FDA label d136a9ee-9d2e-4c3f-8cd2-f5b40c3ef67b

5 WARNINGS AND PRECAUTIONS Patients should be advised to report promptly any unexplained and/or persistent muscle pain, tenderness, or weakness. LYPQOZET 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 CYP3A4 inhibitors, fibric acid derivatives, and cyclosporine. Predisposing factors include advanced age (>65), uncontrolled hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. ( 5.1 , 8.5 ) 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 transaminase can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter. ( 5.3 ) 5.1 Myopathy/Rhabdomyolysis Atorvastatin Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and with other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10 times upper limit of normal (ULN). The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong CYP3A4 inhibitors (e. g., clarithromycin, itraconazole, and HIV protease inhibitors) increases the risk of myopathy/rhabdomyolysis. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing ezetimibe and atorvastatin tablets. Ezetimibe and atorvastatin tablets therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. The risk of myopathy during treatment with statins is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, the hepatitis C antiviral agents telaprevir, a combination of elbasvir plus grazoprevir, combinations of HIV protease inhibitors, including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir, niacin, or azole antifungals. Physicians considering combined therapy with ezetimibe and atorvastatin tablets and fibric acid derivatives, erythromycin, clarithromycin, a combination of elbasvir plus grazoprevir, a combination of saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Lower starting and maintenance doses of ezetimibe and atorvastatin tablets should be considered when taken concomitantly with the aforementioned drugs [see Drug Interactions ( 7 )] . Periodic CPK determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy. Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration ( 2.3 ), Drug Interactions ( 7 ), Clinical Pharmacology ( 12.3 )] . Table 1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis with Atorvastatin Interacting Agents Prescribing Recommendations for Ezetimibe and Atorvastatin Tablets Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir), gemfibrozil Avoid ezetimibe and atorvastatin tablets. HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary. Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir*, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir), hepatitis C antiviral agents (elbasvir and grazoprevir) Do not exceed 10/20 mg ezetimibe and atorvastatin tablets daily. HIV protease inhibitor (nelfinavir), hepatitis C protease inhibitor (boceprevir) Do not exceed 10/40 mg ezetimibe and atorvastatin tablets daily. *Use with caution and with the lowest dose necessary [see Clinical Pharmacology ( 12.3 )] Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin coadministered with colchicine, and caution should be exercised when prescribing ezetimibe and atorvastatin tablets with colchicine [see Drug Interactions ( 7.11 )]. Ezetimibe and atorvastatin tablets therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e. g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures). Ezetimibe In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ezetimibe compared with the relevant control arm (placebo or statin alone). However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. In clinical trials, the incidence of creatine phosphokinase (CPK) >10 times ULN was 0.2% for ezetimibe vs. 0.1% for placebo, and 0.1% for ezetimibe coadministered with a statin vs. 0.4% for statins alone. Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age (>65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs. In 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 atorvastatin tablets and a fenofibrate, if taking concomitantly, should both be immediately discontinued if myopathy is diagnosed or suspected. The presence of muscle symptoms and a CPK level >10 times the ULN indicates myopathy. 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 Atorvastatin Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (>3 times ULN occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg atorvastatin, respectively. One patient in clinical trials of atorvastatin developed jaundice. Increases in liver function tests (LFT) in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with a reduced dose of atorvastatin. Ezetimibe In controlled clinical studies, the incidence of consecutive elevations (≥3 times ULN) in hepatic transaminase levels was similar between ezetimibe (0.5%) and placebo (0.3%). In controlled clinical combination studies of ezetimibe coadministered with atorvastatin, the incidence of consecutive elevations (≥3 times ULN) in hepatic transaminase levels was 0.6% for patients treated with ezetimibe administered with atorvastatin. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. Ezetimibe and Atorvastatin Tablets It is recommended that liver enzyme tests be obtained prior to initiating therapy with ezetimibe and atorvastatin tablets and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with ezetimibe and atorvastatin tablets, promptly interrupt therapy. If an alternate etiology is not found, do not restart ezetimibe and atorvastatin tablets. Ezetimibe and atorvastatin tablets should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of ezetimibe and atorvastatin tablets [see Contraindications ( 4 )] . 5.4 Endocrine Function Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin. Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve and that ezetimibe did not impair adrenocortical steroid hormone production. The effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if ezetimibe and atorvastatin tablets are administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine. 5.5 Use in Patients with Recent Stroke or TIA In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where atorvastatin 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin (38, 1.6%) group as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group. 5.6 CNS Toxicity Atorvastatin Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0-24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0-24) based on the maximum recommended human dose of 80 mg/day. CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose.

