ZOCOR (Brand for SIMVASTATIN)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Avoid administration with grapefruit juice to avoid potential increases in drug serum concentrations.
-As peak cholesterol synthesis occurs in the early morning hours, evening dosing is recommended.
Oral Solid Formulations
-Administer without regard to food once daily in the evening.

Oral Liquid Formulations
-Shake the bottle well. Measure dosage with an oral syringe or calibrated measuring device.
-Administer on an empty stomach once daily in the evening.
-Storage: Use within 30 days of opening the bottle; store at room temperature (20 to 25 degrees C or 68 to 77 degrees F). Do not freeze or refrigerate.

Amyotrophic lateral sclerosis (ALS, Lou Gehrig's Disease) has been reported to the FDA in a higher than expected number of patients taking statins, such as simvastatin. ALS is a progressive motor neuron disorder with symptoms such as difficulty walking or standing, difficulty with fine motor skills, atrophy of tongue and hand muscles, dysphagia, dysarthria, and muscle paralysis. Due to the seriousness of ALS and the extensive use of statins, FDA further examined data from 41 long-term controlled clinical trials. The results of the review showed no increased incidence of ALS in patients treated with a statin compared with placebo. Specifically, 9 of approximately 64,000 patients treated with a statin (4.2 cases per 100,000 patient-years) and 10 of approximately 56,000 patients treated with placebo (5 case per 100,000 patient-years) were diagnosed with ALS. The FDA is examining the feasibility of performing additional epidemiologic studies to further examine the incidence and clinical course of ALS in patients taking statins.

Simvastatin was well tolerated in controlled clinical trials. In a 48-week controlled study of children and adolescents aged 10 to 17 years with heterozygous familial hypercholesterolemia, the safety and tolerability profile of simvastatin was generally similar to placebo. The most common gastrointestinal adverse reactions in pediatric patients included abdominal pain and nausea. The most commonly reported gastrointestinal adverse reactions in adult patients were constipation (2.2% to 6.6%), abdominal pain (5.9% to 7.3%), gastritis (4.9%), and nausea (5.4%). In other clinical studies, diarrhea, dyspepsia, and flatulence were also reported (incidence unknown). Vomiting has been reported in post marketing experience of simvastatin.

HMG-CoA reductase inhibitors have been associated with toxicity to skeletal muscles. Myopathy (manifested as muscle pain, tenderness, or weakness with creatine phosphokinase [CPK] 10 times above the upper limit of normal), rhabdomyolysis, and acute renal failure (secondary to myoglobinuria) have been reported during simvastatin therapy. Monitor for symptoms of myopathy (myalgia, muscle cramps, musculoskeletal pain, lethargy/drowsiness, tiredness, fever, and/or myasthenia). Periodic CPK measurements may be considered at the initiation of therapy or when the dose is increased; however, there is no assurance that monitoring will prevent myopathy. Discontinue simvastatin immediately if myopathy is suspected or diagnosed. In general, rhabdomyolysis is a rare (less than 1/100,000 prescriptions) complication of HMG-CoA reductase inhibitor ('statin') therapy. In the Heart Protection Study, the incidence of myopathy/rhabdomyolysis was less than 0.1% in adult patients treated with simvastatin (40 mg/day). In the 4S study, myalgia was reported in 3.7% of adult patients taking simvastatin compared to 3.2% of those receiving placebo. Statin-induced myopathy is generally dose-related and, in most cases, symptoms resolve when treatment is discontinued. The risk of myopathy, including rhabdomyolysis, is greater in patients taking 80 mg compared to other statins or lower doses of simvastatin. The risk is also greatest during the first year of therapy and decreases during subsequent years of treatment. During simvastatin clinical trials where patients were carefully monitored and some interacting drugs were excluded, the frequency of myopathy in adult patients was reported to be 0.03% for 20 mg/day, 0.08% for 40 mg/day, and 0.61% for 80 mg/day. Rhabdomyolysis was reported in 0.4% of adult patients receiving 80 mg/day compared to 0% of those receiving 20 mg/day. Chinese patients may be at greater risk. The incidence of myopathy was 0.24% for Chinese patients (n = 5,468) compared to 0.05% for non-Chinese patients (n = 7,367) in a clinical trial in which patients were treated with simvastatin 40 mg/day (median follow-up 3.9 years). The incidence in Chinese patients increased to 1.2% when simvastatin was coadministered with niacin 2 g/day.

