Side effects of vytorin

Contents

Vytorin

WARNINGS

Included as part of the “PRECAUTIONS” Section

PRECAUTIONS

Myopathy/Rhabdomyolysis

Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by elevated plasma levels of simvastatin and simvastatin acid. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment.

The risk of myopathy, including rhabdomyolysis, is dose related. In a clinical trial database in which 41,413 patients were treated with simvastatin, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase >10 times upper limit of normal ) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.

The risk of myopathy, including rhabdomyolysis, is greater in patients on simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-lowering efficacy and compared with lower doses of simvastatin. Therefore, the 10/80-mg dose of VYTORIN should be used only in patients who have been taking VYTORIN 10/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity . If, however, a patient who is currently tolerating the 10/80-mg dose of VYTORIN needs to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin or statin-based regimen with less potential for the drug-drug interaction. Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, and to report promptly any unexplained muscle pain, tenderness or weakness. If symptoms occur, treatment should be discontinued immediately .

In the Study 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 >10 times upper limit of normal ) 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.

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.

All patients starting therapy with VYTORIN or whose dose of VYTORIN is being increased should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing VYTORIN. VYTORIN therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when simvastatin treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with VYTORIN or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.

Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of longstanding diabetes mellitus. Such patients taking VYTORIN merit closer monitoring.

VYTORIN therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. VYTORIN therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

Drug Interactions

The risk of myopathy and rhabdomyolysis is increased by elevated plasma levels of simvastatin and simvastatin acid. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs that inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, posaconazole, and voriconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, cobicistat-containing products, or grapefruit juice. Combination of these drugs with VYTORIN is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with VYTORIN must be suspended during the course of treatment.

The combined use of VYTORIN with gemfibrozil, cyclosporine, or danazol is contraindicated .

Caution should be used when prescribing fenofibrates with VYTORIN, as these agents can cause myopathy when given alone and the risk is increased when they are coadministered .

Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing VYTORIN with colchicine .

The benefits of the combined use of VYTORIN with the following drugs should be carefully weighed against the potential risks of combinations: other lipid-lowering drugs (fenofibrates, ≥1 g/day of niacin, or, for patients with HoFH, lomitapide), amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine .

Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In an ongoing, double-blind, randomized cardiovascular outcomes trial, an independent safety monitoring committee identified that the incidence of myopathy is higher in Chinese compared with non-Chinese patients taking simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg coadministered with lipid-modifying doses of a niacin-containing product. Caution should be used when treating Chinese patients with VYTORIN in doses exceeding 10/20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive VYTORIN 10/80 mg coadministered with lipid-modifying doses of niacin-containing products. It is unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients .

Prescribing recommendations for interacting agents are summarized in Table 1 .

Table 1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis

Interacting Agents Prescribing Recommendations
Strong CYP3A4 Inhibitors, e.g.: Contraindicated with VYTORIN
Itraconazole
Ketoconazole
Posaconazole
Voriconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Boceprevir
Telaprevir
Nefazodone
Cobicistat-containing products
Gemfibrozil
Cyclosporine
Danazol
Verapamil Do not exceed 10/10 mg VYTORIN daily
Diltiazem
Dronedarone
Amiodarone Do not exceed 10/20 mg VYTORIN daily
Amlodipine
Ranolazine
Lomitapide For patients with HoFH, do not exceed 10/20 mg VYTORIN daily*
Grapefruit juice Avoid grapefruit juice
* For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 10/40 mg VYTORIN when taking lomitapide.

Liver Enzymes

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.

It is recommended that liver function tests be performed before the initiation of treatment with VYTORIN, and thereafter when clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with VYTORIN, promptly interrupt therapy. If an alternate etiology is not found do not restart VYTORIN. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy .

VYTORIN should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained persistent transaminase elevations are contraindications to the use of VYTORIN.

Endocrine Function

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including simvastatin.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel. Patients should be advised about substances they should not take concomitantly with VYTORIN . Patients should also be advised to inform other healthcare professionals prescribing a new medication or increasing the dose of an existing medication that they are taking VYTORIN.

Muscle Pain

All patients starting therapy with VYTORIN should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing VYTORIN. Patients using the 10/80-mg dose should be informed that the risk of myopathy, including rhabdomyolysis, is increased with the use of the 10/80-mg dose. The risk of myopathy, including rhabdomyolysis, occurring with use of VYTORIN is increased when taking certain types of medication or consuming grapefruit juice. Patients should discuss all medication, both prescription and over the counter, with their healthcare professional.

It is recommended that liver function tests be performed before the initiation of VYTORIN, and thereafter when clinically indicated. All patients treated with VYTORIN should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.

Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using VYTORIN. Discuss future pregnancy plans with your patients, and discuss when to stop taking VYTORIN if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking VYTORIN and call their healthcare professional.

Breastfeeding

Women who are breastfeeding should be advised to not use VYTORIN. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professional.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No animal carcinogenicity or fertility studies have been conducted with the combination of ezetimibe and simvastatin. The combination of ezetimibe with simvastatin did not show evidence of mutagenicity in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with ezetimibe and simvastatin with or without metabolic activation. There was no evidence of genotoxicity at doses up to 600 mg/kg with the combination of ezetimibe and simvastatin (1:1) in the in vivo mouse micronucleus test.

A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice.

No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test.

In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).

In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively, (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid-and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid-and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid-and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day.

In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC).

In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC).

A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other statins. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after an 80-mg daily dose.

No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.

There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180 mg/kg/day (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m2), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear.

Use In Specific Populations

Pregnancy

Pregnancy Category X.

VYTORIN is contraindicated in women who are or may become pregnant. Lipid-lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of VYTORIN use during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero. Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because statins, such as simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, VYTORIN may cause fetal harm when administered to a pregnant woman. If VYTORIN is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Women of childbearing potential, who require VYTORIN treatment for a lipid disorder, should be advised to use effective contraception. For women trying to conceive, discontinuation of VYTORIN should be considered. If pregnancy occurs, VYTORIN should be immediately discontinued.

In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses.

Multiple-dose studies of ezetimibe coadministered with statins in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in coadministration therapy compared to monotherapy.

Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m2 surface area. However, in studies with another structurally-related statin, skeletal malformations were observed in rats and mice.

There are rare reports of congenital anomalies following intrauterine exposure to statins. In a review1 of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally-related statin, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate only to exclude a 3-to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.

Nursing Mothers

It is not known whether simvastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not nurse their infants. A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother .

In rat studies, exposure to ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe or simvastatin are excreted into human breast milk. Because a small amount of another drug in the same class as simvastatin is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women who are nursing should not take VYTORIN .

