EZETIMIBE: 13,117 Adverse Event Reports & Safety Profile

Ezetimibe and simvastatin tablets contain ezetimibe USP, a selective inhibitor of intestinal cholesterol and related phytosterol absorption, and simvastatin USP, an HMG-CoA reductase inhibitor. The chemical name of ezetimibe, USP is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. The molecular formula is C 24 H 21 F 2 NO 3 and its molecular weight is 409.4. Ezetimibe, USP is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water. Its structural formula is: Simvastatin, USP, an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form, which is an inhibitor of HMG-CoA reductase. Simvastatin, USP is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2 H -pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1 S -[1α,3α,7β,8β(2 S *,4 S *),-8aβ]]. The molecular formula of simvastatin, USP is C 25 H 38 O 5 and its molecular weight is 418.57. Simvastatin, USP is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water and freely soluble in chloroform, methanol and ethanol. Its structural formula is: Ezetimibe and simvastatin is available for oral use as tablets containing 10 mg of ezetimibe USP, and 10 mg of simvastatin, USP (ezetimibe and simvastatin tablets 10 mg/10 mg), 20 mg of simvastatin, USP (ezetimibe and simvastatin tablets 10 mg/20 mg), 40 mg of simvastatin, USP (ezetimibe and simvastatin tablets 10 mg/40 mg), or 80 mg of simvastatin, USP (ezetimibe and simvastatin tablets 10 mg/80 mg). Each tablet contains the following inactive ingredients: ascorbic acid, butylated hydroxyanisole, citric acid anhydrous, croscarmellose sodium, hypromellose, iron oxide black, iron oxide red, iron oxide yellow, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and propyl gallate. formula 1 formula 2

AND USAGE Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. Ezetimibe tablet is an inhibitor of intestinal cholesterol (and related phytosterol) absorption indicated as an adjunct to diet to: 5. Reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with primary hyperlipidemia, alone or in combination with an HMG-CoA reductase inhibitor (statin) ( 1.1 ) 6. Reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia in combination with fenofibrate ( 1.1 ) 7. Reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), in combination with atorvastatin or simvastatin ( 1.2 ) 8. Reduce elevated sitosterol and campesterol in patients with homozygous sitosterolemia (phytosterolemia) ( 1.3 ) Limitations of Use ( 1.4 ) 3. The effect of ezetimibe tablets on cardiovascular morbidity and mortality has not been determined. 4. Ezetimibe tablets have not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.

1.1 Primary Hyperlipidemia Monotherapy Ezetimibe tablets, administered alone, are indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia.

Combination

Therapy with HMG-CoA Reductase Inhibitors (Statins) Ezetimibe tablets, administered in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin), are indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with primary (heterozygous familial and non-familial) hyperlipidemia.

Combination

Therapy with Fenofibrate Ezetimibe tablets, administered in combination with fenofibrate, are indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-HDL-C in adult patients with mixed hyperlipidemia.

1.2 Homozygous Familial Hypercholesterolemia (HoFH) The combination of ezetimibe and atorvastatin or simvastatin is indicated for the reduction of elevated total-C and LDL-C levels in patients with HoFH, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.

1.3 Homozygous Sitosterolemia Ezetimibe tablets are indicated as adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia.

1.4 Limitations of Use The effect of ezetimibe tablets on cardiovascular morbidity and mortality has not been determined. Ezetimibe tablets have not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.

