1 INDICATIONS AND USAGE Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia.

Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.

In patients with coronary heart disease (CHD) or at high risk of CHD, simvastatin can be started simultaneously with diet.

Simvastatin is an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet to: • Reduce the risk of total mortality by reducing CHD deaths and reduce the risk of non-fatal myocardial infarction, stroke, and the need for revascularization procedures in patients at high risk of coronary events.

( 1.1 ) • Reduce elevated total-C, LDL-C, Apo B, TG and increase HDL-C in patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia.

( 1.2 ) • Reduce elevated TG in patients with hypertriglyceridemia and reduce TG and VLDL-C in patients with primary dysbeta­-lipoproteinemia.

( 1.2 ) • Reduce total-C and LDL-C in adult patients with homozygous familial hypercholesterolemia.

( 1.2 ) • Reduce elevated total-C, LDL-C, and Apo B in boys and postmenarchal girls, 10 to 17 years of age with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy.

( 1.2 , 1.3 ) Limitations of Use Simvastatin has not been studied in Fredrickson Types I and V dyslipidemias.

( 1.4 ) 1.1 Reductions in Risk of CHD Mortality and Cardiovascular Events In patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, simvastatin is indicated to: • Reduce the risk of total mortality by reducing CHD deaths.

• Reduce the risk of non-fatal myocardial infarction and stroke.

• Reduce the need for coronary and non-coronary revascularization procedures.

1.2 Hyperlipidemia Simvastatin is indicated to: • Reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb).

• Reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type IV hyperlipidemia).

• Reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson type III hyperlipidemia).

• Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.

1.3 Adolescent Patients with Heterozygous Familial Hypercholesterolemia (HeFH) Simvastatin is indicated as an adjunct to diet to reduce total-C, LDL-C, and Apo B levels in adolescent boys and girls who are at least one year post-menarche, 10 to 17 years of age, with HeFH, if after an adequate trial of diet therapy the following findings are present: 1.

LDL cholesterol remains ≥190 mg/dL; or 2.

LDL cholesterol remains ≥160 mg/dL and • There is a positive family history of premature cardiovascular disease (CVD) or • Two or more other CVD risk factors are present in the adolescent patient.

The minimum goal of treatment in pediatric and adolescent patients is to achieve a mean LDL-C <130 mg/dL.

The optimal age at which to initiate lipid-lowering therapy to decrease the risk of symptomatic adulthood CAD has not been determined.

1.4 Limitations of Use Simvastatin has not been studied in conditions where the major abnormality is elevation of chylomicrons (i.e., hyperlipidemia Fredrickson types I and V).

6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥5.0%) are: upper respiratory infection, headache, abdominal pain, constipation, and nausea.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Blu Pharmaceuticals at 1-888-374-2791 or FDA at 1-800-FDA-1088 or www .fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical ttials 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 pre-marketing controlled clinical studies and their open extensions (2,423 patients with median duration of follow-up of approximately 18 months), 1.4% of patients were discontinued due to adverse reactions.

The most common adverse reactions that led to treatment discontinuation were: gastrointestinal disorders (0.5%), myalgia (0.1%), and arthralgia (0.1%).

The most commonly reported adverse reactions (incidence ≥5%) in simvastatin controlled clinical trials were: upper respiratory infections (9.0%), headache (7.4%), abdominal pain (7.3%), constipation (6.6%), and nausea (5.4%).

Scandinavian Simvastatin Survival Study In 4S involving 4,444 (age range 35 to 71 years, 19% women, 100% Caucasians) treated with 20 to 40 mg/day of simvastatin (n=2,221) or placebo (n=2,223) over a median of 5.4 years, adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 2.

Heart Protection Study In the Heart Protection Study (HPS), involving 20,536 patients (age range 40 to 80 years, 25% women, 97% Caucasians, 3% other races) treated with simvastatin 40 mg/day (n=10,269) or placebo (n=10,267) over a mean of 5 years, only serious adverse reactions and discontinuations due to any adverse reactions were recorded.

Discontinuation rates due to adverse reactions were 4.8% in patients treated with simvastatin compared with 5.1% in patients treated with placebo.

The incidence of myopathy/rhabdomyolysis was <0.1% in patients treated with simvastatin.

Other Clinical Studies 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 in clinical trials were: diarrhea, rash, dyspepsia, flatulence, and asthenia.

Laboratory Tests Marked persistent increases of hepatic transaminases have been noted [see Warnings and Precautions (5.3) ].

Elevated alkaline phosphatase and γ-glutamyl transpeptidase have also been reported.

About 5% of patients 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).

] Adolescent Patients (ages 10 to17 years) In a 48-week, controlled study in adolescent boys and girls who were at least 1 year post-menarche, 10 to17 years of age (43.4% female, 97.7% Caucasians, 1.7% Hispanics, 0.6% Multiracial) with heterozygous familial hypercholesterolemia (n=175), treated with placebo or simvastatin (10 to 40 mg daily), the most common adverse reactions observed in both groups were upper respiratory infection, headache, abdominal pain, and nausea [see Use in Specific Populations (8.4) and Clinical Studies (14.2 ) ].

table2 6.2 Postmarketing Experience Because the below reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during postapproval use of simvastatin: pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), dizziness, muscle cramps, myalgia, pancreatitis, paresthesia, peripheral neuropathy, vomiting, anemia, erectile dysfunction, interstitial lung disease, rhabdomyolysis, hepatitis/jaundice, fatal and non-fatal hepatic failure, and depression.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.1) ] .

An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens- Johnson syndrome.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use.

These cognitive issues have been reported for all statins.

The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).