ATORVASTATIN CALCIUM (Page 2 of 9)

5.3 Hepatic Dysfunction

Increases in serum transaminases have been reported with use of atorvastatin calcium tablets [see Adverse Reactions ( 6.1)] . In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 0.7% of patients receiving atorvastatin calcium tablets in clinical trials. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin.

Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury [see Use in Specific Populations ( 8.7)] .

Consider liver enzyme testing before atorvastatin calcium tablets initiation and when clinically indicated thereafter. Atorvastatin calcium tablets are contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications ( 4) ]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue atorvastatin calcium tablets.

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. 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 80 mg, a higher incidence of hemorrhagic stroke was seen in the atorvastatin calcium 80 mg group compared to placebo (55, 2.3% atorvastatin calcium 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 calcium 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 calcium group [see Adverse Reactions ( 6.1)] . Consider the risk/benefit of use of atorvastatin calcium 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 calcium placebo-controlled clinical trial database of 16,066 patients (8,755 atorvastatin calcium vs. 7,311 placebo; age range 10 to 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 calcium 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 calcium (n=8,755), from seventeen placebo-controlled trials.

Table 1: Adverse Reactions Occurring in ≥ 2% in Patients Atorvastatin Calcium tablets-Treated with any Dose and Greater than Placebo

Adverse Reaction % Placebo N=7,311 % 10 mg N=3,908 % 20 mg N=188 % 40 mg N=604 % 80 mg N=4055 % Any dose N=8,755
Nasopharyngitis 8.2 12.9 5.3 7 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
Urinary tract infection 5.6 6.9 6.4 8 4.1 5.7
Dyspepsia 4.3 5.9 3.2 6 3.3 4.7
Nausea 3.5 3.7 3.7 7.1 3.8 4
Musculoskeletal pain 3.6 5.2 3.2 5.1 2.3 3.8
Muscle spasms 3 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
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 calcium 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 calcium.

Treating to New Targets Study (TNT)

In TNT, [see Clinical Studies ( 14.1)] 10,001 patients (age range 29 to 78 years, 19% women; 94% White, 3% Black, 1% Asian, 2% other) with clinically evident CHD were treated with atorvastatin calcium 10 mg daily (n=5006) or atorvastatin calcium 80 mg daily (n=4995). In the high-dose atorvastatin calcium 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 to 10 days) occurred in 1.3% of individuals with atorvastatin calcium 80 mg and in 0.2% of individuals with atorvastatin calcium 10 mg. Elevations of CK (≥ 10 x ULN) were higher in the high-dose atorvastatin calcium group (0.3%) compared to the low-dose atorvastatin calcium group (0.1%).

Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)

In SPARCL, 4731 patients (age range 21 to 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 calcium 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 to 10 days) in the atorvastatin calcium group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 x ULN) were rare, but were higher in the atorvastatin calcium group (0.1%) compared to placebo (0%). Diabetes was reported as an adverse reaction in 6.1% of subjects in the atorvastatin calcium group and 3.8% of subjects in the placebo group.

In a post-hoc analysis, atorvastatin calcium 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 calcium vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin calcium 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 calcium vs. 4% placebo].

Adverse Reactions from Clinical Studies of Atorvastatin Calcium 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 calcium 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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