AND ADMINISTRATION

• Dose range is 10/10 mg/day to 10/40 mg/day. ( 2.1 )
• Recommended usual starting dose is 10/10 or 10/20 mg/day. ( 2.1 )
• Due to the increased risk of myopathy, including rhabdomyolysis, use of the 10/80 mg dose of ezetimibe and simvastatin tablets should be restricted to patients who have been taking ezetimibe and simvastatin tablets 10/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. ( 2.2 )
• Patients who are currently tolerating the 10/80 mg dose of ezetimibe and simvastatin tablets who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin or statin-based regimen with less potential for the drug-drug interaction. ( 2.2 )
• Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 10/80 mg dose of ezetimibe and simvastatin tablets, patients unable to achieve their LDL-C goal utilizing the 10/40 mg dose of ezetimibe and simvastatin tablets should not be titrated to the 10/80 mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering. ( 2.2 )
• Dosing of ezetimibe and simvastatin tablets should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant. ( 2.3 , Error! Hyperlink reference not valid. )

2.1 Recommended Dosing The usual dosage range is 10/10 mg/day to 10/40 mg/day. The recommended usual starting dose is 10/10 mg/day or 10/20 mg/day. Ezetimibe and simvastatin tablets should be taken as a single daily dose in the evening, with or without food. Patients who require a larger reduction in LDL-C (greater than 55%) may be started at 10/40 mg/day in the absence of moderate to severe renal impairment (estimated glomerular filtration rate less than 60 mL/min/1.73 m 2 ). After initiation or titration of ezetimibe and simvastatin tablets, lipid levels may be analyzed after 2 or more weeks and dosage adjusted, if needed.

2.2 Restricted Dosing for 10/80 mg Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 10/80 mg dose of ezetimibe and simvastatin tablets should be restricted to patients who have been taking ezetimibe and simvastatin tablets 10/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> . Patients who are currently tolerating the 10/80 mg dose of ezetimibe and simvastatin tablets who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin or statin-based regimen with less potential for the drug-drug interaction. Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 10/80 mg dose of ezetimibe and simvastatin tablets, patients unable to achieve their LDL-C goal utilizing the 10/40 mg dose of ezetimibe and simvastatin tablets should not be titrated to the 10/80 mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering.

2.3 Coadministration with Other Drugs Patients taking Verapamil, Diltiazem, or Dronedarone

• The dose of ezetimibe and simvastatin tablets should not exceed 10/10 mg/day [see Warnings and Precautions ( 5.1 ), Drug Interactions ( Error! Hyperlink reference not valid. ), and Clinical Pharmacology ( 12.3 )]. Patients taking Amiodarone, Amlodipine or Ranolazine
• The dose of ezetimibe and simvastatin tablets should not exceed 10/20 mg/day [see Warnings and Precautions ( 5.1 ), Drug Interactions ( Error! Hyperlink reference not valid. ), and Clinical Pharmacology ( 12.3 )]. Patients taking Bile Acid Sequestrants
• Dosing of ezetimibe and simvastatin tablets should occur either greater than or equal to 2 hours before or greater than or equal to 4 hours after administration of a bile acid sequestrant [see Drug Interactions ( Error! Hyperlink reference not valid. )].

2.4 Patients with Homozygous Familial Hypercholesterolemia The recommended dosage for patients with homozygous familial hypercholesterolemia is ezetimibe and simvastatin tablets 10/40 mg/day in the evening <span class="opacity-50 text-xs">[see Dosage and Administration, Restricted Dosing for 10/80 mg ( 2.2 )]</span> . Ezetimibe and simvastatin tablets should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable. Simvastatin exposure is approximately doubled with concomitant use of lomitapide; therefore, the dose of ezetimibe and simvastatin tablets should be reduced by 50% if initiating lomitapide. Ezetimibe and simvastatin tablets dosage should not exceed 10/20 mg/day (or 10/40 mg/day for patients who have previously taken simvastatin 80 mg/day chronically, e.g., for 12 months or more, without evidence of muscle toxicity) while taking lomitapide.

2.5 Patients with Renal Impairment/Chronic Kidney Disease In patients with mild renal impairment (estimated GFR greater than or equal to 60 mL/min/1.73 m 2 ), no dosage adjustment is necessary. In patients with chronic kidney disease and estimated glomerular filtration rate less than 60 mL/min/1.73 m 2 , the dose of ezetimibe and simvastatin tablets is 10/20 mg/day in the evening. In such patients, higher doses should be used with caution and close monitoring <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 ); Clinical Pharmacology ( 12.3 )]</span>.

