Side Effects of Vytorin (ezetimibe and simvastatin)

Vytorin (ezetimibe and simvastatin) is a combination of a lipid-lowering compound and an HMG-CoA reductase inhibitor (a statin) used to treat high levels of cholesterol in the blood. 

Vytorin reduces total cholesterol and low-density lipoprotein (LDL or "bad") cholesterol while it increases high-density lipoprotein (HDL or "good") cholesterol. The ezetimibe component of Vytorin lowers blood cholesterol by blocking the absorption of cholesterol, including dietary cholesterol, from the intestine. 

It does not affect the absorption of triglycerides. The simvastatin component of Vytorin is a statin that reduces cholesterol by blocking an enzyme in the liver (HMG-CoA reductase) that produces cholesterol. Statins lower total and LDL cholesterol in the blood as well as triglycerides. 

They also increase HDL cholesterol. LDL cholesterol is believed to be an important cause of coronary artery disease. Lowering LDL cholesterol levels slows and may even reverse coronary artery disease. Raising HDL cholesterol levels also may slow coronary artery disease.

Common side effects of Vytorin include

• headache,
• nausea,
• vomiting,
• diarrhea,
• muscle pain, and
• abnormal liver tests.

Serious side effects of Vytorin include

• hypersensitivity reactions,
• liver damage,
• muscle inflammation or breakdown (rhabdomyolysis) that can cause kidney failure and even death,
• increases in HbA1c and fasting serum glucose levels that are seen in diabetes,
• memory loss,
• forgetfulness,
• amnesia,
• confusion, and
• memory impairment. 

Drug interactions of Vytorin include drugs that decrease its elimination such as erythromycin, ketoconazole, itraconazole, clarithromycin, telithromycin, cyclosporine, nefazodone, boceprevir, telaprevir, voriconazole, posaconazole, and HIV protease inhibitors such as indinavir and ritonavir.

• Large quantities of grapefruit juice (more than 1 quart daily) also will increase blood levels of simvastatin and should be avoided.
• Amiodarone, verapamil, diltiazem, amlodipine, danazol, ranolazine, cyclosporine, niacin, gemfibrozil, and fenofibrate also may increase the risk of muscle toxicity when combined with simvastatin.
• Patients taking amiodarone, amlodipine, or ranolazine should not exceed 10/20 mg, and those taking verapamil or diltiazem should not exceed 10/10 mg of of Vytorin daily.
• Patients taking gemfibrozil or danazol should not take Vytorin. Simvastatin increases the effect of warfarin and the blood concentration of digoxin.
• Patients taking simvastatin and warfarin or digoxin should be monitored carefully.
• Cholestyramine decreases the absorption of ezetimibe, and, therefore, Vytorin should be administered two hours before or at least four hours after cholestyramine is administered.
• Chinese patients taking more than 1 gram of niacin daily in combination with simvastatin, 40 mg, have an increased risk of muscle-related side effects.
• Therefore, these patients should not receive Vytorin 10/80 mg combined with niacin doses greater than 1 gram daily. Other doses of Vytorin should be administered cautiously when combined with niacin, 1 gram daily. 

Vytorin should not be taken during pregnancy because the developing fetus requires cholesterol for development, and Vytorin, due to the simvastatin component, reduces the production of cholesterol. Vytorin should only be administered to women of child bearing age if they are not likely to become pregnant. 

Because of the risk of adverse effects to the developing infant, Vytorin should not be administered to breastfeeding mothers.

The most common side effects of Vytorin are:

• headache,
• nausea,
• vomiting,
• diarrhea,
• muscle pain, and
• abnormal liver tests.

Hypersensitivity reactions also have been reported. The most serious potential side effects are liver damage and muscle inflammation or breakdown. The simvastatin component of Vytorin is a statin.