Pediatric Use

The effects of ezetimibe coadministered 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% multiracial) with HeFH were randomized to receive either ezetimibe coadministered 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 ezetimibe coadministered with simvastatin group compared to 219 mg/dL (range: 149-336 mg/dL) in the simvastatin monotherapy group. The patients received coadministered ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, coadministered ezetimibe and 40 mg simvastatin or 40 mg simvastatin monotherapy for the next 27 weeks, and open-label coadministered ezetimibe 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.

Table 3:Mean Percent Difference at Week 6 Between the PooledEzetimibeCoadministered with Simvastatin Group and the Pooled Simvastatin Monotherapy Group in Adolescent Patients with Heterozygous Familial Hypercholesterolemia

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 ezetimibe coadministered 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 ≥3 X ULN) occurred in four (3%) individuals in the ezetimibe coadministered with simvastatin group and in two (2%) individuals in the simvastatin monotherapy group. Elevations of CPK (≥10 X ULN) occurred in two (2%) individuals in the ezetimibe coadministered 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.

Coadministration of ezetimibe with simvastatin at doses greater than 40 mg/day has not been studied in adolescents. Also, VYTORIN 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 <10 years of age are not available.

The pharmacokinetics of simvastatin has not been studied in the pediatric population.

Geriatric Use

Of the 10,189 patients who received VYTORIN in clinical studies, 3242 (32%) were 65 and older (this included 844 (8%) who were 75 and older). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, 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. Since advanced age (≥65 years) is a predisposing factor for myopathy, VYTORIN should be prescribed with caution in the elderly. .

Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, VYTORIN should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age. .

Renal Impairment

In the SHARP trial of 9270 patients with moderate to severe renal impairment (6247 non-dialysis patients with median serum creatinine 2.5 mg/dL and median estimated glomerular filtration rate 25.6 mL/min/1.73 m2, and 3023 dialysis patients), the incidence of serious adverse events, adverse events leading to discontinuation of study treatment, or adverse events of special interest (musculoskeletal adverse events, liver enzyme abnormalities, incident cancer) was similar between patients ever assigned to VYTORIN 10/20 mg (n=4650) or placebo (n=4620) during a median follow-up of 4.9 years. However, because 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. .

Hepatic Impairment

VYTORIN is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminases. .

SIDE EFFECTS

The following serious adverse reactions are discussed in greater detail in other sections of the label:

  • Rhabdomyolysis and myopathy
  • Liver enzyme abnormalities

Clinical Trials Experience

VYTORIN

Because 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 practice.

In the VYTORIN (ezetimibe and simvastatin) placebo-controlled clinical trials database of 1420 patients (age range 20-83 years, 52% women, 87% Caucasians, 3% Blacks, 5% Hispanics, 3% Asians) 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 common adverse reactions in the group treated with VYTORIN that led to treatmentdiscontinuation and occurred at a rate greater than placebo were:

  • Increased ALT (0.9%)
  • Myalgia (0.6%)
  • Increased AST (0.4%)
  • Back pain (0.4%)

VYTORIN has been evaluated for safety in more than 10,189 patients in clinical trials.

Table 2 summarizes the frequency of clinical adverse reactions reported in ≥2% of patients treated with VYTORIN (n=1420) and at an incidence greater than placebo, regardless of causality assessment, fromfour placebo-controlled trials.

Table 2*: Clinical Adverse Reactions Occurring in ≥2% of Patients Treated with VYTORINand atan Incidence Greater than Placebo, Regardless of Causality

Body System/Organ Class Adverse Reaction Placebo (%)
n=371
Ezetimibe 10 mg (%)
n=302
Simvastatin† (%)
n = 1234
VYTORIN† (%)
n = 1420
Body as a whole – general disorders
Headache 5.4 6.0 5.9 5.8
Gastrointestinal systemdisorders
Diarrhea 2.2 5.0 3.7 2.8
Infections and infestations
Influenza 0.8 1.0 1.9 2.3
Upper respiratory tract infection 2.7 5.0 5.0 3.6
Musculoskeletal and connective tissue disorders
Myalgia 2.4 2.3 2.6 3.6
Pain in extremity 1.3 3.0 2.0 2.3
*Includes two placebo-controlled combination studies in which the active ingredients equivalent to VYTORIN were co-administered and two placebo-controlled studies in which VYTORIN was administered.
†All doses.

Study 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 studytreatment 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 (>3XULN) occurred in 0.7% vs. 0.6%, respectively. Patients were asked about the occurrence of unexplained muscle pain or weakness at each study 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 trial in which 12,064 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 >10 times upper limit of normal ) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence ofrhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent yearsof 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 studies, regardless of causality assessment: Cardiac disorders: atrial fibrillation; Ear and labyrinth disorders: vertigo; Gastrointestinal disorders: abdominal pain, constipation, dyspepsia, flatulence, gastritis; Skin and subcutaneous tissue disorders: eczema, rash; Endocrine disorders: diabetes mellitus; Infections and infestations: bronchitis, sinusitis, urinary tract infections; Body as a whole – general disorders: asthenia, edema/swelling; Psychiatric disorders: 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 .

Postmarketing Experience

Because the below reactions are reported voluntarily from a population of uncertain size, it is generallynot possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been reported in postmarketing experience for VYTORIN orezetimibe or simvastatin: pruritus; alopecia; erythema multiforme; a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails); dizziness; muscle cramps;myalgia; arthralgia; pancreatitis; paresthesia; peripheral neuropathy; vomiting; nausea; anemia; erectile dysfunction; interstitial lung disease; myopathy/rhabdomyolysis ; hepatitis/jaundice; fatal and non-fatal hepatic failure; depression; cholelithiasis; cholecystitis; thrombocytopenia; elevations in liver transaminases; elevated creatine phosphokinase.

There have beenrare reportsof immune-mediated necrotizing myopathy associated with statin use .

Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria have been reported.

In addition, an apparent hypersensitivity syndrome has been reported rarely that has included one ormore of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever,chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness,amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation,with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

Read the entire FDA prescribing information for Vytorin (Ezetimibe and Simvastatin)

Generic Name: ezetimibe and simvastatin (ez ET i mibe and SIM va stat in)
Brand Names: Vytorin

Medically reviewed by P. Thornton, DipPharm Last updated on Nov 1, 2019.

  • Overview
  • Side Effects
  • Dosage
  • Professional
  • Interactions
  • More

What is Vytorin?

Vytorin contains a combination of ezetimibe and simvastatin. Ezetimibe reduces the amount of cholesterol absorbed by the body.

Simvastatin belongs to a group of drugs called HMG CoA reductase inhibitors, or “statins.”