Simvastatin therapy is associated with elevated hepatic enzymes. Perform liver function tests (LFTs) at the start of simvastatin therapy, and thereafter when clinically indicated. Persistent elevations of serum transaminases to more than 3 times the upper limit of normal (ULN) have been reported in approximately 1% of adult patients during clinical studies. These elevations appeared soon after initiation of therapy and were not associated with jaundice or other signs or symptoms of hepatotoxicity. Enzyme concentrations will decrease to pretreatment concentrations after discontinuation of simvastatin. In the 4S trial, 8 (0.4%) adult patients who had normal LFTs at baseline developed LFT elevations of 3 times the ULN and/or had therapy discontinued during the 5.4 year follow-up period. Five of these patients developed the elevated LFTs within the first year of therapy. In other clinical trials, the 12 month incidence of LFT elevations was 0.9% and 2.1% in adult patients receiving doses of 40 mg and 80 mg, respectively. No patients in these trials developed persistent liver function abnormalities following the initial 6 months of treatment. Although rare, severe hepatotoxicity may occur during HMG-CoA reductase inhibitor therapy. Hepatitis, fatty changes of the liver, cholestasis with jaundice, cirrhosis, fulminant hepatic necrosis, fatal and non-fatal hepatic failure, and pancreatitis have been reported during therapy with HMG-CoA reductase inhibitors. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with simvastatin, promptly interrupt therapy. If an alternate etiology is not found, do not restart simvastatin.

Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occurred rarely (1 to 3 of every 100,000 patients) with HMG-CoA reductase inhibitors, such as simvastatin. Recurrence of IMNM has been reported following administration of the same or a different statin. IMNM is characterized by myalgia with symmetrical and proximal muscle weakness and elevated serum creatine phosphokinase, which persist despite discontinuation of HMG-CoA reductase inhibitor treatment. Some cases have occurred months to years after starting HMG-CoA reductase therapy and the myopathy progressed following therapy discontinuation. Other characteristics include positive anti-HMG-CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement with immunosuppressive agents. Dysphagia and respiratory failure have also been reported in patients with IMNM. Reported serum creatine phosphokinase levels have ranged from 576 to 35,000 International Units/L. Patients who develop IMNM may require additional neuromuscular and serologic testing. If IMNM develops, HMG-CoA reductase inhibitor therapy should be discontinued and treatment with immunosuppressants, such as high dose corticosteroids, intravenous immune globulin (IVIG), or other immunosuppressive agents, may be needed.

Allergic and dermatologic reactions can occur with simvastatin therapy. In the 4S trial, eczema was reported in 4.5% of adult patients (vs. 3% for placebo). Rash has been reported during clinical trials of simvastatin. Pruritus, alopecia, and lichen planus-like eruption have been reported during postmarketing surveillance of simvastatin. A variety of general skin changes (e.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails) have also been reported. An apparent hypersensitivity syndrome has rarely been reported with HMG-CoA reductase inhibitors and has included some of the following features: anaphylactoid reactions, angioedema, lupus-like symptoms, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson syndrome.

An association between HMG-CoA reductase inhibitors (statins), including simvastatin, and peripheral neuropathy has been reported in the literature (case series, case-control studies, cohort studies). In a nested case-control study of a Danish population, the odds ratio for idiopathic peripheral neuropathy in 166 adult patients that ever or were currently taking a statin, was 3.7 (95% CI 1.8 to 7.6) ; similar results have been found in other population based studies, although the number of patients studied was significantly smaller. Case reports and series indicate that the onset of neuropathy is typically more than 1 year after drug initiation and is reversible with drug discontinuation. However, cases describing irreversible neuropathy are also reported. The adverse effect appears to be a class effect because in all cases, when a patient is either rechallenged or treated with a different statin, the symptoms of neuropathy return. While the data appear to support an association between HMG-CoA reductase inhibitors and peripheral neuropathy, the incidence is rare and estimated to be approximately 1 per 14,000 person-years. Furthermore, a causal relationship cannot be definitively established based on the observational nature of the available data. The benefits of statin therapy far outweigh any risk of peripheral neuropathy; however, until more information is available, health care providers should be aware of this adverse effect.