2.6 Geriatric Patients No dosage adjustment is necessary in geriatric patients <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>.

Ezetimibe and simvastatin tablets are contraindicated in the following conditions:

• Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing products) [see Warnings and Precautions ( 5.1 )].
• Concomitant administration of gemfibrozil, cyclosporine, or danazol [see Warnings and Precautions ( 5.1 )].
• Hypersensitivity to any component of this medication [see Adverse Reactions ( Error! Hyperlink reference not valid. )].
• Active liver disease or unexplained persistent elevations in hepatic transaminase levels [see Warnings and Precautions ( 5.3 )].
• Women who are pregnant or may become pregnant . Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins), such as simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ezetimibe and simvastatin may cause fetal harm when administered to a pregnant woman. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of ezetimibe and simvastatin use during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. Ezetimibe and simvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, ezetimibe and simvastatin should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations ( 8.1 )].
• Nursing mothers. It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require ezetimibe and simvastatin treatment should not breastfeed their infants [see Use in Specific Populations ( Error! Hyperlink reference not valid. )].
• Concomitant administration of strong CYP3A4 inhibitors. ( 4 , 5.1 )
• Concomitant administration of gemfibrozil, cyclosporine, or danazol. ( 4 , 5.1 )
• Hypersensitivity to any component of this medication ( 4 , Error! Hyperlink reference not valid. )
• Active liver disease or unexplained persistent elevations of hepatic transaminase levels ( 4 , 5.3 )
• Women who are pregnant or may become pregnant ( 4 , 8.1 )
• Nursing mothers ( 4 , Error! Hyperlink reference not valid. )

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

• Rhabdomyolysis and myopathy [see Warnings and Precautions ( 5.1 )]
• Liver enzyme abnormalities [see Warnings and Precautions ( 5.3 )]
• Common (incidence ≥2% and greater than placebo) adverse reactions in clinical trials: headache, increased ALT, myalgia, upper respiratory tract infection, and diarrhea. ( Error! Hyperlink reference not valid. ) To report SUSPECTED ADVERSE REACTIONS, contact NorthStar RxLLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Ezetimibe and Simvastatin Tablets Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the ezetimibe and simvastatin tablets placebo-controlled clinical trials database of 1420 patients (age range 20 to 83 years, 52% women, 87% Caucasians, 3% Blacks, 5% Hispanics, 3% Asians) with a median treatment duration of 27 weeks, 5% of patients on ezetimibe and simvastatin tablets and 2.2% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group treated with ezetimibe and simvastatin tablets that led to treatment discontinuation and occurred at a rate greater than placebo were:

• Increased ALT (0.9%)
• Myalgia (0.6%)
• Increased AST (0.4%)
• 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 tract infection (3.6%), and diarrhea (2.8%). Ezetimibe and simvastatin tablets have 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 ezetimibe and simvastatin tablets (n=1420) and at an incidence greater than placebo, regardless of causality assessment, from four placebo-controlled trials.

Table

2*: Clinical Adverse Reactions Occurring in ≥2% of Patients Treated with Ezetimibe and Simvastatin Tablets and at an Incidence Greater than Placebo, Regardless of Causality Body System/Organ Class Adverse Reaction Placebo (%) n=371 Ezetimibe 10 mg (%) n=302 Simvastatin † (%) n=1234 Ezetimibe and Simvastatin Tablets † (%) n=1420 Body as a whole – general disorders Headache 5.4 6 5.9

