Ezetimibe and Simvastatin
Generic: EZETIMIBE AND SIMVASTATIN
Basic Information
Manufacturer
Amneal Pharmaceuticals NY LLC
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
5ea3ca31-cfee-4978-8b7a-755986f6b091
Indications & Usage
1 INDICATIONS AND USAGE Ezetimibe and Simvastatin Tablets Ezetimibe and simvastatin tablets are a combination of simvastatin and ezetimibe indicated: As an adjunct to diet to reduce elevated low density lipoprotein cholesterol (LDL-C): In adults with primary hyperlipidemia.
In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH).
As an adjunct to other LDL-C-lowering therapies to reduce elevated LDL-C in adults with homozygous familial hypercholesterolemia (HoFH).
Simvastatin Simvastatin, when used as a component of ezetimibe and simvastatin tablets, are indicated to reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events.
Ezetimibe and simvastatin tablets are a combination of ezetimibe, a dietary cholesterol absorption inhibitor, and simvastatin, an HMG-CoA reductase inhibitor (statin) indicated: ( 1 ) As an adjunct to diet to reduce elevated low density lipoprotein cholesterol (LDL-C): In adults with primary hyperlipidemia.
In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH).
As an adjunct to other LDL-C lowering therapies to reduce LDL-C in adults with homozygous familial hypercholesterolemia (HoFH).
Simvastatin Simvastatin, when used as a component of ezetimibe and simvastatin tablets, is indicated to reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events.
In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH).
As an adjunct to other LDL-C-lowering therapies to reduce elevated LDL-C in adults with homozygous familial hypercholesterolemia (HoFH).
Simvastatin Simvastatin, when used as a component of ezetimibe and simvastatin tablets, are indicated to reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events.
Ezetimibe and simvastatin tablets are a combination of ezetimibe, a dietary cholesterol absorption inhibitor, and simvastatin, an HMG-CoA reductase inhibitor (statin) indicated: ( 1 ) As an adjunct to diet to reduce elevated low density lipoprotein cholesterol (LDL-C): In adults with primary hyperlipidemia.
In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH).
As an adjunct to other LDL-C lowering therapies to reduce LDL-C in adults with homozygous familial hypercholesterolemia (HoFH).
Simvastatin Simvastatin, when used as a component of ezetimibe and simvastatin tablets, is indicated to reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events.
Adverse Reactions
6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: 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) ] Common (incidence ≥ 2% and greater than placebo) adverse reactions in clinical trials: headache, increased ALT, myalgia, upper respiratory tract infection, and diarrhea.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience 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.
Ezetimibe and Simvastatin In the ezetimibe and simvastatin placebo-controlled clinical trials database of 1,420 patients (age range 20 to 83 years, 52% female, 87% White, 3% Black or African American, 3% Asians, 5% other races identified as Hispanic or Latino ethnicity) with a median treatment duration of 27 weeks, 5% of patients on ezetimibe and simvastatin and 2.2% of patients on placebo discontinued due to adverse reactions.
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%).
The most common adverse reactions in the group treated with ezetimibe and simvastatin 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%), and back pain (0.4%).
Ezetimibe and simvastatin has been evaluated for safety in more than 10,189 patients in clinical trials.
Table 1 summarizes the frequency of clinical adverse reactions reported in ≥ 2% of patients treated with ezetimibe and simvastatin (n = 1,420) and at an incidence greater than placebo from four placebo-controlled trials.
Table 1 * : Adverse Reactions Reported ≥ 2% of Patients Treated with E zetimibe and Simvastatin at an Incidence Greater than Placebo Regardless of Causality % Placebo N = 371 % Ezetimibe 10 mg N = 302 % Simvastatin † N = 1,234 % Ezetimibe and Simvastatin † N = 1,420 Headache 5.4 6.0 5.9 5.8 Upper respiratory tract infection 2.7 5.0 5.0 3.6 Myalgia 2.4 2.3 2.6 3.6 Diarrhea 2.2 5.0 3.7 2.8 Pain in extremity 1.3 3.0 2.0 2.3 Influenza 0.8 1.0 1.9 2.3 * Includes two placebo-controlled combination studies in which the active ingredients equivalent to ezetimibe and simvastatin were co-administered and two placebo-controlled studies in which ezetimibe and simvastatin was administered.
† All doses.
Study of Heart and Renal Protection In SHARP, 9,270 patients were allocated to ezetimibe and simvastatin 10/20 mg daily (n = 4,650) or placebo (n = 4,620) for a median follow-up period of 4.9 years.
The proportion of patients who permanently discontinued trial 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 and placebo, respectively.
Comparing those allocated to ezetimibe and simvastatin 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 trial visit: 21.5% vs.
20.9% patients ever reported muscle symptoms in the ezetimibe and simvastatin and placebo groups, respectively.
Cancer was diagnosed during the trial in 9.4% vs.
9.5% of patients assigned to ezetimibe and simvastatin and placebo, respectively.
Ezetimibe 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.
Simvastatin In a clinical outcome trial 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 creatine kinase [CK] > 10 times (1,200 U/L) upper limit of normal [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 > 40 times ULN) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0% and 0.4%.
The incidence of myopathy and 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 trials: atrial fibrillation; vertigo; abdominal pain, constipation, dyspepsia, flatulence, gastritis; eczema, rash; diabetes mellitus; bronchitis, sinusitis, urinary tract infections; asthenia, edema/swelling; and 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) ] .