Increased hemoglobin A1C and fasting serum glucose (hyperglycemia) have been reported during therapy with HMG-CoA reductase inhibitors. A meta-analysis of 13 statin trials with 91,140 adult participants showed a 9% increase in the likelihood of the development of diabetes (OR 1.09; 95% CI 1.02 to 1.17). The incidence of diabetes was higher in high-risk patients (i.e., age 70 to 82 years with or at high risk of cardiovascular disease, myocardial infarction within the last 6 months, or heart failure) compared to patients with low diabetes risk (i.e., low BMI). Additionally, an analysis of the data from the Women's Health Initiative (WHI) trial found that statin use in postmenopausal women is associated with an increased risk of new-onset diabetes mellitus (multivariate-adjusted HR 1.48; 95% CI 1.38 to 1.59). No difference in the risk for diabetes between statins was detected in either analysis. Because the use of statins has been associated with significant benefit for cardiovascular risk reduction and all-cause mortality at comparable rates in diabetic and non-diabetic patients , no changes to clinical practice guidelines have been recommended in either population. However, the increased risk of diabetes should be considered when initiating simvastatin therapy in patients at low risk for cardiovascular events and in patient groups where the cardiovascular benefit of statin therapy has not been established.

Central nervous system effects can occur during simvastatin therapy. In a 48 week controlled study of children and adolescents aged 10 to 17 years with heterozygous familial hypercholesterolemia, headache was reported at a rate similar to placebo. One of the most commonly reported adverse events in simvastatin controlled clinical trials in adults was headache (7.4%). During the 4S trial, headache was reported in 2.5% of patients (vs. 2.1% placebo), insomnia was reported in 4% of patients (vs. 3.8% placebo), and vertigo was reported in 4.5% of patients (vs. 4.2% placebo). Dizziness, paresthesias, and depression were reported during the post marketing experience of simvastatin. Rare cases of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) have been associated with the use of statins. A review of available data by the FDA did not find an association between the event and a specific statin, statin dose, concomitant medication, or age of the patient. In general, post-marketing reports described patients over the age of 50 years who experienced notable, but ill-defined memory loss or impairment that was reversible upon statin discontinuation. The cases did not appear to be associated with progressive or fixed dementia. The time to symptom onset (1 day to years) and resolution (median 3 weeks) is variable.

In a 48 week controlled study of children and adolescents aged 10 to 17 years with heterozygous familial hypercholesterolemia, upper respiratory infection was reported at a rate similar to placebo. One of the most common adverse reactions reported in controlled clinical trials of simvastatin in adults was upper respiratory infection (9%). During the 4S trial, bronchitis was reported in 6.6% of patients (vs. 6.3% placebo), sinusitis was reported in 2.3% of patients (vs. 1.8% placebo), and urinary tract infection was reported in 3.2% of patients (vs. 3.1% placebo). Interstitial lung disease has been reported with the postmarketing surveillance of simvastatin.

During the 4S clinical trial, atrial fibrillation was reported in 5.7% of patients (vs. 5.1% placebo) and edema or swelling was reported in 2.7% of patients (vs. 2.3% placebo).

Asthenia was reported in clinical trials of simvastatin (incidence unknown).

Moderate doses of simvastatin (20 mg/day PO) were associated with tiredness and exertional fatigue in a study that randomized 1016 adult patients with LDL levels 115 to 190 mg/dL and no cardiovascular disease or diabetes to simvastatin 20 mg/day PO, pravastatin 40 mg/day PO, or placebo for 6 months. Patients rated their change in energy and fatigue with exertion on a five-point scale from "much less" (-2) to "much more" (+2) at 6 months of follow-up compared to baseline. Results showed a statistically significant adverse effect on energy and exertional fatigue associated with statin use compared to placebo (-0.21 vs. -0.06, respectively; p = 0.005). The effects appeared to be stronger with simvastatin (-0.25) than pravastatin (-0.17) and were more common in women than men. The authors recommend clinicians consider the impact of these adverse effects on quality of life when prescribing statins particularly in primary prevention patients where a mortality benefit has not been established (e.g., non-smokers and those without raised CRP).