Vytorin is used to lower blood levels of “bad” cholesterol (low-density lipoprotein, or LDL) and triglycerides, to increase levels of “good” cholesterol (high-density lipoprotein, or HDL), and to lower triglycerides (a type of fat in the blood).

Vytorin is used together with a low-fat diet and other treatments to lower total cholesterol in adults and children who are at least 10 years old. It is not known whether this medicine reduces your risk of heart disease.

Important Information

You should not use Vytorin if you have active liver disease or abnormal liver function tests.

Do not use Vytorin if you are pregnant or if you could become pregnant. Use effective birth control.

Do not breastfeed while using ezetimibe and simvastatin.

The following drugs should not be used while you are taking Vytorin: boceprevir, cyclosporine, danazol, gemfibrozil, nefazodone, telaprevir, certain antibiotics (clarithromycin, erythromycin, telithromycin), antifungal medication (itraconazole, ketoconazole, posaconazole, voriconazole), or certain HIV/AIDS medication (atazanavir, cobicistat (Stribild, Tybost), indinavir, nelfinavir, ritonavir, saquinavir, tipranavir).

Before taking this medicine

You should not use Vytorin if you are allergic to simvastatin (Zocor) or ezetimibe (Zetia), or if you have:

  • active liver disease; or

  • abnormal liver function tests.

Do not use if you are pregnant. This medicine can harm an unborn baby. Use effective birth control to prevent pregnancy. Stop taking this medicine and tell your doctor at once if you become pregnant.

Ezetimibe and simvastatin can cause the breakdown of muscle tissue, which can lead to kidney failure. This happens more often in women, in older adults, in people of Chinese descent, and in people who have kidney disease or poorly controlled hypothyroidism (underactive thyroid).

Other medicines may increase your risk of serious muscle problems if you take them together with Vytorin. Do not take these medicines at the same time:

  • cyclosporine;

  • danazol;

  • gemfibrozil;

  • nefazodone;

  • an antibiotic – clarithromycin, erythromycin, telithromycin;

  • antifungal medication – itraconazole, ketoconazole, posaconazole, voriconazole;

  • hepatitis C medications – boceprevir, telaprevir; or

  • HIV/AIDS medication – atazanavir, cobicistat, indinavir, nelfinavir, ritonavir, saquinavir, tipranavir.

Your doses of certain other medicines may need to be adjusted while you are taking Vytorin. This includes:

  • amiodarone or dronedarone;

  • amlodipine (sometimes in combination medicines – Azor, Caduet, Consensi, Exforge, Lotrel, Prestalia, Twynsta, Tribenzor);

  • colchicine;

  • diltiazem, verapamil;

  • fenofibrate, fenofibric acid;

  • lomitapide;

  • ranolazine; or

  • medicines that contain niacin, nicotinic acid, or vitamin B3, such as Advicor, Niaspan, Niacor, Simcor, Slo-Niacin, and others.

Tell your doctor if you have ever had:

  • unexplained weakness or muscle pain;

  • a thyroid disorder;

  • liver or kidney disease;

  • liver problems caused by alcohol;

  • a habit of drinking more than 2 alcoholic drinks per day; or

  • if you are older than 65.

Vytorin is not approved for use by anyone younger than 10 years old.

This medicine should not be given to a girl who has not yet had menstrual periods.

How should I take Vytorin?

Take Vytorin exactly as prescribed. Follow all directions on your prescription label and read all medication guides or instruction sheets. Your doctor may occasionally change your dose. Use the medicine exactly as directed.

Take this medicine in the evening, with or without food.

While using ezetimibe and simvastatin, you may need frequent blood tests.

Make sure any doctor caring for you knows you that you use Vytorin, especially if you have an infection, injury or surgery.

Vytorin is only part of a complete program of treatment that also includes diet, exercise, and weight control. Follow your doctor’s instructions very closely.

Store at room temperature away from moisture and heat. Keep the bottle tightly closed when not in use.

What happens if I miss a dose?

Take the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking Vytorin?

Grapefruit may interact with ezetimibe and simvastatin and lead to unwanted side effects. Avoid the use of grapefruit products.

Avoid drinking alcohol. It can raise triglyceride levels and may increase your risk of liver damage.

Avoid eating foods high in fat or cholesterol, or ezetimibe and simvastatin will not be as effective.

Vytorin side effects

Get emergency medical help if you have signs of an allergic reaction to Vytorin: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using this medicine and call your doctor at once if you have:

  • unexplained muscle pain, tenderness, or weakness;

  • fever, unusual tiredness;

  • upper stomach pain, loss of appetite;

  • dark colored urine; or

  • jaundice (yellowing of the skin or eyes).

Common Vytorin side effects may include:

  • headache;

  • muscle pain;

  • abnormal liver function tests;

  • diarrhea; or

  • cold symptoms such as stuffy nose, sneezing, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Vytorin?

If you also take cholestyramine, colesevelam, or colestipol: Take your ezetimibe and simvastatin dose 2 hours before or 4 hours after you take the other medicine.

Tell your doctor about all your current medicines. Many drugs can interact with ezetimibe and simvastatin, especially:

  • a blood thinner such as warfarin, Coumadin, or Jantoven; or

  • heart or blood pressure medication.

This list is not complete and many other drugs may interact with ezetimibe and simvastatin. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible drug interactions are listed here.

Further information

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use Vytorin only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Copyright 1996-2020 Cerner Multum, Inc. Version: 10.02.

Medical Disclaimer

More about Vytorin (ezetimibe / simvastatin)

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  • Drug class: antihyperlipidemic combinations
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  • Vytorin (FDA)

Related treatment guides

  • High Cholesterol
  • High Cholesterol, Familial Heterozygous
  • High Cholesterol, Familial Homozygous

FDA approves Impax generic of Merck’s cholesterol drug Vytorin

A view shows the U.S. Food and Drug Administration (FDA) headquarters in Silver Spring Thomson Reuters (Reuters) – The U.S. Food and Drug Administration on Wednesday approved Impax Laboratories Inc’s generic version of Merck & Co’s cholesterol-reducing drug Vytorin, the first cheap competitor for a drug that in 2016 generated more than $1 billion in sales.

Vytorin is a combination product that includes the drugs ezetimibe and simvastatin, sold under the brand names Zocor and Zetia. Zocor lost patent protection in 2006. Zetia lost patent protection on Tuesday. Zetia generated 2016 sales of $2.6 billion.

In general, revenue from branded products falls by 90 percent once multiple generics hit the market. Vytorin currently costs about $300 for a supply of 30 tablets.

Merck faces generic competition this year not only to Vytorin and Zetia, but also to its antibiotic Cubicin and its Nasonex nasal spray in the United States and for its arthritis drug Remicade in Europe.