6.2 Post-marketing Experience The following adverse reactions have been identified during post-approval use of ezetimibe and simvastatin.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body as Whole: fever, chills, malaise, asthenia Blood and Lymphatic System Disorders: anemia, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia Gastrointestinal Disorders: pancreatitis, nausea, vomiting Hepatobiliary Disorders: cholelithiasis, cholecystitis, elevations in liver transaminases including elevations more than 5 X ULN, hepatitis/jaundice, fatal and non-fatal hepatic failure Immune System Disorders: hypersensitivity syndrome including: anaphylaxis, angioedema, lupus erythematous-like syndrome, dermatomyositis, vasculitis Musculoskeletal and Connective Tissue Disorders: muscle cramps, immune-mediated necrotizing myopathy, rhabdomyolysis, myalgia, arthralgia, polymyalgia rheumatica, arthritis, elevated creatine phosphokinase Nervous System Disorders: dizziness, depression, paresthesia, peripheral neuropathy, rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use.
Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered.
Skin and Subcutaneous Tissue Disorders: rash, pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), purpura, lichen planus, urticaria, photosensitivity, flushing, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.
Respiratory and Thoracic: interstitial lung disease, dyspnea Reproductive System Disorders: erectile dysfunction
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience 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.
Ezetimibe and Simvastatin In the ezetimibe and simvastatin placebo-controlled clinical trials database of 1,420 patients (age range 20 to 83 years, 52% female, 87% White, 3% Black or African American, 3% Asians, 5% other races identified as Hispanic or Latino ethnicity) with a median treatment duration of 27 weeks, 5% of patients on ezetimibe and simvastatin and 2.2% of patients on placebo discontinued due to adverse reactions.
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%).
The most common adverse reactions in the group treated with ezetimibe and simvastatin 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%), and back pain (0.4%).
Ezetimibe and simvastatin has been evaluated for safety in more than 10,189 patients in clinical trials.
Table 1 summarizes the frequency of clinical adverse reactions reported in ≥ 2% of patients treated with ezetimibe and simvastatin (n = 1,420) and at an incidence greater than placebo from four placebo-controlled trials.
Table 1 * : Adverse Reactions Reported ≥ 2% of Patients Treated with E zetimibe and Simvastatin at an Incidence Greater than Placebo Regardless of Causality % Placebo N = 371 % Ezetimibe 10 mg N = 302 % Simvastatin † N = 1,234 % Ezetimibe and Simvastatin † N = 1,420 Headache 5.4 6.0 5.9 5.8 Upper respiratory tract infection 2.7 5.0 5.0 3.6 Myalgia 2.4 2.3 2.6 3.6 Diarrhea 2.2 5.0 3.7 2.8 Pain in extremity 1.3 3.0 2.0 2.3 Influenza 0.8 1.0 1.9 2.3 * Includes two placebo-controlled combination studies in which the active ingredients equivalent to ezetimibe and simvastatin were co-administered and two placebo-controlled studies in which ezetimibe and simvastatin was administered.
† All doses.
Study of Heart and Renal Protection In SHARP, 9,270 patients were allocated to ezetimibe and simvastatin 10/20 mg daily (n = 4,650) or placebo (n = 4,620) for a median follow-up period of 4.9 years.
The proportion of patients who permanently discontinued trial 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 and placebo, respectively.
Comparing those allocated to ezetimibe and simvastatin 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 trial visit: 21.5% vs.
20.9% patients ever reported muscle symptoms in the ezetimibe and simvastatin and placebo groups, respectively.
Cancer was diagnosed during the trial in 9.4% vs.
9.5% of patients assigned to ezetimibe and simvastatin and placebo, respectively.
Ezetimibe 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.
Simvastatin In a clinical outcome trial 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 creatine kinase [CK] > 10 times (1,200 U/L) upper limit of normal [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 > 40 times ULN) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0% and 0.4%.
The incidence of myopathy and 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 trials: atrial fibrillation; vertigo; abdominal pain, constipation, dyspepsia, flatulence, gastritis; eczema, rash; diabetes mellitus; bronchitis, sinusitis, urinary tract infections; asthenia, edema/swelling; and 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) ] .
6.2 Post-marketing Experience The following adverse reactions have been identified during post-approval use of ezetimibe and simvastatin.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body as Whole: fever, chills, malaise, asthenia Blood and Lymphatic System Disorders: anemia, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia Gastrointestinal Disorders: pancreatitis, nausea, vomiting Hepatobiliary Disorders: cholelithiasis, cholecystitis, elevations in liver transaminases including elevations more than 5 X ULN, hepatitis/jaundice, fatal and non-fatal hepatic failure Immune System Disorders: hypersensitivity syndrome including: anaphylaxis, angioedema, lupus erythematous-like syndrome, dermatomyositis, vasculitis Musculoskeletal and Connective Tissue Disorders: muscle cramps, immune-mediated necrotizing myopathy, rhabdomyolysis, myalgia, arthralgia, polymyalgia rheumatica, arthritis, elevated creatine phosphokinase Nervous System Disorders: dizziness, depression, paresthesia, peripheral neuropathy, rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use.
Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered.
Skin and Subcutaneous Tissue Disorders: rash, pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), purpura, lichen planus, urticaria, photosensitivity, flushing, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.
Respiratory and Thoracic: interstitial lung disease, dyspnea Reproductive System Disorders: erectile dysfunction