Gynecomastia has been reported with statins. Statins interfere with cholesterol synthesis and lower circulating cholesterol concentrations and theoretically may blunt gonadal steroid hormone production. In a limited controlled study by the manufacturer in pediatric patients (n = 175, age 10 to 17 years), there was no detectable effect of simvastatin on growth or sexual maturation in boys or on menstrual cycle length in postmenarchal girls. Monitor patients carefully for any potential adverse effects on endocrine function and use caution if other drugs that affect endogenous steroid hormones are used concomitantly.

HMG-CoA reductase inhibitors (statins), such as simvastatin, inhibit the synthesis of mevalonate and decrease Co-Enzyme Q-10 concentrations, which may lead to Co-Enzyme Q-10 deficiency. Supplementation with Co-Enzyme Q-10 may limit potential adverse reactions.

Simvastatin has been associated with rare reports of new-onset or exacerbation of myasthenia gravis (including ocular myasthenia) and reports of recurrence when the same or different statin was administered. In a review of adult patients enrolled at a neuromuscular disease clinic over a 4-year time period, 6 of 54 myasthenia gravis patients (11%) receiving statin therapy experienced worsening myasthenia gravis. In a disproportionality analysis of the World Health Organization's VigiBase pharmacovigilance database, 169 of 3,967 (4.2%) of adverse reactions with the term 'myasthenia gravis and related conditions' were related to statin therapy. The reporting odds ratio (ROR) of myasthenia gravis relative to all other adverse reactions was 2.66 [95% CI: 2.28, 3.1] for statin therapy. In addition, the ROR was greater than 1 and statistically significant for all individual statins except lovastatin. The onset of symptoms following initiation of statin therapy has ranged from 1 week to 4 months for exacerbation and 6 months to 6 years for induction of myasthenia gravis. Partial or complete recovery has been reported following discontinuation of statin therapy; however, some patients have required treatment with pyridostigmine or immunosuppressive agents. Though this appears to be a rare adverse reaction, clinicians should closely monitor patients with myasthenia gravis for disease exacerbation and encourage them to report any muscle-related symptoms.

Simvastatin is contraindicated in patients with certain types of hepatic disease, specifically acute liver failure and decompensated cirrhosis (hepatic decompensation). Patients who consume large amounts of alcohol or have a history of liver disease, including cholestasis, hepatic encephalopathy, hepatitis, or jaundice, are at an increased risk for hepatic injury. In addition, advise patients to minimize alcohol intake while receiving simvastatin therapy, and avoid simvastatin in patients with alcoholism. Assess liver enzymes prior to initiation of simvastatin therapy and repeat as clinically indicated. After extensive data review, the FDA concluded that the risk of serious liver injury is very low and routine periodic monitoring of liver enzymes has not been effective in detection or prevention of serious hepatic injury. Instruct patients to promptly report any symptoms of hepatic injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice). If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with simvastatin, discontinue therapy. If an alternate etiology is not found, do not restart simvastatin.