The company is betting it will ultimately offset those losses with other drugs, including its cancer drug Keytruda, which is approved for certain patients with non-small cell lung cancer and melanoma and is being tested in a range of other cancers as well.

Merck in February issued a 2017 profit forecast that was in line with Wall Street expectations.

(Reporting by Toni Clarke in Washington; Editing by Savio D’Souza)

Merck cholesterol drug Vytorin faces competition from Impax, Teva generics

A view shows the U.S. Food and Drug Administration (FDA) headquarters in Silver Spring, Maryland August 14, 2012. REUTERS/Jason Reed/File Photo

(Reuters) – Merck & Co’s cholesterol-reducing drug Vytorin faces competition for the first time ever after two companies announced progress on their generic versions of a drug that generated more than $1 billion in sales last year.

The U.S. Food and Drug Administration on Wednesday approved Impax Laboratories Inc’s generic version of Vytorin, while Teva Pharmaceutical Industries Ltd launched its generic version of the drug in the United States.

Impax said it will immediately start commercialization for its generic version of Vytorin.

Vytorin is a combination product that includes the drugs ezetimibe and simvastatin, sold under the brand names Zocor and Zetia. Zocor lost patent protection in 2006 and Zetia, which generated 2016 sales of $2.6 billion, lost patent protection on Tuesday.

In general, revenue from branded products falls by 90 percent once multiple generics hit the market. Vytorin currently costs about $300 for a supply of 30 tablets.

Merck faces generic competition this year not only to Vytorin and Zetia, but also to its antibiotic Cubicin and its Nasonex nasal spray in the United States and for its arthritis drug Remicade in Europe.

The company is betting it will ultimately offset those losses with other drugs, including its cancer drug Keytruda, which is approved for certain patients with non-small cell lung cancer and melanoma and is being tested in a range of other cancers as well.

Merck in February issued a 2017 profit forecast that was in line with Wall Street expectations.

Impax shares gained 2.8 percent to $14.40 in trading after the bell on Wednesday. Teva and Merck shares were little changed.

Reporting by Toni Clarke in Washington and Divya Grover in Bengaluru; Editing by Savio D’Souza

Our Standards:The Thomson Reuters Trust Principles.

Vytorin Side Effects

Generic Name: ezetimibe / simvastatin

Medically reviewed by Drugs.com. Last updated on Feb 4, 2019.

  • Overview
  • Side Effects
  • Dosage
  • Professional
  • Interactions
  • More

Note: This document contains side effect information about ezetimibe / simvastatin. Some of the dosage forms listed on this page may not apply to the brand name Vytorin.

For the Consumer

Applies to ezetimibe / simvastatin: oral tablet

Along with its needed effects, ezetimibe/simvastatin may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking ezetimibe / simvastatin:

Incidence not known

  • Abdominal or stomach fullness
  • bloating
  • chills
  • constipation
  • darkened urine
  • fast heartbeat
  • fever
  • hives
  • hoarseness
  • indigestion
  • itching
  • joint pain
  • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
  • loss of appetite
  • nausea
  • pains in the stomach, side, or abdomen, possibly radiating to the back
  • rash
  • redness of the skin
  • shortness of breath
  • stiffness
  • swelling of the eyelids, face, lips, hands, or feet
  • tightness in the chest
  • trouble breathing or swallowing
  • vomiting
  • yellow eyes or skin

Some side effects of ezetimibe / simvastatin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

  • Body aches or pain
  • cough
  • diarrhea
  • difficulty with breathing
  • difficulty with moving
  • ear congestion
  • general feeling of discomfort or illness
  • headache
  • loss of voice
  • muscle aches and pains or cramping
  • muscle stiffness
  • nasal congestion
  • pain in the arms or legs
  • runny nose
  • shivering
  • sneezing
  • sore throat
  • sweating
  • swollen joints
  • trouble sleeping
  • unusual tiredness or weakness

For Healthcare Professionals

Applies to ezetimibe / simvastatin: oral tablet

General

The more commonly reported adverse effects have included headache, increased ALT, myalgia, upper respiratory tract infection, and diarrhea.

Gastrointestinal

Ezetimibe-simvastatin:

Common (1% to 10%): Diarrhea

Ezetimibe:

Common (1% to 10%): Diarrhea, abdominal pain, nausea

Postmarketing reports: Pancreatitis

Simvastatin:

Very rare (less than 0.01%): Protein losing enteropathy

Musculoskeletal

Ezetimibe-simvastatin:

Common (1% to 10%): Myalgia, extremity pain

Very rare (less than 0.01%): Tendon rupture (one case)

Frequency not reported: Back pain

Postmarketing reports: Muscle cramps

Ezetimibe:

Common (1% to 10%): Back pain, arthralgia

Postmarketing reports: Myalgia, elevated creatine phosphokinase, rare reports of myopathy/rhabdomyolysis

Simvastatin:

Uncommon (0.1% to 1%): Myopathy, rhabdomyolysis

Frequency not reported: Elevations in creatine kinase, dermatomyositis, arthralgia, myalgia

Simvastatin has been associated with rare cases of severe myopathy and rhabdomyolysis. This is accompanied by elevations in creatine kinase, myoglobinuria, and proteinuria, as well as renal failure. Experience with HMG-CoA reductase inhibitors indicates that concomitant use with gemfibrozil, niacin, cyclosporine, or erythromycin may increase the incidence and the severity of musculoskeletal side effects.

A case of spontaneous biceps tendon rupture developed in a patient after 4 months of treatment with ezetimibe-simvastatin. Upon rechallenge 2 months later, the patient developed pain in the contralateral arm overlying the biceps tendon. Following discontinuation of ezetimibe-simvastatin, pain resolved 2 weeks later. Inhibition of matrix metalloproteinases has been suggested as the contributing factor in the development of tendon rupture.

Renal

Simvastatin:

Frequency not reported: Myoglobinuria, acute renal failure secondary to rhabdomyolysis

Hepatic

Persistent elevations in liver function tests three times normal values are reported in up to 1.5% of patients on simvastatin in clinical trials. In one study, this led to the discontinuation of simvastatin in 0.6% of patients. In other patients, elevations in liver function tests were transient and returned to normal with continued simvastatin therapy.