5.8 Gastrointestinal system disorders Diarrhea 2.2 5 3.7

2.8 Infections and infestations Influenza 0.8 1 1.9

2.3 Upper respiratory tract infection 2.7 5 5

3.6 Musculoskeletal and connective tissue disorders Myalgia 2.4 2.3 2.6

3.6 Pain in extremity 1.3 3 2 2.3 * Includes two placebo-controlled combination studies in which the active ingredients equivalent to ezetimibe and simvastatin tablets were coadministered and two placebo-controlled studies in which ezetimibe and simvastatin tablets was administered. † All doses. Study of Heart and Renal Protection In SHARP , 9270 patients were allocated to ezetimibe and simvastatin tablets 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 study treatment as a result of either an adverse event or abnormal safety blood result was 10.4% vs. 9.8% among patients allocated to ezetimibe and simvastatin tablets and placebo, respectively. Comparing those allocated to ezetimibe and simvastatin tablets vs. placebo, the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum CK &gt;10 times ULN) was 0.2% vs. 0.1% and the incidence of rhabdomyolysis (defined as myopathy with a CK &gt;40 times ULN) was 0.09% vs. 0.02%, respectively. Consecutive elevations of transaminases (&gt;3 X ULN) occurred in 0.7% vs. 0.6%, respectively. Patients were asked about the occurrence of unexplained muscle pain or weakness at each study visit: 21.5% vs. 20.9% patients ever reported muscle symptoms in the ezetimibe and simvastatin tablets and placebo groups, respectively. Cancer was diagnosed during the trial in 9.4% vs. 9.5% of patients assigned to ezetimibe and simvastatin tablets 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 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. 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 [see Warnings and Precautions ( 5.3 )] . 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 [see Warnings and Precautions ( 5.1 )] .

6.2 Postmarketing Experience Because the below reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been reported in postmarketing experience for ezetimibe and simvastatin tablets or ezetimibe 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> ; hepatitis/jaundice; fatal and non-fatal hepatic failure; depression; cholelithiasis; cholecystitis; thrombocytopenia; elevations in liver transaminases; elevated creatine phosphokinase. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> . 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. 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).

AND PRECAUTIONS Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, with the 10 mg/80 mg dose. ( 5.1 ) Patients should be advised to report promptly any unexplained and/or persistent muscle pain, tenderness, or weakness. Ezetimibe and simvastatin tablets should be discontinued immediately if myopathy is diagnosed or suspected. ( 5.1 ). Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with higher doses and concomitant use of certain medicines. Predisposing factors include advanced age (≥65), female gender, uncontrolled hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. ( 4 , 5.1 , 8.5 , 8.6 ). Immune-Mediated Necrotizing Myopathy (IMNM): There have been rare reports of 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; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. ( 5.2 ). Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter. ( 5.3 )

