Ezetimibe and Simvastatin (Page 3 of 11)
5.2 Immune-Mediated Necrotizing Myopathy
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.
5.3 Liver Enzymes
In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (≥3 X ULN) in serum transaminases was 1.7% overall for patients treated with Ezetimibe and Simvastatin Tablets and appeared to be dose-related with an incidence of 2.6% for patients treated with Ezetimibe and Simvastatin Tablets 10/80. In controlled long-term (48 week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations (≥3 X ULN) in serum transaminases was 1.8% overall and 3.6% for patients treated with Ezetimibe and Simvastatin Tablets 10/80. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment.
In SHARP, 9270 patients with chronic kidney disease were allocated to receive Ezetimibe and Simvastatin Tablets 10/20 mg daily (n=4650), or placebo (n=4620). During a median follow-up period of 4.9 years, the incidence of consecutive elevations of transaminases (>3 X ULN) was 0.7% for Ezetimibe and Simvastatin Tablets and 0.6% for placebo.
It is recommended that liver function tests be performed before the initiation of treatment with Ezetimibe and Simvastatin Tablets, and thereafter when clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Ezetimibe and Simvastatin Tablets, promptly interrupt therapy. If an alternate etiology is not found do not restart Ezetimibe and Simvastatin Tablets. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy [see Warnings and Precautions (5.1)].
Ezetimibe and Simvastatin Tablets should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained persistent transaminase elevations are contraindications to the use of Ezetimibe and Simvastatin Tablets.
5.4 Endocrine Function
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including simvastatin.
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 (5.3)]
6.1 Clinical Trials Experience
Ezetimibe and Simvastatin Tablets
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.
In the Ezetimibe and Simvastatin Tablets (ezetimibe/simvastatin) placebo-controlled clinical trials database of 1420 patients (age range 20 to 83 years, 52% women, 87% Caucasians, 3% Blacks, 5% Hispanics, 3% Asians) with a median treatment duration of 27 weeks, 5% of patients on Ezetimibe and Simvastatin Tablets and 2.2% of patients on placebo discontinued due to adverse reactions.
The most common adverse reactions in the group treated with Ezetimibe and Simvastatin Tablets 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%)
· Back pain (0.4%)
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%).
Ezetimibe and Simvastatin Tablets has been evaluated for safety in more than 10,189 patients in clinical trials.
Table 2 summarizes the frequency of clinical adverse reactions reported in ≥2% of patients treated with Ezetimibe and Simvastatin Tablets (n=1420) and at an incidence greater than placebo, regardless of causality assessment, from four placebo-controlled trials.
Table 2*: Clinical Adverse Reactions Occurring in ≥2% of Patients Treated with Ezetimibe and Simvastatin Tablets and at an Incidence Greater than Placebo, Regardless of Causality
|Body System/Organ Class Adverse Reaction||Placebo (%) n=371||Ezetimibe 10 mg (%) n=302||Simvastatin† (%) n=1234||Ezetimibe and Simvastatin† Tablets(%) n=1420|
|Body as a whole – general disorders|
|Gastrointestinal system disorders|
|Infections and infestations|
|Upper respiratory tract infection||2.7||5.0||5.0||3.6|
|Musculoskeletal and connective tissue disorders|
|Pain in extremity||1.3||3.0||2.0||2.3|
*Includes two placebo-controlled combination studies in which the active ingredients equivalent to Ezetimibe and Simvastatin Tablets were coadministered and two placebo-controlled studies in which Ezetimibe and Simvastatin Tablet was administered.
Study of Heart and Renal Protection
In SHARP, 9270 patients were allocated to Ezetimibe and Simvastatin Tablets 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 study treatment as a result of either an adverse event or abnormal safety blood result was 10.4% vs. 9.8% among patients allocated to Ezetimibe and Simvastatin Tablets and placebo, respectively. Comparing those allocated to Ezetimibe and Simvastatin Tablets 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 study visit: 21.5% vs. 20.9% patients ever reported muscle symptoms in the Ezetimibe and Simvastatin Tablets and placebo groups, respectively. Cancer was diagnosed during the trial in 9.4% vs. 9.5% of patients assigned to Ezetimibe and Simvastatin Tablets and placebo, respectively.
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.
In a clinical trial in which 12,064 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 upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including 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 studies, regardless of causality assessment: Cardiac disorders: atrial fibrillation; Ear and labyrinth disorders: vertigo; Gastrointestinal disorders: abdominal pain, constipation, dyspepsia, flatulence, gastritis; Skin and subcutaneous tissue disorders: eczema, rash; Endocrine disorders: diabetes mellitus; Infections and infestations: bronchitis, sinusitis, urinary tract infections; Body as a whole – general disorders: asthenia, edema/swelling; Psychiatric disorders: insomnia.Laboratory Tests
Marked persistent increases of hepatic serum transaminases have been noted [see Warnings and Precautions (5.3)]. 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 [see Warnings and Precautions (5.1)].
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