Ezetimibe-simvastatin:

Common (1% to 10%): Increased ALT

Frequency not reported: Increased AST

Ezetimibe:

Postmarketing reports: Elevations in liver transaminases, hepatitis, cholelithiasis, cholecystitis

Simvastatin:

Common (1% to 10%): Elevations in liver function tests

Frequency not reported: Hepatitis (including chronic active hepatitis), cholestatic jaundice, fatty changes in the liver, cirrhosis, fulminant hepatic necrosis

Postmarketing reports: Hepatic failure, jaundice

Dermatologic

Simvastatin:

Frequency not reported: Eczematous, pruritic rash, toxic epidermal necrolysis, photosensitivity, purpura, erythema multiforme, photosensitivity, purpura, alopecia

Immunologic

Ezetimibe-simvastatin:

Frequency not reported: Influenza

Ezetimibe:

Common (1% to 10%): Viral infection

Simvastatin:

Very rare (less than 0.01%): Lupus-like syndrome

Frequency not reported: Positive ANA, ESR increase, polymyalgia rheumatica, vasculitis

Statin use:

Rare (0.01% to 0.1%): Immune-mediated necrotizing myopathy (IMNM)

Respiratory

Ezetimibe-simvastatin:

Common (1% to 10%): Upper respiratory tract infection

Frequency not reported: Interstitial lung disease causing breathing problems including persistent cough and/or shortness of breath or fever

Ezetimibe:

Common (1% to 10%): Coughing

Frequency not reported: Sinusitis

Simvastatin:

Frequency not reported: Sinusitis, pharyngitis

Cardiovascular

Simvastatin:

Common (1% to 10%): Angina

Frequency not reported: Atrial fibrillation, edema

Endocrine

Simvastatin:

Frequency not reported: Gynecomastia, thyroid function abnormalities

Genitourinary

Simvastatin:

Frequency not reported: Erectile dysfunction, impotence, urinary tract infections

Hematologic

Ezetimibe-simvastatin:

Postmarketing reports: Epistaxis (one report), anemia

Ezetimibe:

Postmarketing reports: Thrombocytopenia

Simvastatin:

Frequency not reported: Hemolytic anemia, thrombocytopenia, leukopenia (possibly manifestations of a hypersensitivity reaction)

A 65-year-old male with hereditary hemorrhagic telangiectasia (HHT) who had a history of minimal epistaxis began to experience profuse epistaxis 8 to 10 weeks after starting ezetimibe-simvastatin, The patient had been treated with simvastatin 20 mg alone for 9 years without any adverse effects. Two months after starting combination therapy with ezetimibe-simvastatin he noticed epistaxis that increased from a few drops every other day to profuse bleeding for 20 to 30 minutes daily. The patient reported initiation of ezetimibe-simvastatin as the only change in his treatment regimen in the past year. When he stopped ezetimibe-simvastatin, his epistaxis decreased. After six weeks without ezetimibe-simvastatin, he had only one moderate nose bleed. Four months later, the patient’s hemoglobin was stable. He then started simvastatin 40 mg monotherapy. The profound epistaxis returned and the patient discontinued the medication. It remains unclear whether the patient’s accelerated epistaxis was due to the combination therapy or the double dosage of simvastatin.

Hypersensitivity

Hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria have been reported. In addition, an apparent hypersensitivity syndrome has been reported rarely that has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.

Ezetimibe:

Postmarketing reports: Angioedema, anaphylaxis, rash, urticaria

Simvastatin:

Postmarketing reports: Hypersensitivity reactions

Nervous system

A case of memory loss possibly related to simvastatin use has been reported. The patient developed gradual memory loss following 12 months of simvastatin therapy. He was switched to pravastatin, and within a month his memory was intact. Rechallenge with simvastatin was not performed.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These reports have been generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

Ezetimibe-simvastatin:

Common (1% to 10%): Headache

Frequency not reported: Confusion, fatigue

Ezetimibe:

Postmarketing reports: Dizziness, paraesthesia

Simvastatin:

Frequency not reported: Cranial nerve dysfunction, tremor, vertigo, memory loss, paraesthesias, peripheral neuropathy, peripheral nerve palsy

Statins:

Postmarketing reports: Cognitive impairment

Ocular

Simvastatin:

Frequency not reported: Progression of cataracts, ophthalmoplegia

Oncologic

Simvastatin:

Frequency not reported: Liver, thyroid, and lung adenomas and carcinomas

Psychiatric

Simvastatin:

Frequency not reported: Depression, suicidal thoughts, delusions, paranoia, agitation, decreased libido, anxiety, insomnia

Metabolic

Simvastatin:

Frequency not reported: Increases in HbA1c and fasting serum glucose levels

Other

Ezetimibe:

Frequency not reported: Fatigue, asthenia

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Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Some side effects may not be reported. You may report them to the FDA.

Medical Disclaimer

Visit your doctor or health care professional for regular check-ups. You may need regular tests to make sure your liver is working properly.

Tell your doctor or health care professional right away if you get any unexplained muscle pain, tenderness, or weakness, especially if you also have a fever and tiredness. Your doctor or health care professional may tell you to stop taking this medicine if you develop muscle problems. If your muscle problems do not go away after stopping this medicine, contact your health care professional.

This medicine may affect blood sugar levels. If you have diabetes, check with your doctor or health care professional before you change your diet or the dose of your diabetic medicine.

This drug is only part of a total heart-health program. Your doctor or a dietician can suggest a low-cholesterol and low-fat diet to help. Avoid alcohol and smoking, and keep a proper exercise schedule.

Do not use this drug if you are pregnant or breast-feeding. Serious side effects to an unborn child or to an infant are possible. Talk to your doctor or pharmacist for more information.

If you are going to have surgery tell your health care professional that you are taking this drug.

Some drugs may increase the risk of side effects from this medicine. If you are given certain antibiotics or antifungals, your doctor or health care professional may stop this medicine for a short time. Check with your doctor or pharmacist for advice.

This medicine may cause a decrease in Co-Enzyme Q-10. You should make sure that you get enough Co-Enzyme Q-10 while you are taking this medicine. Discuss the foods you eat and the vitamins you take with your health care professional.

VYTORIN®

Ezetimibe/Simvastatin

Consumer Medicine Information

What is in this leaflet

This leaflet answers some common questions about VYTORIN. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking VYTORIN against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What VYTORIN is used for

VYTORIN helps to lower cholesterol and triglyceride levels. It is used in people whose cholesterol levels are too high and when diet alone cannot lower these levels adequately.

Cholesterol

Cholesterol is one of several fatty substances found in the bloodstream. Your total cholesterol is made up mainly of LDL and HDL cholesterol.

LDL cholesterol is often called ‘bad’ cholesterol because it can build up in the walls of your arteries forming plaque. Eventually this plaque build-up can lead to a narrowing of the arteries.

This narrowing can slow or block blood flow to vital organs such as the heart and brain. This blocking of blood flow can result in a heart attack or stroke.

HDL cholesterol is often called ‘good’ cholesterol because it helps keep the bad cholesterol from building up in the arteries and protects against heart disease.

Triglycerides

Triglycerides are another form of fat in your blood that may increase your risk for heart disease.