5.1 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 elevated plasma levels of simvastatin and simvastatin acid. Predisposing factors for myopathy include advanced age (≥ 65 years), female gender, uncontrolled hypothyroidism, and renal impairment. Chinese patients may be at increased risk for myopathy <span class="opacity-50 text-xs">[see Use in Specific Populations (8.8) ]</span> 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 [CK] &gt; 10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK &gt; 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 mg/80 mg dose of ezetimibe and simvastatin tablets should be used only in patients who have been taking ezetimibe and simvastatin tablets 10 mg/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [ see Dosage and Administration, Restricted Dosing for 10 mg/80 mg ( 2.2 ) ]. If, however, a patient who is currently tolerating the 10 mg/80 mg dose of ezetimibe and simvastatin tablets 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 [ see Warnings and Precautions ( 5.2 ) ]. In the Study of Heart and Renal Protection (SHARP), 9,270 patients with chronic kidney disease were allocated to receive ezetimibe and simvastatin tablets 10 mg/20 mg daily (n = 4,650) or placebo (n = 4,620). During a median follow-up period of 4.9 years, the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] &gt; 10 times upper limit of normal [ULN]) was 0.2% for ezetimibe and simvastatin and 0.1% for placebo: the incidence of rhabdomyolysis (defined as myopathy with a CK &gt; 40 times ULN) was 0.09% for ezetimibe and simvastatin 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. Ezetimibe and simvastatin tablets and a fenofibrate, if taking concomitantly, should both be immediately discontinued if myopathy is diagnosed or suspected. All patients starting therapy with ezetimibe and simvastatin tablets or whose dose of ezetimibe and simvastatin tablets 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 ezetimibe and simvastatin tablets. Ezetimibe and simvastatin tablet 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 ezetimibe and simvastatin tablets or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy. Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients taking ezetimibe and simvastatin tablets merit closer monitoring. Ezetimibe and simvastatin tablet therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Ezetimibe and simvastatin tablet 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 [see Clinical Pharmacology ( 12.3 ) ]. Combination of these drugs with ezetimibe and simvastatin tablets is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with ezetimibe and simvastatin tablets must be suspended during the course of treatment [ see Contraindications ( 4 ) and Drug Interactions ( 7 ) ]. The combined use of ezetimibe and simvastatin tablets with gemfibrozil, cyclosporine, or danazol is contraindicated [ see Contraindications ( 4 ) and Drug Interactions ( 7.1 and 7.2 ) ]. Caution should be used when prescribing fenofibrates with ezetimibe and simvastatin tablets, as these agents can cause myopathy when given alone and the risk is increased when they are coadministered [ see Drug Interactions ( 7.2 , 7.7 ) ]. Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing ezetimibe and simvastatin tablets with colchicine [ see Drug Interactions ( 7.9 ) ]. The benefits of the combined use of ezetimibe and simvastatin tablets 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 [see Dosage and Administration (2.4) , Drug Interactions (7.3 )]. Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (≥ 1 g/day niacin) of niacin-containing products. [ see Drug Interactions ( 7.4 ) ]. Cases of rhabdomyolysis have been reported with ezetimibe and simvastatin tablets administered with daptomycin. Temporarily suspend ezetimibe and simvastatin tablets in patients taking daptomycin [see Drug Interactions ( 7.10 )]. Prescribing recommendations for interacting agents are summarized in Table 1 [ see also Dosage and Administration ( 2.3 , 2.4 ), Drug Interactions ( 7 ), and Clinical Pharmacology ( 12.3 ) ].

Table

1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis Interacting Agents Prescribing Recommendations Strong CYP3A4 Inhibitors, e.g.: Contraindicated with ezetimibe and simvastatin tablets Itraconazole Ketoconazole Posaconazole Voriconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Boceprevir Telaprevir Nefazodone Cobicistat-containing products Gemfibrozil CyclosporineDanazol Niacin (≥1 g/day)

For

Chinese patients, not recommended with ezetimibe and simvastatin tablets Verapamil Do not exceed 10 mg/10 mg ezetimibe and simvastatin tablets, daily Diltiazem Dronedarone Amiodarone Do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets, daily Amlodipine Ranolazine Lomitapide For patients with HoFH, do not exceed ezetimibe and simvastatin tablets, 10 mg/20 mg daily1 Daptomycin Temporarlly Suspend ezetimibe and simvastatin tablets Grapefruit juice Avoid grapefruit juice 1 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 ezetimibe and simvastatin tablets, 10 mg/40 mg daily when taking lomitapide. 5.2 immune-mediated necrotizing myopathy 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; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.

5.3 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 ezetimibe and simvastatin tablet and appeared to be dose-related with an incidence of 2.6% for patients treated with ezetimibe and simvastatin tablet 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 ezetimibe and simvastatin tablet 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 ezetimibe and simvastatin tablet 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 (&gt;3 X ULN) was 0.7% for ezetimibe and simvastatin tablet and 0.6% for placebo. It is recommended that liver function tests be performed before the initiation of treatment with ezetimibe and simvastatin tablet, 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 ezetimibe and simvastatin tablet, promptly interrupt therapy. If an alternate etiology is not found do not restart ezetimibe and simvastatin tablet. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1)]</span>. ezetimibe and simvastatin tablet 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 ezetimibe and simvastatin tablet.