Discontinue simvastatin immediately in any patient who develops myopathy, elevations in CPK, or signs of rhabdomyolysis. The risk of myopathy, including rhabdomyolysis, is greater in patients receiving 80 mg/day compared to lower doses or other statin therapies. Therefore, the 80 mg dose is restricted to adult patients who have taken 80 mg/day chronically (e.g. 12 months or more) without evidence of myopathy. The risk is highest during the first year of treatment. Females, patients with renal impairment, and those with uncontrolled hypothyroidism appear to be predisposed to developing myopathy. Simvastatin is contraindicated in organ transplant patients receiving cyclosporine because of an increased risk of rhabdomyolysis and renal failure. The risk of developing myopathy is increased when HMG-CoA reductase inhibitors are used in combination with CYP3A4 inhibitors or drugs that have an independent risk of myopathy; some drug combinations are contraindicated for this reason. In addition, the manufacturer suggests a lower maximum dosage of simvastatin when used with some drugs known to increase the risk of myopathy. If a patient who is stabilized on the 80 mg/day dose needs to be initiated on an interacting drug that is contraindicated or is associated with a lower maximum simvastatin dose, then switching that patient to an alternative statin with less potential for the drug interaction is recommended. Do not treat Chinese patients taking lipid-modifying doses of niacin-containing products (1 g/day or greater niacin) with the 80 mg dose of simvastatin due to an increased risk for myopathy. Temporary withdrawal of simvastatin is recommended in patients with acute or serious conditions that can cause decreased renal perfusion since renal failure is possible if simvastatin-induced rhabdomyolysis occurs. Predisposing conditions include renal disease or renal insufficiency, hypotension, acute infection, endocrine disease, electrolyte imbalance, uncontrolled seizure disorder, major surgery, and trauma. Although pharmacokinetic data are lacking for simvastatin in patients with renal failure or renal impairment, data for a related HMG-CoA reductase inhibitor (lovastatin) suggest the need for cautious dosage escalation in such patients. In patients with severe renal impairment (CrCl 10 to 30 ml/min), the plasma concentrations of total inhibitors after a single dose of lovastatin are approximately two-fold higher than those in healthy volunteers.

Chinese patients may be at increased risk for myopathy; monitor patients appropriately. Coadministration of simvastatin with lipid-modifying doses of niacin-containing products (1 gram or more per day of niacin) is not recommended in Chinese patients. It is unknown if this risk applies to other Asian patients.

Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occurred rarely (1 to 3 of every 100,000 patients) with HMG-CoA reductase inhibitors, such as simvastatin. Recurrence of IMNM has been reported following administration of the same or a different statin. IMNM is characterized by myalgia with symmetrical and proximal muscle weakness and elevated serum creatine phosphokinase, which persist despite discontinuation of HMG-CoA reductase inhibitor treatment. Some cases have occurred months to years after starting HMG-CoA reductase therapy and the myopathy progressed following therapy discontinuation. Other characteristics include positive anti-HMG-CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement with immunosuppressive agents. Dysphagia and respiratory failure have also been reported in patients with IMNM. Reported serum creatine phosphokinase levels have ranged from 576 to 35,000 International Units/L. Patients who develop IMNM may require additional neuromuscular and serologic testing. If IMNM develops, HMG-CoA reductase inhibitor therapy should be discontinued and treatment with immunosuppressants, such as high dose corticosteroids, intravenous immune globulin (IVIG), or other immunosuppressive agents, may be needed.

If simvastatin is initiated in a patient with diabetes, increased monitoring of blood glucose control may be warranted. Increased hemoglobin A1c, hyperglycemia, and worsening glycemic control have been reported during therapy with HMG-CoA reductase inhibitors. Because the use of statins has been associated with significant benefit for cardiovascular risk reduction and all-cause mortality at comparable rates in diabetic and non-diabetic adult patients , no changes to clinical practice guidelines have been recommended in either population. However, consider the increased risk of diabetes mellitus when initiating simvastatin therapy in patients at low risk for cardiovascular events and in patient groups where the cardiovascular benefit of statin therapy has not been established.

Safety and efficacy of simvastatin have not been established in infants and children younger than 10 years of age. The long-term efficacy of statin therapy in childhood to reduce morbidity and mortality later in adulthood has not been established. Because cholesterol plays a crucial role in growth and development, the clinical implications of using pharmacologic therapy to alter the normal production of cholesterol in young children is not clear. Because of these potential safety concerns and lack of safety data, most experts generally recommend delaying cholesterol-lowering medications until the child is at least 8 to 10 years old. In some cases of severe familial hypercholesterolemia, however, HMG-CoA reductase inhibitors have been used in younger children with careful monitoring of growth and development.

Use simvastatin with caution in persons with myasthenia gravis. Closely monitor for myasthenia gravis exacerbation and encourage reporting of any muscle-related symptoms. Exacerbation of myasthenia gravis, including ocular myasthenia gravis, has been reported during treatment with statins, including simvastatin. Reports of recurrence have been noted when the same or a different statin was administered. The onset of symptom exacerbation following initiation of statin therapy has ranged from 1 week to 4 months. Partial or complete recovery has been reported following discontinuation of statin therapy; however, some patients have required treatment with pyridostigmine or immunosuppressive agents.