How VYTORIN works

VYTORIN reduces elevated total-cholesterol, LDL (bad) cholesterol and triglycerides and increases HDL (good) cholesterol.

VYTORIN works by decreasing the absorption of cholesterol in the small intestine and by reducing the amount of cholesterol made in the liver. VYTORIN does not help you lose weight.

If you have heart disease and a history of heart attack or hospitalisation for unstable angina (chest pain), VYTORIN reduces the risk of heart attack, stroke, surgery to increase heart blood flow, or hospitalisation for chest pain.

Your doctor may have prescribed VYTORIN for another reason. Ask your doctor if you have any questions about why VYTORIN has been prescribed for you.

VYTORIN is not addictive.

Use in Children and Adolescents

VYTORIN is used in children and adolescents (10 to 17 years of age) to treat familial hypercholesterolaemia, a type of high cholesterol that is hereditary (i.e. passed on through families).

VYTORIN is not recommended for use in children under 10 years of age, as there have been no studies of its effects in this age group.

Your doctor will assess whether VYTORIN is suitable for your child. Depending on the pubertal development of your child, VYTORIN may not be suitable for him or her.

Before you take VYTORIN

When you must not take it

Do not take VYTORIN if:

  • you have an allergy to VYTORIN or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include skin rash, itchiness, shortness of breath, swelling of the face, lips, mouth, tongue or throat.
  • you are pregnant or breast feeding.
    VYTORIN is contraindicated (i.e. should not be used) during pregnancy and breastfeeding. If you take this medicine during pregnancy and breastfeeding, your baby may absorb this medicine and it may affect your baby’s normal development causing foetal malformations (birth defects) or irreversible damage.
  • you have active liver disease or repeated blood tests indicating possible liver problems.
  • you have had muscle pain, tenderness or weakness from other medicines used to treat high cholesterol or triglycerides.
  • You are taking certain medicines such as gemfibrozil, ciclosporin, danazol, fusidic acid and strong CYP3A4 inhibitors like itraconazole and ketoconazole. Please see the section “Taking other medicines” in this CMI for more information.
  • the packaging is torn or shows signs of tampering.
  • the expiry date on the pack has passed.
    If you take this medicine after the expiry date has passed, it may not work.

If you are not sure whether you should start taking VYTORIN, talk to your doctor.

Before you start to take it

Tell your doctor if:

  1. you are pregnant or intend to become pregnant.

VYTORIN should not be used during pregnancy.

  1. you are breast-feeding.

VYTORIN should not be used while breast feeding.

  1. you have unexplained muscle pain, tenderness or weakness not caused by exercise. This is because on rare occasions, muscle problems can be serious, including muscle breakdown resulting in kidney damage that can lead to death.

Your doctor may do a blood test to check for certain muscle problems.

  1. you are Asian.
  2. you are taking niacin or a niacin-containing product.
  3. you have, or have had, any medical conditions, including liver disease or liver problems.

Your doctor will do a blood test to make sure you have no problems with your liver.

  1. you have kidney disease, diabetes or any other medical problems.
  2. you drink alcohol regularly.
  3. you have any allergies to any other medicines or any other substances, such as foods, preservatives or dyes.

If you have not told your doctor about any of the above, tell them before you take any VYTORIN.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines should not be taken with VYTORIN. These include:

  • nefazodone, used to treat depression
  • medicines containing cobicistat, a drug used in the treatment of HIV infection.
  • protease inhibitors, including indinavir, nelfinavir, ritonavir, saquinavir, used to treat HIV infection
  • certain hepatitis C virus protease inhibitors (such as boceprevir or telaprevir)
  • gemfibrozil, used to treat high cholesterol levels
  • ciclosporin, used to suppress the immune system
  • danazol
  • erythromycin, clarithromycin, telithromycin and fusidic acid, antibiotics used to treat infections
  • ketoconazole, itraconazole, posaconazole and voriconazole used to treat certain fungal infections

If you are taking any of the above, your doctor may suggest stopping VYTORIN temporarily or permanently.

Some medicines and VYTORIN may interfere with each other. These include:

  • Certain hepatitis C antiviral agents, such as elbasvir, or grazoprevir
  • bile acid sequestrants, such as cholestyramine, used to lower cholesterol levels.
  • other medicines to lower cholesterol levels, for example, other fibrates, nicotinic acid (also known as niacin).
  • Warfarin, fluindione, or other drugs used to prevent blood clots
  • colchicine, used for gout
  • verapamil, used to treat high blood pressure and angina
  • diltiazem, used to treat angina
  • amiodarone, used to treat irregular heart beat
  • amlodipine, used to treat high blood pressure and angina
  • digoxin, used to treat heart failure
  • lomitapide (a drug used to treat a serious and rare genetic cholesterol condition)
  • daptomycin, a drug used to treat complicated skin and skin structure infections and bacteraemia

These medicines may be affected by VYTORIN, may affect how well it works, or may increase the risk of side effects with VYTORIN. You may need different amounts of your medicine, or you may need to take different medicines or take your medicines at different times.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking VYTORIN.

You should also tell any doctor who is prescribing a new medication for you that you are taking VYTORIN.

How to take VYTORIN

How much to take

Take VYTORIN only when prescribed by your doctor.

The recommended dose in adults (18 years and over) is one VYTORIN 10/10, 10/20, 10/40 or 10/80 tablet once a day, in the evening. Your doctor will adjust your VYTORIN dose depending on your response.

The recommended dose in adolescents (10 to 17 years of age) with familial hypercholesterolaemia is one VYTORIN 10/10, 10/20 or 10/40 tablet once a day, in the evening. The maximum recommended dose in adolescents is 10/40 mg.

Because of the increased risk of muscle problems, the VYTORIN 10/80 tablet is only for patients at high risk of heart disease problems who have not yet reached their cholesterol goal on lower doses.

Swallow VYTORIN with a glass of water.

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor or pharmacist for help.

When to take it

VYTORIN should be taken once a day, in the evening.

The liver produces its greatest amount of cholesterol when the body is at rest and when there is no dietary intake. For most people this is at night when asleep. Therefore, VYTORIN is more effective when taken in the evening. A good time would be after your evening meal. However, it does not matter whether you take it before or after food.

However, take VYTORIN about the same time each day. Taking VYTORIN at the same time each day will have the best effect. It will also help you remember when to take your dose.

Your doctor may ask you to take VYTORIN with other cholesterol lowering agents such as bile acid sequestrants.

If you are taking a bile acid sequestrant, such as cholestyramine, take your VYTORIN either at least two hours before or four hours after taking the bile acid sequestrant.

How long to take it

VYTORIN helps lower your cholesterol. It does not cure your condition.

