin in placebo-controlled clinical trials: atrial fibrillation; vertigo; abdominal pain, constipation, dyspepsia, flatulence, gastritis; eczema, rash; diabetes mellitus; bronchitis, sinusitis, urinary tract infections; asthenia, edema/swelling; and insomnia. Laboratory Tests Marked persistent increases of hepatic serum transaminases have been noted . Elevated alkaline phosphatase and γ-glutamyl transpeptidase have been reported.

About 5% of patients taking simvastatin had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK .

6.2Postmarketing Experience The

following adverse reactions have been identified during post-approval use of VYTORIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as Whole: fever, chills, malaise, asthenia Blood and Lymphatic System Disorders: anemia, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia Gastrointestinal Disorders: pancreatitis, nausea, vomiting Hepatobiliary Disorders: cholelithiasis, cholecystitis, elevations in liver transaminases including elevations more than 5 X ULN, hepatitis/jaundice, fatal and non-fatal hepatic failure Immune System Disorders: hypersensitivity syndrome including: anaphylaxis, angioedema, lupus erythematous-like syndrome, dermatomyositis, vasculitis Musculoskeletal and Connective Tissue Disorders: muscle cramps, immune-mediated necrotizing myopathy, rhabdomyolysis, myalgia, arthralgia, polymyalgia rheumatica, arthritis, elevated creatine phosphokinase Nervous System Disorders: dizziness, depression, paresthesia, peripheral neuropathy, rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered. Skin and Subcutaneous Tissue Disorders: rash, pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), purpura, lichen planus, urticaria, photosensitivity, flushing, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome. Respiratory and Thoracic: interstitial lung disease, dyspnea Reproductive System Disorders: erectile dysfunction