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

INTERACTIONS Ezetimibe and simvastatin tablets

• See full prescribing information for details regarding concomitant use of ezetimibe and simvastatin tablets with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis. ( 2.3 , 7.1 )
• Cholestyramine : Combination decreases exposure of ezetimibe. ( 2.3 , 7.2 )
• Coumarin Anticoagulants : Obtain INR before ezetimibe and simvastatin tablets initiation and monitor INR during ezetimibe and simvastatin tablets dosage initiation or adjustment. ( 7.3 )
• Digoxin : During ezetimibe and simvastatin tablets initiation, monitor digoxin levels. ( 7.3 )
• Fenofibrates : Combination increases exposure of ezetimibe. If cholelithiasis is suspected in a patient receiving ezetimibe and a fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. (7.3, 12.3)

7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Ezetimibe and Simvastatin Tablets Ezetimibe and simvastatin tablets are a substrate of CYP3A4 and of the transport protein OATP1B1. ezetimibe and simvastatin tablets plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and OATP1B1.

Table

2 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with ezetimibe and simvastatin tablets and instructions for preventing or managing them [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )].

Table

2: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Ezetimibe and Simvastatin Tablets Strong CYP3A4 inhibitors Clinical Impact: Simvastatin is a substrate of CYP3A4. Concomitant use of strong CYP3A4 inhibitors with ezetimibe and simvastatin tablets increases simvastatin exposure and increases the risk of myopathy and rhabdomyolysis, particularly with higher ezetimibe and simvastatin tablets dosages. Intervention: Concomitant use of strong CYP3A4 inhibitors with ezetimibe and simvastatin tablets are contraindicated [see Contraindications ( 4 )] . If treatment with a CYP3A4 inhibitor is unavoidable, suspend ezetimibe and simvastatin tablets during the course of strong CYP3A4 inhibitor treatment. Examples: Select azole anti-fungals (e.g., itraconazole, ketoconazole, posaconazole, and voriconazole), select macrolide antibiotics (e.g., erythromycin and clarithromycin, telithromycin), select HIV protease inhibitors (e.g., nelfinavir, ritonavir, and darunavir/ritonavir), select HCV protease inhibitors (e.g., boceprevir and telaprevir), cobicistat-containing products, and nefazodone. Cyclosporine, Danazol, or Gemfibrozil Clinical Impact: The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine, danazol, or gemfibrozil with ezetimibe and simvastatin tablets. Gemfibrozil may cause myopathy when given alone. Intervention: Concomitant use of cyclosporine, danazol, or gemfibrozil with ezetimibe and simvastatin tablets are contraindicated [see Contraindications ( 4 )] . Amiodarone, Dronedarone, Ranolazine, or Calcium Channel Blockers Clinical Impact: The risk of myopathy and rhabdomyolysis is increased by concomitant use of amiodarone, dronedarone, ranolazine, or calcium channel blockers with ezetimibe and simvastatin tablets. Intervention: For patients taking verapamil, diltiazem, or dronedarone, do not exceed ezetimibe and simvastatin tablets 10/10 mg daily . For patients taking amiodarone, amlodipine, or ranolazine, do not exceed ezetimibe and simvastatin tablets 10/20 mg daily [see Dosage and Administration ( 2.3 )] .

Lomitapide Clinical

Impact: Simvastatin exposure is approximately doubled with concomitant use of lomitapide and the risk of myopathy and rhabdomyolysis is increased . Intervention: Reduce the dose of ezetimibe and simvastatin tablets by 50% if initiating lomitapide. Do not exceed ezetimibe and simvastatin tablets 10/20 mg daily (or ezetimibe and simvastatin tablets 10/40 mg daily for patients who have previously taken ezetimibe and simvastatin tablets 10/80 mg daily chronically) while taking lomitapide [see Dosage and Administration ( 2.1 , 2.3 )] .