<table width="50%"><caption>Table 1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis with Atorvastatin</caption><tbody><tr><td styleCode="Botrule Toprule Rrule"><content styleCode="bold">Interacting Agents</content></td><td styleCode="Botrule Toprule"><content styleCode="bold">Prescribing Recommendations for Ezetimibe and Atorvastatin Tablets</content></td></tr><tr><td styleCode="Botrule Toprule Rrule">Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir), gemfibrozil</td><td styleCode="Botrule Toprule">Avoid ezetimibe and atorvastatin tablets.</td></tr><tr><td styleCode="Botrule Toprule Rrule">HIV protease inhibitor (lopinavir plus ritonavir)</td><td styleCode="Botrule Toprule">Use with caution and lowest dose necessary.</td></tr><tr><td styleCode="Botrule Toprule Rrule">Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir*, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir), hepatitis C antiviral agents (elbasvir and grazoprevir)</td><td styleCode="Botrule Toprule">Do not exceed 10/20 mg ezetimibe and atorvastatin tablets daily.</td></tr><tr><td styleCode="Botrule Toprule Rrule">HIV protease inhibitor (nelfinavir), hepatitis C protease inhibitor (boceprevir)</td><td styleCode="Botrule Toprule">Do not exceed 10/40 mg ezetimibe and atorvastatin tablets daily.</td></tr></tbody></table>

6 ADVERSE 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 adverse reactions (incidence ≥2% and greater than placebo) are: increased ALT, increased AST, and musculoskeletal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Althera at 1-877-495-3908 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Ezetimibe and Atorvastatin Tablets 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 clinical practice. In an ezetimibe and atorvastatin tablets placebo-controlled clinical trial, 628 patients (age range 18 to 86 years, 59% women, 85% Caucasians, 6% Blacks, 5% Hispanics, 3% Asians) with a median treatment duration of 12 weeks, 6% of patients on ezetimibe and atorvastatin tablets and 5% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group treated with ezetimibe and atorvastatin tablets that led to treatment discontinuation and occurred at a rate greater than placebo were: Myalgia (0.8%) Abdominal pain (0.8%) Increased hepatic enzymes (0.8%) The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in this trial were: increased ALT (5%), increased AST (4%), and musculoskeletal pain (4%). Ezetimibe and atorvastatin tablets have been evaluated for safety in 2403 patients in 7 clinical trials (one placebo-controlled trial and six active-controlled trials). Table 2 summarizes the frequency of clinical adverse reactions reported in ≥2% of patients treated with ezetimibe and atorvastatin tablets (n=255) and at an incidence greater than placebo, regardless of causality assessment, from the placebo-controlled trial. Table 2 * : Clinical and Selected Laboratory Adverse Reactions Occurring in ≥2% of Patients Treated with Ezetimibe and Atorvastatin Tablets and at an Incidence Greater than Placebo, Regardless of Causality Body System/Organ Class Adverse Reaction Placebo (%) n=60 Ezetimibe 10 mg (%) n=65 Atorvastatin † (%) n=248 Ezetimibe and Atorvastatin Tablets † (%) n=255 Nervous system disorders Dizziness 0 6 <1 2 Respiratory, thoracic, and mediastinal disorders Coughing 0 3 <1 2 Gastrointestinal disorders Abdominal pain 2 2 4 3 Nausea 0 2 5 3 Musculoskeletal and connective tissue disorders Arthralgia 0 5 6 3 Muscle weakness 