Ezetimibeside effects

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

6.1 Clinical

Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. VYTORIN In the VYTORIN (ezetimibe and simvastatin) placebo-controlled clinical trials database of 1420 patients (age range 20-83 years, 52% female, 87% White, 3% Black or African American, 3% Asians, 5% other races identified as Hispanic or Latino ethnicity) with a median treatment duration of 27 weeks, 5% of patients on VYTORIN and 2.2% of patients on placebo discontinued due to adverse reactions. The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in controlled clinical trials were: headache (5.8%), increased ALT (3.7%), myalgia (3.6%), upper respiratory tract infection (3.6%), and diarrhea (2.8%). The most common adverse reactions in the group treated with VYTORIN that led to treatment discontinuation and occurred at a rate greater than placebo were: increased ALT (0.9%), myalgia (0.6%), increased AST (0.4%), and back pain (0.4%). VYTORIN has been evaluated for safety in more than 10,189 patients in clinical trials. Table 1 summarizes the frequency of clinical adverse reactions reported in ≥2% of patients treated with VYTORIN (n=1420) and at an incidence greater than placebo from four placebo-controlled trials. Table 1 Includes two placebo-controlled combination studies in which the active ingredients equivalent to VYTORIN were coadministered and two placebo-controlled studies in which VYTORIN was administered.: Adverse Reactions Reported ≥2% of Patients Treated with VYTORIN at an Incidence Greater than Placebo Regardless of Causality % Placebo N = 371 % Ezetimibe 10 mg N = 302 % Simvastatin All doses. N = 1234 % VYTORIN N = 1420 Headache 5.4 6.0 5.9 5.8 Upper respiratory tract infection 2.7 5.0 5.0 3.6 Myalgia 2.4 2.3 2.6 3.6 Diarrhea 2.2 5.0 3.7 2.8 Pain in extremity 1.3 3.0 2.0 2.3 Influenza 0.8 1.0 1.9

2.3 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 trial treatment as a result of either an adverse event or abnormal safety blood result was 10.4% vs. 9.8% among patients allocated to VYTORIN and placebo, respectively. Comparing those allocated to VYTORIN vs. placebo, the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum CK >10 times ULN) was 0.2% vs. 0.1% and the incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) was 0.09% vs. 0.02%, respectively. Consecutive elevations of transaminases (>3 X ULN) occurred in 0.7% vs. 0.6%, respectively. Patients were asked about the occurrence of unexplained muscle pain or weakness at each trial visit: 21.5% vs. 20.9% patients ever reported muscle symptoms in the VYTORIN and placebo groups, respectively. Cancer was diagnosed during the trial in 9.4% vs. 9.5% of patients assigned to VYTORIN and placebo, respectively. Ezetimibe Other adverse reactions reported with ezetimibe in placebo-controlled studies, regardless of causality assessment: Musculoskeletal system disorders: arthralgia;

Infections and infestations: sinusitis; Body as a whole – general disorders: fatigue. Simvastatin In a clinical outcome trial in which 12,064 adult patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times (1200 U/L) upper limit of normal [ULN]) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0.02% and 0.9% respectively. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0% and 0.4%. The incidence of myopathy and rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded. Other adverse reactions reported with simvastatin in placebo-controlled clinical trials: atrial fibrillation; vertigo; abdominal pain, constipation, dyspepsia, flatulence, gastritis; eczema, rash; diabetes mellitus; bronchitis, sinusitis, urinary tract infections; asthenia, edema/swelling; and insomnia. Laboratory Tests Marked persistent increases of hepatic serum transaminases have been noted. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have been reported. About 5% of patients taking simvastatin had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK.

6.2 Postmarketing

Experience The following adverse reactions have been identified during post-approval use of VYTORIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as Whole: fever, chills, malaise, asthenia Blood and Lymphatic System Disorders: anemia, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia Gastrointestinal Disorders: pancreatitis, nausea, vomiting Hepatobiliary Disorders: cholelithiasis, cholecystitis, elevations in liver transaminases including elevations more than 5 X ULN, hepatitis/jaundice, fatal and non-fatal hepatic failure Immune System Disorders: hypersensitivity syndrome including: anaphylaxis, angioedema, lupus erythematous-like syndrome, dermatomyositis, vasculitis Musculoskeletal and Connective Tissue Disorders: muscle cramps, immune-mediated necrotizing myopathy, rhabdomyolysis, myalgia, arthralgia, polymyalgia rheumatica, arthritis, elevated creatine phosphokinase Nervous System Disorders: dizziness, depression, paresthesia, peripheral neuropathy, rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered. Skin and Subcutaneous Tissue Disorders: rash, pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), purpura, lichen planus, urticaria, photosensitivity, flushing, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.

Respiratory and Thoracic: interstitial lung disease, dyspnea Reproductive System Disorders: erectile dysfunction