ZOCOR^® 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.
• As an adjunct to diet to reduce 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).
• As an adjunct to diet for the treatment of adults with:
  • Primary dysbetalipoproteinemia.
  • Hypertriglyceridemia.

ZOCOR is an HMG-CoA reductase inhibitor indicated: (1)

• 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.
• As an adjunct to diet to reduce 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).
• As an adjunct to diet for the treatment of adults with:
  • Primary dysbetalipoproteinemia.
  • Hypertriglyceridemia.

• Important Dosage and Administration Information: (2.1)
  • ZOCOR is no longer marketed in the 5 mg and 80 mg strengths. For dosing with the 5 mg strength, use another simvastatin product.
  • Take ZOCOR orally once daily in the evening.
  • Maximum recommended dosage is ZOCOR 40 mg once daily. An 80 mg daily dosage of ZOCOR is restricted to patients who have been taking simvastatin 80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity.
  • For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving ZOCOR 40 mg daily, prescribe alternative LDL-C lowering treatment.
  • Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating, and adjust the dosage if necessary.
• Adults: Recommended dosage is 20 mg to 40 mg once daily. (2.2)
• Pediatric Patients Aged 10 Years and Older with HeFH: Recommended dosage is 10 mg to 40 mg once daily. (2.3)
• Patients with Severe Renal Impairment: Recommended starting dosage is simvastatin 5 mg once daily. (2.4, 8.6)
• See full prescribing information for ZOCOR dosage modifications due to drug interactions. (2.5)

• ZOCOR is no longer marketed in the 5 mg and 80 mg strengths. For dosing with the 5 mg strength, use another simvastatin product.
• Take ZOCOR orally once daily in the evening.
• The maximum recommended dosage is ZOCOR 40 mg once daily [see Dosage and Administration (2.2, 2.3)]. An 80 mg daily dosage of ZOCOR is restricted to patients who have been taking simvastatin 80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Warnings and Precautions (5.1)].
• If as dose is missed, take the missed dose as soon as possible. Do not double the next dose.
• For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving ZOCOR 40 mg daily, prescribe alternative LDL-C-lowering treatment.
• Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ZOCOR, and adjust the dosage if necessary.

The recommended dosage range of ZOCOR is 20 mg to 40 mg once daily.

The recommended dosage range of ZOCOR is 10 mg to 40 mg daily.

For patients with severe renal impairment [creatinine clearance (CLcr) 15 – 29 mL/min], the recommended starting dosage of simvastatin is 5 mg once daily [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. Use another simvastatin product to initiate dosing in such patients [see Dosage and Administration (2.1)].

There are no dosage adjustment recommendations for patients with mild or moderate renal impairment.

Concomitant use of ZOCOR with the following drugs requires dosage modification of ZOCOR [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].

Patients taking Lomitapide

Reduce the dosage of ZOCOR by 50%. Do not exceed ZOCOR 20 mg once daily (or 40 mg once daily for patients who have previously taken an 80 mg daily dosage of ZOCOR chronically while taking lomitapide) [see Dosage and Administration (2.1)].

Patients taking Verapamil, Diltiazem, or Dronedarone

Do not exceed ZOCOR 10 mg once daily.

Patients taking Amiodarone, Amlodipine, or Ranolazine

Do not exceed ZOCOR 20 mg once daily.

ZOCOR is contraindicated in the following conditions:

• Concomitant use of strong CYP3A4 inhibitors (select azole anti-fungals, macrolide antibiotics, anti-viral medications, and nefazodone) [see Drug Interactions (7.1)].
• Concomitant use of cyclosporine, danazol or gemfibrozil [see Drug Interactions (7.1)].
• Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3)].
• Hypersensitivity to simvastatin or any excipients in ZOCOR. Hypersensitivity reactions, including anaphylaxis, angioedema and Stevens-Johnson syndrome, have been reported [see Adverse Reactions (6.2)].