Therefore, you must continue to take it as directed by your doctor if you expect to lower your cholesterol and keep it down.

You may have to take cholesterol lowering medicine for the rest of your life. If you stop taking VYTORIN, your cholesterol levels may rise again.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, and then go back to taking your tablet as you would normally.

If you are not sure whether to skip the dose, talk to your doctor or pharmacist.

Do not take a double dose to make up for the dose that you missed.

If you have trouble remembering to take your tablet, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26), or go to accident and emergency at your nearest hospital, if you think that you or anyone else may have taken too much VYTORIN. Do this even if there are no signs of discomfort or poisoning.

While you are using VYTORIN

Things you must do

If you become pregnant while taking VYTORIN, stop taking it and tell your doctor immediately.

Have your blood fats checked when your doctor says, to make sure VYTORIN is working. Even if you are taking medicines to treat high cholesterol, it is important to have your cholesterol measured regularly. You should also know your cholesterol levels and goals.

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking VYTORIN.

If you are about to have elective surgery, tell your doctor that you are taking VYTORIN. Your doctor may suggest stopping the tablets a few days before surgery.

Things you must not do

Do not give VYTORIN to anyone else, even if they have the same condition as you.

Things to be careful of

Avoid drinking large quantities of alcohol. Drinking large quantities of alcohol may increase your chance of VYTORIN causing liver problems.

Grapefruit juice should be avoided while taking VYTORIN. Grapefruit juice contains one or more components that alter the metabolism of some medicines, including VYTORIN.

Be careful driving or operating machinery until you know how VYTORIN affects you. There have been side effects reported with VYTORIN that may affect your ability to drive or operate machinery. Individual responses to VYTORIN may vary.

High cholesterol can be treated in two main ways:

Lifestyle Changes –
this includes a cholesterol-lowering diet, increasing physical activity, and weight management. Ask your doctor for advice before increasing physical activity.

Medicines –
cholesterol-lowering medicines are used together with lifestyle changes to help lower cholesterol.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking VYTORIN.

VYTORIN helps most people with high cholesterol, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor immediately or go to accident and emergency at your nearest hospital, if you notice any of the following:

  • swelling of the face, lips, mouth, throat or tongue which may cause difficulty in swallowing or breathing

These are serious side effects. If you have them, you may have had a serious allergic reaction to VYTORIN. You may need urgent medical attention or hospitalisation. Serious side effects are rare.

Tell your doctor immediately if you notice any of the following:

  • skin rash and hives
  • raised red rash, sometimes with target-shaped lesions
  • dark coloured urine
  • light coloured bowel motions
  • joint pain
  • bleeding or bruising more easily than normal
  • steady abdominal pain with nausea and vomiting.

These may be serious side effects. You may need urgent medical attention. Serious side effects are rare.

Liver problems can also occur and may be serious. Your doctor may do blood tests to check your liver

Tell your doctor immediately if you notice any of the following symptoms of liver problems:

  • feel tired or weak
  • loss of appetite
  • upper belly pain
  • dark urine
  • yellowing of the skin or the white of your eyes.

Tell your doctor immediately if you notice the following:

  • unexplained muscle aches, tenderness or weakness, not caused by exercise (in very rare cases this may not go away after stopping VYTORIN).

This may be a serious side effect. This is because on rare occasions, muscle problems can be serious, including muscle breakdown resulting in kidney damage that can lead to death. You may need urgent medical attention.

The risk of muscle breakdown is greater at higher doses of VYTORIN, particularly the 10/80 mg dose.

The risk of muscle breakdown is also greater for older patients (65 years of age and older), female patients, patients with kidney problems, and patients with thyroid problems.

Serious side effects are rare.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice any other effects.

Tell your doctor if you notice any of the following:

  • Headache
  • Nausea
  • Muscle aches
  • Dizziness
  • Feeling tired
  • Cough
  • Stomach irritation
  • Diarrhoea
  • Decreased appetite
  • Hot flush
  • Hypertension
  • Pain

These are the more common side effects of VYTORIN or of either ezetimibe or simvastatin.

Tell your doctor if you notice any of the following:

  • Depression
  • Tingling or numbness of the hands or feet
  • Trouble sleeping
  • Poor memory
  • Confusion
  • Erectile dysfunction
  • Breathing problems including persistent cough and/or shortness of breath, that may also occur with fatigue, unexplained weight loss or fever

These are rare side effects of ezetimibe or simvastatin.

In adolescent patients (10 to 17 years of age) there have been no studies longer than 1 year of the effect of taking VYTORIN on bone development, growth, social and emotional development, or fertility.

Do not be alarmed by these lists of possible side effects. You may not experience any of them.

After using VYTORIN

Storage

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the blister pack they may not keep well.

Keep VYTORIN in a cool dry place where the temperature stays below 25°C. Do not store it or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking VYTORIN or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

VYTORIN comes in four types of tablets:

  • VYTORIN 10/10 – 10mg Ezetimibe/10mg Simvastatin: White to off-white, capsule shaped, biconvex compressed tablet marked with “311”.
  • VYTORIN 10/20 – 10mg Ezetimibe/ 20mg Simvastatin: White to off-white, capsule shaped, biconvex compressed tablet marked with “312”.
  • VYTORIN 10/40 – 10mg Ezetimibe/ 40mg Simvastatin: White to off-white, capsule shaped, biconvex compressed tablet marked with “313”.
  • VYTORIN 10/80 – 10mg Ezetimibe/ 80mg Simvastatin: White to off-white, capsule shaped, biconvex compressed tablet marked with “315”.

A starter pack of VYTORIN contains 5 or 10 tablets. A trade pack contains 30 tablets.

Ingredients

Active ingredient:

VYTORIN 10/10 –
10mg ezetimibe/10mg simvastatin per tablet

VYTORIN 10/20 –
10mg ezetimibe/20mg simvastatin per tablet

VYTORIN 10/40 –
10mg ezetimibe/ 40mg simvastatin per tablet

VYTORIN 10/80 –
10mg ezetimibe/ 80mg simvastatin per tablet

Inactive ingredients:

  • butylated hydroxyanisole
  • citric acid monohydrate
  • croscarmellose sodium
  • hypromellose
  • lactose monohydrate
  • magnesium stearate
  • microcrystalline cellulose
  • propyl gallate

VYTORIN does not contain gluten, sucrose, tartrazine or any other azo dyes.

Supplier

VYTORIN is supplied in Australia by:

Merck Sharp & Dohme (Australia) Pty Limited
A.B.N 14000 173 508
Level 1, Building A
26 Talavera Road
MACQUARIE PARK NSW 2113

This leaflet was prepared in March 2019.