0 2 0 2 Musculoskeletal pain 3 8 5 4 Metabolism and nutrition disorders Hyperkalemia 0 0 <1 2 Infections and infestations Bronchitis 0 2 2 2 Sinusitis 0 3 2 2 Vascular disorders Hot flushes 0 0 <1 2 Investigations ALT increased 0 0 2 5 AST increased 0 0 <1 4 * Placebo-controlled combination study in which the active ingredients equivalent to ezetimibe and atorvastatin tablets were coadministered. † All doses. After completing the 12-week study, eligible patients were assigned to coadministered ezetimibe and atorvastatin equivalent to ezetimibe and atorvastatin tablets (10/10 to 10/80) or atorvastatin (10 to 80 mg/day) for an additional 48 weeks. The long-term coadministration of ezetimibe plus atorvastatin had an overall safety profile similar to that of atorvastatin alone. Ezetimibe In 10 double-blind, placebo-controlled clinical trials, 2396 patients with primary hyperlipidemia (age range 9 to 86 years, 50% women, 90% Caucasians, 5% Blacks, 3% Hispanics, 2% Asians) and elevated LDL-C were treated with ezetimibe 10 mg/day for a median treatment duration of 12 weeks (range 0 to 39 weeks). Adverse reactions reported in ≥2% of patients treated with ezetimibe and at an incidence greater than placebo regardless of causality assessment are shown in Table 3. Table 3: Clinical Adverse Reactions Occurring in ≥2% of Patients Treated with Ezetimibe and at an Incidence Greater than Placebo, Regardless of Causality Body System/Organ Class Adverse Reaction Ezetimibe 10 mg (%) n=2396 Placebo (%) n=1159 Gastrointestinal disorders Diarrhea 4.1 3.7 General disorders and administration site conditions Fatigue 2.4 1.5 Infections and infestations Influenza 2.0 1.5 Sinusitis 2.8 2.2 Upper respiratory tract infection 4.3 2.5 Musculoskeletal and connective tissue disorders Arthralgia 3.0 2.2 Pain in extremity 2.7 2.5 Atorvastatin In an atorvastatin placebo-controlled clinical trial database of 16,066 patients (8755 atorvastatin vs. 7311 placebo; age range 10 to 93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other) with a median treatment duration of 53 weeks, 9.7% of patients on atorvastatin and 9.5% of the patients on placebo discontinued due to adverse reactions regardless of causality. The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) regardless of causality, in patients treated with atorvastatin in placebo controlled trials (n=8755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%). Table 4 summarizes the frequency of clinical adverse reactions, regardless of causality, reported in ≥2% and at a rate greater than placebo in patients treated with atorvastatin (n=8755), from seventeen placebo-controlled trials. Table 4: Clinical Adverse Reactions Occurring in >2% in Patients Treated with any dose of Atorvastatin and at an Incidence Greater than Placebo Regardless of Causality (% of patients). Adverse Reaction* Any Dose n=8755 Atorvastatin 10 mg n=3908 Atorvastatin 20 mg n=188 Atorvastatin 40 mg n=604 Atorvastatin 80 mg n=4055 Placebo n=7311 Nasopharyngitis 8.3 12.9 5.3 7.0 4.2 8.2 Arthralgia 6.9 8.9 11.7 10.6 4.3 6.5 Diarrhea 6.8 7.3 6.4 14.1 5.2 6.3 Pain in extremity 6.0 8.5 3.7 9.3 3.1 5.9 Urinary tract infection 5.7 6.9 6.4 8.0 4.1 5.6 Dyspepsia 4.7 5.9 3.2 6.0 3.3 4.3 Nausea 4.0 3.7 3.7 7.1 3.8 3.5 Musculoskeletal pain 3.8 5.2 3.2 5.1 2.3 3.6 Muscle spasms 3.6 4.6 4.8 5.1 2.4 3.0 Myalgia 3.5 3.6 5.9 8.4 2.7 3.1 Insomnia 3.0 2.8 1.1 5.3 2.8 2.9 Pharyngolaryngeal pain 2.3 3.9 1.6 2.8 0.7 2.1 *Adverse Reaction >2% in any