Simvastatin (Page 2 of 7)

5.2 Immune-Mediated Necrotizing Myopathy

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including simvastatin. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy without significant inflammation; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue simvastatin if IMNM is suspected.

5.3 Hepatic Dysfunction

Increases in serum transaminases have been reported with use of simvastatin [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 3xULN in serum transaminases have occurred in approximately 1% of patients receiving simvastatin in clinical studies. Marked persistent increases of hepatic transaminases have also occurred with simvastatin . There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin.
Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. Consider liver enzyme testing before simvastatin initiation and when clinically indicated thereafter. Simvastatin is 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 simvastatin.

5.4 Increases in HbA1C and Fasting Serum Glucose Levels

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

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 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 practice.
In clinical studies, 2,423 adult patients were exposed to simvastatin with a median duration of follow-up of approximately 18 months. The most commonly reported adverse reactions (incidence ≥5%) in these simvastatin clinical studies were: upper respiratory infections (9%), headache (7%), abdominal pain (7%), constipation (7%), and nausea (5%). Overall, 1.4% of patients discontinued simvastatin due to adverse reactions. The most common adverse reactions that led to discontinuation were: gastrointestinal disorders (0.5%), myalgia (0.1%), and arthralgia (0.1%).
In a Cardiovascular Outcomes Study (the Scandinavian Simvastatin Survival Study [Study 4S]), adult patients (age range 35 to 71 years, 19% women, 100% Caucasians) were treated with 20 to 40 mg per day of simvastatin or placebo over a median of 5.4 years [see Clinical Studies ( 14)] ; adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 1. Table 1: Adverse Reactions Reported ≥2% of Patients Treated with simvastatin and Greater than Placebo in Study 4S

% Placebo (N = 2,223) % simvastatin (N = 2,221)
Bronchitis 6.3 6.6
Abdominal pain 5.8 5.9
Atrial fibrillation 5.1 5.7
Gastritis 3.9 4.9
Eczema 3.0 4.5
Vertigo 4.2 4.5
Diabetes mellitus 3.6 4.2
Insomnia 3.8 4.0
Myalgia 3.2 3.7
Urinary tract infection 3.1 3.2
Edema/swelling 2.3 2.7
Headache 2.1 2.5
Sinusitis 1.8 2.3
Constipation 1.6 2.2

Myopathy/Rhabdomyolysis
In clinical studies with a median follow-up of at least 4 years, in which 24,747 patients received simvastatin, the incidence of myopathy (defined as unexplained muscle weakness, pain, or tenderness accompanied by CK increases greater than 10xULN) was approximately 0.03%, 0.08%, and 0.61% for the simvastatin 20 mg, 40 mg, and 80 mg daily groups, respectively.
In a clinical outcomes study 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 CK >10x [1200 U/L] 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 >40xULN) in patients on simvastatin 20 mg and 80 mg daily was approximately 0% and 0.4%, respectively. The incidence of myopathy and rhabdomyolysis were highest during the first year and then decreased during the subsequent years of treatment.
In another clinical outcomes study in which 10,269 adult patients were treated with simvastatin 40 mg per day (mean follow-up of 5 years), the incidence of myopathy/rhabdomyolysis was <0.1% in patients treated with simvastatin.
Elevations in Liver Enzyme Tests
Moderate (less than 3xULN) elevations of serum transaminases have been reported with use of simvastatin.
Persistent increases to more than 3xULN in serum transaminases have occurred in approximately 1% of patients receiving simvastatin in clinical studies. Marked persistent increases of hepatic transaminases have occurred with simvastatin. Elevated alkaline phosphatase and γ -glutamyl transpeptidase have also been reported.
In Study 4S, with a median follow-up of 5.4 years, 1,986 adult patients were treated with simvastatin 20 mg once daily, of whom 37% titrated to 40 mg once daily. The percentage of patients with one or more occurrences of transaminase elevations to > 3xULN was 0.7% in patients taking simvastatin compared with 0.6% in patients taking placebo. Elevated transaminases leading to discontinuation of study treatment occurred in 0.4% of patients taking simvastatin and 0.2% of patients taking placebo. The majority of elevated transaminases leading to treatment discontinuation occurred within in the first year.
Adverse Reactions in Pediatric Patients with Heterozygous Familial Hypercholesterolemia In a 48-week clinical study in pediatric patients 10 years of age and older (43% female, 97.7% Caucasians, 1.7% Hispanics, 0.6% Multiracial) with HeFH (n=175), treated with placebo or simvastatin (10 to 40 mg daily), the most common adverse reactions were upper respiratory infection, headache, abdominal pain, and nausea [see Use in Specific Populations ( 8.4) and Clinical Studies ( 14)].

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