Description: Simvastatin is an oral antilipemic agent that inhibits HMG-CoA reductase. Simvastatin is the methylated form of lovastatin. Both simvastatin and lovastatin are prodrugs that require hydrolysis for activation. Simvastatin is effective in reducing total and LDL-cholesterol as well as plasma triglycerides and apolipoprotein B. Simvastatin has a high affinity for HMG-CoA reductase. At doses of 20 to 40 mg once daily, simvastatin reduces mean LDL concentrations in pediatric patients by approximately 37% to 41%. Simvastatin is indicated in adult patients to prevent fatal and nonfatal cardiovascular events based on the favorable findings of several studies, which demonstrated reduced all-cause mortality, coronary deaths, and rates of stroke, myocardial infarction, and revascularization. Although evidence of beneficial long term effects on cardiovascular outcomes and mortality in pediatric patients is not available, statins are recommended as first-line for pharmacologic therapy of hyperlipidemia in pediatric patients based on evidence of short-term safety and efficacy. Simvastatin is FDA-approved in pediatric patients as young as 10 years of age with heterozygous familial hypercholesterolemia.

For the treatment of hypercholesterolemia, hyperlipoproteinemia, and/or hypertriglyceridemia, as an adjunct to dietary control, for the purpose of reducing the risk of cardiovascular events (e.g., myocardial infarction prophylaxis, stroke prophylaxis):
Oral dosage:
Children younger than 10 years*: An initial dose of 5 mg PO once daily titrated up to 10 to 20 mg PO once daily has been used in small studies. Although pharmacologic therapy is not routinely recommended for patients younger than 10 years of age, it may be considered in patients with severe primary hyperlipidemia or high level risk factors (e.g. diabetes, organ transplant, obesity, hypertension, chronic renal disease, strong family history of premature cardiovascular disease). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a study of pediatric patients with total cholesterol more than 300 mg/dL after 6 months of diet modification, patients younger than 10 years of age (specific ages not reported) were started on simvastatin 5 mg PO once daily. Doses were increased, if necessary, to 10 mg PO once daily after 4 weeks and then increased further after an additional 4 weeks to 20 mg PO once daily. Sixteen patients younger than 17 years received a mean simvastatin dose of 16 mg daily for 2 years. Mean serum total cholesterol, LDL, and triglyceride concentrations were decreased by 25.5%, 37.3%, and 8.8%, respectively, and mean HDL concentrations were increased by 22.5%. In a study of pediatric patients with hyperlipidemia secondary to kidney disorders (n = 25 including 3 patients younger than 10 years, [4 years, 5 years, and 10 years]), an initial dose of 5 mg PO once daily was administered to patients weighing less than 30 kg, and an initial dose of 10 mg PO once daily to patients 30 kg or more. Doses were doubled after 1 month. Mean serum total cholesterol, LDL, and triglyceride concentrations were decreased by 23.3%, 33.7%, and 21%, respectively, after 3 months of treatment.
Children and Adolescents 10 to 17 years (females should be at least 1 year post-menarche): 10 mg PO once daily in the evening. The recommended dosage range is 10 to 40 mg/day PO. Doses more than 40 mg/day PO have not been studied. Adjust dosage at intervals of 4 weeks or more to attain the target LDL and lipid goals. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Simvastatin is FDA-approved for the treatment of heterozygous familial hypercholesterolemia and is recommended for hyperlipidemia when either: 1) the LDL remains 190 mg/dL or more, or 2) the LDL remains 160 mg/dL or more and there is an increased risk for cardiovascular disease (e.g., positive family history of premature cardiovascular disease or 2 or more other risk factors are present). In a randomized, placebo controlled trial of pediatric patients with heterozygous familial hypercholesterolemia (n = 173), mean serum total cholesterol, LDL, and triglyceride concentrations were decreased by 30.9%, 40.7%, and 8.7%, respectively, after 48 weeks of treatment with simvastatin 40 mg/day PO. In a study of pediatric patients with total cholesterol more than 300 mg/dL after 6 months of diet modification, 16 patients younger than 17 years received a mean simvastatin dose of 16 mg daily for 2 years. Mean serum total cholesterol, LDL, and triglyceride concentrations were decreased by 25.5%, 37.3%, and 8.8%, respectively, and mean HDL concentrations were increased by 22.5%.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
1 to 9 years: Safety and efficacy have not been established; however, doses up to 20 mg/day PO have been included in some study protocols.
10 to 12 years: 40 mg/day PO.
-Adolescents
40 mg/day PO.