dose greater than placebo 6.2 Postmarketing Experience Because the reactions below are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The additional events described below have been identified during post-approval use of ezetimibe and/or atorvastatin. Blood and lymphatic system disorders: thrombocytopenia Nervous system disorders: headache; dizziness; paresthesia; peripheral neuropathy 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). Gastrointestinal disorders: pancreatitis Skin and subcutaneous tissue disorders: angioedema; bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis); rash; urticaria Musculoskeletal and connective tissue disorders: myositis; myopathy/rhabdomyolysis [see Warnings and Precautions ( 5.1 )] There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions ( 5.1 )] . Injury, poisoning and procedural complications: tendon rupture Immune system disorders: anaphylaxis; hypersensitivity reactions Hepatobiliary disorders: hepatitis; cholelithiasis; cholecystitis; fatal and nonfatal hepatic failure Psychiatric disorders: depression Respiratory: interstitial lung disease Laboratory abnormalities: elevated creatine phosphokinase General disorders and administration site conditions: fatigue

<table width="100%"><caption>Table 2^*: Clinical and Selected Laboratory Adverse Reactions Occurring in &#x2265;2% of Patients Treated with Ezetimibe and Atorvastatin Tablets and at an Incidence Greater than Placebo, Regardless of Causality</caption><tbody><tr><td styleCode="Botrule"><paragraph>Body System/Organ Class</paragraph><paragraph>Adverse Reaction</paragraph></td><td styleCode="Botrule" align="center"><paragraph>Placebo</paragraph><paragraph>(%)</paragraph><paragraph>n=60</paragraph></td><td styleCode="Botrule" align="center"><paragraph>Ezetimibe</paragraph><paragraph>10 mg</paragraph><paragraph>(%)</paragraph><paragraph>n=65</paragraph></td><td styleCode="Botrule" align="center"><paragraph>Atorvastatin^&#x2020;</paragraph><paragraph>(%)</paragraph><paragraph>n=248</paragraph></td><td styleCode="Botrule" align="center"><paragraph>Ezetimibe and Atorvastatin Tablets^&#x2020;</paragraph><paragraph>(%)</paragraph><paragraph>n=255</paragraph></td></tr><tr><td><content styleCode="italics">Nervous system disorders</content></td><td/><td/><td/><td/></tr><tr><td> Dizziness</td><td align="center">0</td><td align="center">6</td><td align="center">&lt;1</td><td align="center">2</td></tr><tr><td><content styleCode="italics">Respiratory, thoracic, and mediastinal disorders</content></td><td/><td/><td/><td/></tr><tr><td> Coughing</td><td align="center">0 </td><td align="center">3 </td><td align="center">&lt;1</td><td align="center">2 </td></tr><tr><td><content styleCode="italics">Gastrointestinal disorders</content></td><td/><td/><td/><td/></tr><tr><td> Abdominal pain</td><td align="center">2 </td><td align="center">2 </td><td align="center">4</td><td align="center">3 </td></tr><tr><td> Nausea</td><td align="center">0 </td><td align="center">2 </td><td align="center">5 </td><td align="center">3 </td></tr><tr><td><content styleCode="italics">Musculoskeletal and connective tissue disorders</content></td><td/><td/><td/><td/></tr><tr><td> Arthralgia</td><td align="center">0 </td><td align="center">5 </td><td align="center">6 </td><td align="center">3 </td></tr><tr><td> Muscle weakness</td><td align="center">0 </td><td align="center">2 </td><td align="center">0 </td><td align="center">2 </td></tr><tr><td> Musculoskeletal