• Concomitant use of strong CYP3A4 inhibitors (select azole anti-fungals, macrolide antibiotics, anti-viral medications, and nefazodone) (4, 7.1)
• Concomitant use of cyclosporine, danazol or gemfibrozil (4, 7.1)
• Acute liver failure or decompensated cirrhosis (4, 5.3)
• Hypersensitivity to simvastatin or any excipient in ZOCOR (4, 6.2)

• Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher ZOCOR dosage. Chinese patients may be at higher risk for myopathy. Discontinue ZOCOR if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue ZOCOR in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing ZOCOR dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. (5.1, 7.1, 8.5, 8.6, 8.8)
• Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported. Discontinue ZOCOR if IMNM is suspected. (5.2)
• Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzyme before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue ZOCOR. (4, 5.3, 8.7)

ZOCOR may cause myopathy and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including ZOCOR.

In clinical studies of 24,747 ZOCOR-treated patients with a median follow-up of 4 years, the incidence of myopathy, defined as unexplained muscle weakness, pain, or tenderness accompanied by creatinine kinase (CK) increases greater than ten times the upper limit of normal (10xULN), were approximately 0.03%, 0.08%, and 0.61% in patients treated with ZOCOR 20 mg, 40 mg, and 80 mg daily, respectively. In another clinical study of 12,064 ZOCOR-treated patients (with a history of myocardial infarction) with a mean follow-up of 6.7 years, the incidences of myopathy in patients taking ZOCOR 20 mg and 80 mg daily were approximately 0.02% and 0.9%, respectively. The incidences of rhabdomyolysis (defined as myopathy with a CK >40xULN) in patients taking ZOCOR 20 mg and 80 mg daily were approximately 0% and 0.4%, respectively [see Adverse Reactions (6.1)].

Risk Factors for Myopathy

Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher ZOCOR dosage; Chinese patients on ZOCOR may be at higher risk for myopathy [see Contraindications (4), Drug Interactions (7.1), and Use in Specific Populations (8.8)]. The risk of myopathy is increased by elevated plasma levels of simvastatin and simvastatin acid. The risk is also greater in patients taking an 80 mg daily dosage of ZOCOR compared with patients taking lower ZOCOR dosages and compared with patients using other statins with similar or greater LDL-C-lowering efficacy [see Adverse Reactions (6.1)].

Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis

The concomitant use of strong CYP3A4 inhibitors with ZOCOR is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is required, temporarily suspend ZOCOR during the duration of strong CYP3A4 inhibitor treatment. The concomitant use of ZOCOR with gemfibrozil, cyclosporine, or danazol is also contraindicated [see Contraindications (4) and Drug Interactions (7.1)].

ZOCOR dosage modifications are recommended for patients taking lomitapide, verapamil, diltiazem, dronedarone, amiodarone, amlodipine or ranolazine [see Dosage and Administration (2.5)]. ZOCOR use should be temporarily suspended in patients taking daptomycin. Lipid modifying doses (≥1 gram/day) of niacin, fibrates, colchicine, and grapefruit juice may also increase the risk of myopathy and rhabdomyolysis [see Drug Interactions (7.1)].

Use the 80 mg daily dosage of ZOCOR only in patients who have been taking simvastatin 80 mg daily chronically without evidence of muscle toxicity [see Dosage and Administration (2.1)]. If patients treated with an 80 mg daily dosage of ZOCOR are prescribed an interacting drug that increases the risk for myopathy and rhabdomyolysis, switch to an alternate statin [see Drug Interactions (7.1)].

Discontinue ZOCOR if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK increases may resolve if ZOCOR is discontinued. Temporarily discontinue ZOCOR in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis, e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the ZOCOR dosage and advise patients receiving an 80 mg daily dosage of ZOCOR of the increased risk of myopathy and rhabdomyolysis. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. 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 ZOCOR if IMNM is suspected.

Increases in serum transaminases have been reported with use of ZOCOR [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 ZOCOR in clinical studies. