ating 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.
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 (5.2)]
6.1 Clinical Trials ExperienceLIPTRUZET
LIPTRUZET
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 a LIPTRUZET (ezetimibe and atorvastatin) placebo-controlled clinical trial, 628 patients (age range 18-86 years, 59% women, 85% Caucasians, 6% Blacks, 5% Hispanics, 3% Asians) with a median treatment duration of 12 weeks, 6% of patients on LIPTRUZET and 5% of patients on placebo discontinued due to adverse reactions.
The most common adverse reactions in the group treated with LIPTRUZET 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%).
LIPTRUZET has been eva luated 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 LIPTRUZET (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 LIPTRUZET and at an Incidence Greater than Placebo, Regardless of Causality Body System/Organ ClassAdverse Reaction Placebo(%)n=60 Ezetimibe10 mg(%)n=65 Atorvastatin †(%)n=248 LIPTRUZET †(%)n=255
* Placebo-controlled combination study in which the active ingredients equivalent to LIPTRUZET were coadministered.
† All doses.
Nervous system disorders
Dizziness 0 6 <1 2