pain</td><td align="center">3 </td><td align="center">8 </td><td align="center">5 </td><td align="center">4 </td></tr><tr><td><content styleCode="italics">Metabolism and nutrition disorders</content></td><td/><td/><td/><td/></tr><tr><td> Hyperkalemia</td><td align="center">0 </td><td align="center"> 0</td><td align="center">&lt;1</td><td align="center">2 </td></tr><tr><td><content styleCode="italics">Infections and infestations</content></td><td/><td/><td/><td/></tr><tr><td> Bronchitis</td><td align="center">0 </td><td align="center">2 </td><td align="center">2 </td><td align="center">2 </td></tr><tr><td> Sinusitis</td><td align="center">0 </td><td align="center">3 </td><td align="center">2 </td><td align="center">2 </td></tr><tr><td><content styleCode="italics">Vascular disorders</content></td><td/><td/><td/><td/></tr><tr><td> Hot flushes</td><td align="center">0 </td><td align="center">0 </td><td align="center">&lt;1</td><td align="center">2 </td></tr><tr><td><content styleCode="italics">Investigations</content></td><td/><td/><td/><td/></tr><tr><td> ALT increased</td><td align="center">0 </td><td align="center">0 </td><td align="center">2 </td><td align="center">5 </td></tr><tr><td> AST increased</td><td align="center">0 </td><td align="center">0 </td><td align="center">&lt;1</td><td align="center">4 </td></tr></tbody></table>

<table width="100%"><caption>Table 3: Clinical Adverse Reactions Occurring in &#x2265;2% of Patients Treated with Ezetimibe and at an Incidence Greater than Placebo, Regardless of Causality</caption><tbody><tr><td styleCode="Botrule"><paragraph>Body System/Organ Class</paragraph><paragraph>Adverse Reaction</paragraph></td><td styleCode="Botrule" align="center"><paragraph>Ezetimibe 10 mg (%)</paragraph><paragraph>n=2396</paragraph></td><td styleCode="Botrule" align="center"><paragraph>Placebo (%)</paragraph><paragraph>n=1159 </paragraph></td></tr><tr><td><content styleCode="italics">Gastrointestinal disorders</content></td><td/><td/></tr><tr><td> Diarrhea</td><td align="center">4.1 </td><td align="center">3.7</td></tr><tr><td><content styleCode="italics">General disorders and administration site conditions</content></td><td/><td/></tr><tr><td> Fatigue</td><td align="center">2.4 </td><td align="center">1.5 </td></tr><tr><td><content styleCode="italics">Infections and infestations</content></td><td/><td/></tr><tr><td> Influenza</td><td align="center">2.0 </td><td align="center">1.5</td></tr><tr><td> Sinusitis</td><td align="center">2.8 </td><td align="center">2.2 </td></tr><tr><td> Upper respiratory tract infection</td><td align="center">4.3 </td><td align="center">2.5 </td></tr><tr><td><content styleCode="italics">Musculoskeletal and connective tissue disorders</content></td><td/><td/></tr><tr><td> Arthralgia</td><td align="center">3.0 </td><td align="center">2.2</td></tr><tr><td> Pain in extremity</td><td align="center">2.7 </td><td align="center">2.5</td></tr></tbody></table>

<table width="100%"><caption>Table 4: Clinical Adverse Reactions Occurring in &gt;2% in Patients Treated with any dose of Atorvastatin and at an Incidence Greater than Placebo Regardless of Causality (% of patients).</caption><tbody><tr><td styleCode="Botrule"><content styleCode="bold">Adverse Reaction*</content></td><td styleCode="Botrule" align="center"><paragraph><content styleCode="bold">Any Dose</content></paragraph><paragraph><content styleCode="bold">n=8755</content></paragraph></td><td styleCode="Botrule" align="center"><paragraph><content styleCode="bold"> Atorvastatin</content></paragraph><paragraph><content styleCode="bold">10 mg</content></paragraph><paragraph><content styleCode="bold">n=3908</content></paragraph></td><td styleCode="Botrule" align="center"><paragraph><content styleCode="bold">Atorvastatin</content></paragraph><paragraph><content styleCode="bold">20 mg</content></paragraph><paragraph><content styleCode="bold">n=188</content></paragraph></td><td styleCode="Botrule" align="center"><paragraph><content styleCode="bold">Atorvastatin</content></paragraph><paragraph><content styleCode="bold">40 mg</content></paragraph><paragraph><content styleCode="bold">n=604</content></paragraph></td><td styleCode="Botrule" align="center"><paragraph><content styleCode="bold">Atorvastatin</content></paragraph><paragraph><content styleCode="bold">80 mg</content></paragraph><paragraph><content styleCode="bold">n=4055</content></paragraph></td><td styleCode="Botrule" align="center"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">n=7311</content></paragraph></td></tr><tr><td>Nasopharyngitis</td><td align="center">8.3</td><td align="center">12.9</td><td align="center">5.3</td><td align="center">7.0</td><td align="center">4.2</td><td align="center">8.2</td></tr><tr><td>Arthralgia </td><td align="center">6.9 </td><td align="center">8.9 </td><td align="center">11.7 </td><td align="center">10.6 </td><td align="center">4.3 </td><td align="center">6.5 </td></tr><tr><td>Diarrhea </td><td align="center">6.8 </td><td align="center">7.3 </td><td align="center">6.4 </td><td align="center">14.1 </td><td align="center">5.2 </td><td align="center">6.3 </td></tr><tr><td>Pain in extremity </td><td align="center">6.0 </td><td align="center">8.5 </td><td align="center">3.7 </td><td align="center">9.3 </td><td align="center">3.1 </td><td align="center">5.9 </td></tr><tr><td>Urinary tract infection </td><td align="center">5.7 </td><td align="center">6.9 </td><td align="center">6.4 </td><td align="center">8.0 </td><td align="center">4.1 </td><td align="center">5.6 </td></tr><tr><td>Dyspepsia </td><td align="center">4.7 </td><td align="center">5.9 </td><td align="center">3.2 </td><td align="center">6.0 </td><td align="center">3.3 </td><td align="center">4.3 </td></tr><tr><td>Nausea </td><td align="center">4.0 </td><td align="center">3.7 </td><td align="center">3.7 </td><td align="center">7.1 </td><td align="center">3.8 </td><td align="center">3.5 </td></tr><tr><td>Musculoskeletal pain </td><td align="center">3.8 </td><td align="center">5.2 </td><td align="center">3.2 </td><td align="center">5.1 </td><td align="center">2.3 </td><td align="center">3.6 </td></tr><tr><td>Muscle spasms </td><td align="center">3.6 </td><td align="center">4.6 </td><td align="center">4.8 </td><td align="center">5.1 </td><td align="center">2.4 </td><td align="center">3.0 </td></tr><tr><td>Myalgia </td><td align="center">3.5 </td><td align="center">3.6 </td><td align="center">5.9 </td><td align="center">8.4 </td><td align="center">2.7 </td><td align="center">3.1 </td></tr><tr><td>Insomnia </td><td align="center">3.0 </td><td align="center">2.8 </td><td align="center">1.1 </td><td align="center">5.3 </td><td align="center">2.8 </td><td align="center">2.9 </td></tr><tr><td>Pharyngolaryngeal pain </td><td align="center">2.3 </td><td align="center">3.9 </td><td align="center">1.6 </td><td align="center">2.8 </td><td align="center">0.7 </td><td align="center">2.1 </td></tr></tbody></table>