Atorvastatin Calcium (Page 2 of 8)

5.4 Increases in HbA1c and Fasting Serum Glucose Levels

Increases in HbA1c and fasting serum glucose levels have been reported with statins, including atorvastatin calcium tablets. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

5.5 Increased Risk of Hemorrhagic Stroke in Patients on Atorvastatin calcium tablets 80 mg with Recent Hemorrhagic Stroke

In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial where 2365 adult patients, without CHD who had a stroke or TIA within the preceding 6 months, were treated with atorvastatin calcium tablets 80 mg, 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 non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) 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 [see Adverse Reactions (6.1)] . Consider the risk/benefit of use of atorvastatin calcium tablets 80 mg in patients with recent hemorrhagic stroke.

6 ADVERSE REACTIONS

The following important adverse reactions are described below and elsewhere in the labeling:

Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1)]

Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5.2)]

Hepatic Dysfunction [see Warnings and Precautions (5.3)]

Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the 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 atorvastatin placebo-controlled clinical trial database of 16,066 patients (8755 atorvastatin vs. 7311 placebo; age range 10–93 years, 39% women, 91% White, 3% Black, 2% Asian, 4% other) with a median treatment duration of 53 weeks, the most common adverse reactions in patients treated with atorvastatin that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%).

Table 1 summarizes adverse reactions reported in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin (n=8755), from seventeen placebo-controlled trials.

Table 1: Adverse Reactions Occuring in ≥ 2% in Patients Atorvastatin-Treated with any Dose and Greater than Placebo
Adverse Reaction % Placebo N=7311 % 10 mg N=3908 % 20 mg N=188 % 40 mg N=604 % 80 mg N=4055 % Any dose N=8755
Nasopharyngitis 8.2 12.9 5.3 7.0 4.2 8.3
Arthralgia 6.5 8.9 11.7 10.6 4.3 6.9
Diarrhea 6.3 7.3 6.4 14.1 5.2 6.8
Pain in extremity 5.9 8.5 3.7 9.3 3.1 6.0
Urinary tract infection 5.6 6.9 6.4 8.0 4.1 5.7
Dyspepsia 4.3 5.9 3.2 6.0 3.3 4.7
Nausea 3.5 3.7 3.7 7.1 3.8 4.0
Musculoskeletal pain 3.6 5.2 3.2 5.1 2.3 3.8
Muscle spasms 3.0 4.6 4.8 5.1 2.4 3.6
Myalgia 3.1 3.6 5.9 8.4 2.7 3.5
Insomnia 2.9 2.8 1.1 5.3 2.8 3.0
Pharyngolaryngeal pain 2.1 3.9 1.6 2.8 0.7 2.3

Other adverse reactions reported in placebo-controlled trials include:

Body as a whole: malaise, pyrexia

Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis

Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling

Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia

Nervous system: nightmare

Respiratory system: epistaxis

Skin and appendages: urticaria

Special senses: vision blurred, tinnitus

Urogenital system: white blood cells urine positive

Elevations in Liver Enzyme Tests

Persistent elevations in serum transaminases, defined as more than 3 times the ULN and occurring on 2 or more occasions, 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, respectively.

One patient in clinical trials developed jaundice. Increases in liver enzyme tests 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 liver enzyme elevations continued treatment with a reduced dose of atorvastatin.

Treating to New Targets Study (TNT)

In TNT, [see Clinical Studies (14.1)] 10,001 patients (age range 29–78 years, 19% women; 94% White, 3% Black, 1% Asian, 2% other) with clinically evident CHD were treated with atorvastatin 10 mg daily (n=5006) or atorvastatin 80 mg daily (n=4995). In the highdose atorvastatin group, there were more patients with serious adverse reactions (1.8%) and discontinuations due to adverse reactions (9.9%) as compared to the low-dose group (1.4%; 8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥ 3 x ULN twice within 4–10 days) occurred in 1.3% of individuals with atorvastatin 80 mg and in 0.2% of individuals with atorvastatin 10 mg. Elevations of CK (≥ 10 x ULN) were higher in the high-dose atorvastatin treatment group (0.3%) compared to the low-dose atorvastatin group (0.1%).

Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)

In SPARCL, 4731 patients (age range 21–92 years, 40% women; 93% White, 3% Black, 1% Asian, 3% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months were treated with atorvastatin 80 mg (n=2365) or placebo (n=2366) for a median follow-up of 4.9 years. There was a higher incidence of persistent hepatic transaminase elevations (≥ 3 x ULN twice within 4–10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 x ULN) were rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 6.1% of subjects in the atorvastatin group and 3.8% of subjects in the placebo group.

In a post-hoc analysis, atorvastatin 80 mg reduced the incidence of ischemic stroke (9.2% vs. 11.6%) and increased the incidence of hemorrhagic stroke (2.3% vs. 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 atorvastatin vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Patients who entered the trial with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke (16% atorvastatin vs. 4% placebo).

Adverse Reactions from Clinical Studies of Atorvastatin in Pediatric Patients with HeFH

In a 26-week controlled study in pediatric patients with HeFH (ages 10 years to 17 years) (n=140, 31% female; 92% White, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of atorvastatin 10 to 20 mg daily, as an adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels, was generally similar to that of placebo [see Use in Specific Populations (8.4)and Clinical Studies (14.6)] .

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