This CMI leaflet was current at the time of printing. To check if it has been updated, please view our website, www.msdinfo.com.au/vytorincmi, or ask your pharmacist.

Australian Register Number:

VYTORIN 10/10 – AUST R 98100

VYTORIN 10/20 – AUST R 98111

VYTORIN 10/40 – AUST R 98115

VYTORIN 10/80 – AUST R 98117

S-WPPI-MK0653A-T-122018
VYTORIN PI A190322 v16

Published by MIMS May 2019

Cholesterol drug Vytorin may actually work, new data shows


FILE – This 2004 file photo provided by Schering-Plough Corp. shows the cholesterol-lowering drug Vytorin. (AP Photo/Schering-Plough Corp., File) By Ariana Eunjung ChaAriana Eunjung Cha National reporter November 17, 2014

Dismissed by some cardiologists as an expensive placebo several years ago, the cholesterol-lowering pill Vytorin may be poised for a comeback.

Researchers at the American Heart Association meeting on Monday in Chicago presented data from an randomized, double-blind study of 18,144 high-risk patients that found that patients taking Vytorin — a combination of the cholesterol-lowering statin Zocor plus Zetia, a non-statin — experienced fewer heart attacks, strokes and repeat hospitalizations than those taking just statins.

The results, which have not yet been peer-reviewed, could dramatically alter the landscape for the multi-billion-dollar cholesterol drug industry. The American Heart Association and the American College of Cardiologists currently only recommend statins.

Statins, which lower the amount of LDL or bad cholesterol in the blood, are considered a kind of miracle drug in modern medicine. Among the most widely prescribed in the world, they are often able to lower a person’s cholesterol to very low levels with few noticeable side effects. But they don’t work for everyone and some can’t tolerate a full dose — they can cause muscle pain, digestive issues and liver damage — and until now there haven’t been any good alternatives.

Statins work by reducing the cholesterol made in the liver while Zetia or ezetimibe work by blocking absorption of the cholesterol.

The difference between the statin and combination therapy was modest, but significant. The study, which was funded by Merck and conducted at multiple centers around the world, followed patients for an average of six years after a hospitalization and found a 6.4 percent reduction in relative risk of a repeat incident between taking just statins and taking both drugs and that the side effects reported were lower than those for statins.

Vytorin has been among the most controversial drugs in the cardiovascular world. After the drug’s developers — Merck and Schering-Plough — were accused of suppressing negative data in 2007-2008, prescriptions fell and the companies’ stock prices plunged. Merck, which admitted no wrongdoing, paid $688 million to settle lawsuits from shareholders regarding the controversy.

Some researchers who were not involved in the study said back then that they wondered whether Vytorin and Zetia lowered cholesterol but did not reduce heart attacks or strokes. The results released Monday appeared to indicate that bringing a patient’s cholesterol lower does appear to reduce heart incidents.

Merck says it plans to submit the data to the Food and Drug Administration in mid-2015 to get approval to market the drug for reducing major cardiovascular events.

Why you should stop taking Vytorin for high cholesterol

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At the American Heart Association meeting in Orlando, the results of the ARBITER 6-HALTS study were released. No Vytorin was used in the study, but I am sure that all the headlines will mention Vytorin.

The actual study published ahead of press online in the New England Journal of Medicine. Essentially, they enrolled over 200 patients from Walter Reed and Washington Adventist who had known heart disease or were at very high risk. These patients were already on a stable dose of a statin (40-50% on simvastatin – half of the Vytorin combination, and 40-50% on Lipitor) with an LDL cholesterol (bad cholesterol) under 100 and HDL (good cholesterol) under 50 for men/55 for women. These patients were randomized to receive either Zetia (the other half of Vytorin) or niacin (though you can get this vitamin over the counter, patients received the extended release prescription version, whose maker is also the sponsor of the study).

They were looking to see whether or not there would be difference in progression of atherosclerosis (clogging of the arteries) over 14 months as measured by carotid intima-medial thickness (CIMT), and ultrasound of the neck arteries which seems to be a good measure of plaque buildup in the coronary or heart arteries. News broke earlier this year that the study was stopped early because there was a clear winner, but we didn’t know which drug won until now.

Patients who got the niacin had their good cholesterol raised by close to 20%. bad cholesterol lowered by close to 10%. The Zetia group lowered bad cholesterol by close to 20% but also lowered the good cholesterol too. More importantly, those patients taking the niacin had a reduction in the plaque buildup, whereas patients taking the Zetia had no change in plaque build up. Surprisingly, and inexplicably, the more Zetia lowered your cholesterol, the more plaque build up patients had. Finally, and most importantly, only 1% of patients in the niacin group had major cardiovascular events, compared to 4% in the Zetia groups. This was statistically significant.

This trial has broader implications than just the Vytorin issue. It suggests that patients at high risk for cardiovascular disease may have additional benefit beyond lowering their bad cholesterol. Though the addition of niacin was proven to show benefit, it might be possible that other drugs which raise HDL such as fish oil and fenofibrate (Trilipix) might benefit at risk patients as well.

I have posted extensively on Vytorin in the past. Most of the controversy had to do with the ENHANCE trial which I discussed in my post Vytorin and Zetia: What to do now?

Briefly, whereas multiple statin trials have shown that lowering LDL with a statin led to decreased heart attacks and stroke, Vytorin only had data showing it lowered the LDL. Merck, the makers of Zocor (simvastatin), Zetia, and Vytorin (Zocor + Zetia) funded a trial that, similar to the HALT study, looked at CIMT to measure plaque buildup. It compared simvastatin to the same dose of simvastatin plus Zetia, or Vytorin. Though Vytorin lowered cholesterol more that the simvastatin alone, there was no difference in plaque buildup.

Defenders of Vytorin said that ENHANCE was not an outcome study (designed to study actual heart attacks and strokes) and that there were no differences in outcomes between the two groups. Though the HALT study was also not designed as an outcome study, findings were consistent AND there was a difference in heart attacks and strokes: about triple the number in the Vytorin group.

My initial recommendation was that though Vytorin was really useless, if patients couldn’t reach their goal with a potent statin or couldn’t tolerate the statin, then using or adding Zetia was reasonable. This is probably still the case. However, in the HALT study differences were seen in HDL (went up for niacin and down for Zetia), and this may account for some of the difference. For patients whose HDL was low, I will probably be a little more cautious of using or adding Zetia, which may make their HDL go down in addition to their LDL.

There is no good use for Vytorin, and it may even cause harm, not because of safety, but because the LDL goals achieved with Vytorin may lead to fewer heart attacks that could be prevented with a more potent statin. If you are on Vytorin, ask you doctor about considering a switch.

Matthew Mintz is an internal medicine physician and blogs at Dr. Mintz’ Blog.

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