Patients with Hepatic Impairment Dosing
Contraindicated in patients with active liver disease or with unexplained or persistent hepatic transaminase elevations.

Patients with Renal Impairment Dosing
Specific recommendations for dosage adjustment in pediatric patients with renal impairment are not available. Dosage adjustments are not recommended for adult patients with mild to moderate renal impairment. The FDA-approved initial dose for adult patients with severe renal impairment is 5 mg PO once daily in the evening; close monitoring is advised.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Simvastatin is a prodrug with little or no inherent activity. The 6-membered lactone ring is hydrolyzed in vivo to generate mevinolinic acid. Mevinolinic acid, one of simvastatin's several active metabolites, is structurally similar to HMG-CoA (hydroxymethylglutaryl CoA). Once hydrolyzed, simvastatin competes with HMG-CoA for HMG-CoA reductase, a hepatic microsomal enzyme. Interference with the activity of this enzyme reduces the quantity of mevalonic acid, a precursor of cholesterol. Simvastatin decreases total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B, while increasing HDL. This process occurs within the hepatocyte and is one of two mechanisms that generate cholesterol. Cholesterol can also be taken up from LDL by endocytosis. Since de novo synthesis of cholesterol is impaired by simvastatin, cholesterol uptake is augmented. Thus, simvastatin also enhances clearance of LDL.

HMG-CoA reductase inhibitors have been reported to decrease endogenous CoQ10 serum concentrations; the clinical significance of these effects is unknown.

Pharmacokinetics: Simvastatin is administered orally. Simvastatin is an inactive prodrug. It is the methylated derivative of lovastatin and, like lovastatin, must be activated in the liver. Both simvastatin and the active metabolite are strongly bound to plasma proteins (95%). Simvastatin is lipophilic and is taken up by cells other than hepatocytes; simvastatin penetrates the CNS. Sixty percent of an absorbed dose is excreted in the feces and 13% in the urine. The elimination half-life of simvastatin in adults is 2 to 5 hours.

Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6, CYP3A4, P-glycoprotein (P-gp), and OATP1B1
Simvastatin is a substrate of CYP3A4 and CYP2D6 hepatic metabolism. Simvastatin has multiple significant drug interactions with CYP3A4 inhibitors, which may result in increased HMG-CoA reductase inhibition and toxicity including myopathy and rhabdomyolysis. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Simvastatin does not affect the metabolism of CYP3A4 substrates. Simvastatin is a substrate and inhibitor of the P-glycoprotein (P-gp) transport system. Simvastatin acid is also a substrate of the transport protein OATP1B1. Coadministration with inhibitors of OATP1B1 may lead to increased plasma concentrations of simvastatin acid.


-Route-Specific Pharmacokinetics
Oral Route
Oral absorption is 60% to 85%, but bioavailability is less than 5%. Peak plasma concentrations are reached in 1.3 to 2.4 hours. Absorption is not significantly reduced if taken before a low-fat meal. In a food effect study for the oral suspension, administration with a high fat meal (about 540 calories and 56% fat) resulted in an 18% decrease in simvastatin AUC and 44% increase in beta-hydroxyacid simvastatin (active form) AUC compared to exposures observed in the fasted state.


-Special Populations
Renal Impairment
Although pharmacokinetic data are lacking for simvastatin in patients with renal failure, data for a related HMG-CoA reductase inhibitor (lovastatin) suggest the need for cautious dosage escalation in such patients. In adult patients with severe renal impairment (CrCl 10 to 30 mL/minute), the plasma concentrations of total inhibitors after a single dose of lovastatin are approximately two-fold higher than those in healthy volunteers.