• Therefore it shares side effects, such as liver and muscle damage associated with statins. Serious liver damage caused by statins is rare.
• More often, statins cause abnormalities of liver tests, and, therefore, periodic measurement of liver tests in the blood is recommended for all statins.
• Abnormal tests usually return to normal even if a statin is continued, but if the abnormal test value is greater than three times the upper limit of normal, the statin usually is stopped.
• Liver tests should be measured before Vytorin is started and periodically thereafter or if there is a medical concern about liver damage.
• Inflammation of the muscles caused by statins can lead to a serious breakdown of muscle cells called rhabdomyolysis.
• Rhabdomyolysis causes the release of muscle protein (myoglobin) into the blood. Myoglobin can cause kidney failure and even death.
• When used alone, statins cause rhabdomyolysis in less than one percent of patients.
• To prevent the development of rhabdomyolysis, patients taking Vytorin should contact their health care professional immediately if they develop unexplained muscle pain, weakness, or muscle tenderness.
• Statins have been associated with increases in HbA1c and fasting serum glucose levels that are seen in diabetes.
• There are also post-marketing reports of memory loss, forgetfulness, amnesia, confusion, and memory impairment.
• Symptoms may start 1 day to years after starting treatment and resolve within a median of 3 weeks after stopping the statin.

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%)

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 tractinfection (3.6%), and
• diarrhea (2.8%).

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

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 [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day.
• The incidence 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 ?-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).

Strong CYP3A4 Inhibitors, Cyclosporine, Or Danazol

Strong CYP3A4 inhibitors

• The risk of myopathy is increased by reducing the elimination of the simvastatin component of Vytorin.
• Hence when Vytorin is used with an inhibitor of CYP3A4 (e.g., aslisted below), elevated plasma levels of HMG-CoA reductase inhibitory activity increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of Vytorin.
• Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated.
• If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable,therapy with Vytorin must be suspended during the course of treatment.

Cyclosporine Or Danazol

• The risk of myopathy, including rhabdomyolysis is increased by concomitantadministration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated.

Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone

Gemfibrozil

• Contraindicated with Vytorin.

Fenofibrates (e.g., fenofibrate and fenofibric acid)

• Caution should be used when prescribing with Vytorin.

Amiodarone, Dronedarone, Ranolazine, Or Calcium Channel Blockers

• The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amiodarone, dronedarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem or amlodipine.

Niacin

• Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (=1 g/day niacin) of niacin-containing products. The risk of myopathy is greater in Chinese patients.
• In a clinical trial (median follow-up 3.9 years) involving patients at high risk of cardiovascular disease and with well-controlled LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg/day, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses (=1 g/day) of niacin.
• Coadministration of Vytorin with lipid-modifying doses (=1g/day) of niacin is not recommended in Chinese patients. It is unknown if this risk applies to other Asian patients.

Cholestyramine

• Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately55%. The incremental LDL-C reduction due to adding Vytorin to cholestyramine may be reduced by thisinteraction.

Digoxin

• In one study, concomitant administration of digoxin with simvastatin resulted in a slight elevation in plasma digoxin concentrations. Patients taking digoxin should be monitored appropriately when Vytorin is initiated.

Fenofibrates(e.g., fenofibrate and fenofibric acid)

• The safety and effectiveness of Vytorin administered with fibrates have not been established.
• Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors isincreased with concurrent administration of fenofibrates, Vytorin should be administered with caution when used concomitantly with a fenofibrate.
• Fenofibrates may increase cholesterol excretion into the bile, leading to cholelithiasis.
• In a preclinicalstudy in dogs, ezetimibe increased cholesterol in the gallbladder bile.
• If cholelithiasis is suspected in a patient receiving Vytorin and a fenofibrate,gallbladder studies are indicated and alternative lipid-lowering therapy should be considered [see the product labeling for fenofibrate and fenofibric acid].

Coumarin Anticoagulants

• Simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in a normal volunteer studyand in a hypercholesterolemic patient study, respectively.
• With otherstatins, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly.
• In such patients, prothrombin time should be determined before starting Vytorin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs.
• Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants.
• If the dose ofVytorin is changed or discontinued, the same procedure should be repeated.
• Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
• Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailabilityof warfarin and prothrombin time in a study of twelve healthy adult males.
• There have been postmarketing reports of increased INR in patients who had ezetimibe added to warfarin. Most of these patients were also on other medications.
• The effect of Vytorin on the prothrombin time has not been studied.

Colchicine

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