Daptomycin Clinical

Impact: Cases of rhabdomyolysis have been reported with simvastatin administered with daptomycin. Both ezetimibe and simvastatin tablets and daptomycin can cause myopathy and rhabdomyolysis when given alone and the risk of myopathy and rhabdomyolysis may be increased by coadministration. Intervention: If treatment with daptomycin is required, consider temporarily suspending ezetimibe and simvastatin tablets during the course of daptomycin treatment.

Niacin Clinical

Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin-containing products (≥1 gram/day niacin) with ezetimibe and simvastatin tablets. The risk of myopathy is greater in Chinese patients. In a clinical trial (median follow-up 3.9 years) of patients at high risk of CVD 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 of niacin Intervention: Concomitant use of ezetimibe and simvastatin tablets with lipid-modifying dosages of niacin is not recommended in Chinese patients [see Use in Specific Populations ( 8.8 )]. For non-Chinese patients, consider if the benefit of using lipid-modifying doses of niacin concomitantly with ezetimibe and simvastatin tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug. Fibrates (other than Gemfibrozil)

Clinical

Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with ezetimibe and simvastatin tablets. Intervention: Consider if the benefit of using fibrates concomitantly with ezetimibe and simvastatin tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.

Colchicine Clinical

Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with ezetimibe and simvastatin tablets. Intervention: Consider if the benefit of using colchicine concomitantly with ezetimibe and simvastatin tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.

Grapefruit Juice Clinical

Impact: Grapefruit juice can raise the plasma levels of simvastatin and may increase the risk of myopathy and rhabdomyolysis. Intervention: Avoid grapefruit juice when taking ezetimibe and simvastatin tablets.

7.2 Drug Interactions that Decrease the Efficacy of Ezetimibe and Simvastatin Tablets Table 3 presents drug interactions that may decrease the efficacy of ezetimibe and simvastatin tablets and instructions for preventing or managing them.

Table

3: Drug Interactions that Decrease the Efficacy of Ezetimibe and Simvastatin Tablets Bile Acid Sequestrants Clinical Impact: Concomitant cholestyramine administration decreased the mean exposure of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe and simvastatin tablets to cholestyramine may be reduced by this interaction [see Clinical Pharmacology ( 12.3 )] . Intervention: In patients taking a bile acid sequestrant, administer ezetimibe and simvastatin tablets at least 2 hours before or at least 4 hours after cholestyramine [see Dosage and Administration ( 2.3 )] .

7.3 Ezetimibe and Simvastatin Tablets Effect on Other Drugs Table 4 presents ezetimibe and simvastatin tablets effect on other drugs and instructions for preventing or managing them.

Table

4: Ezetimibe and Simvastatin Tablets Effects on Other Drugs Coumarin Anticoagulants Clinical Impact: Ezetimibe and simvastatin tablets may potentiate the effect of coumarin anticoagulants and increase the INR. The concomitant use of simvastatin (20 to 40 mg) and coumarin anticoagulants increased the INR from a baseline of 1.7 to 1.8 in healthy subjects and from 2.6 to 3.4 in patients with hyperlipidemia. There are postmarketing reports of clinically evident bleeding and/or increased INR in patients taking concomitant statins (with or without ezetimibe) and coumarin anticoagulants. Intervention: In patients taking coumarin anticoagulants, obtain an INR before starting ezetimibe and simvastatin tablets and frequently enough after initiation, dose titration, or discontinuation to ensure that no significant alteration in INR occurs. Once the INR is stable, monitor INR at regularly recommended intervals.

Digoxin Clinical

Impact: Concomitant use of digoxin with ezetimibe and simvastatin tablets may result in elevated plasma digoxin concentrations [see Clinical Pharmacology ( 12.3 )] . Intervention: Monitor digoxin levels in patients taking digoxin when ezetimibe and simvastatin tablets are initiated.

Fenofibrates Clinical

Impact: Both ezetimibe and fenofibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. Intervention: If cholelithiasis is suspected in a patient receiving ezetimibe and simvastatin tablets and a fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered [see the product labeling for fenofibrate and fenofibric acid] .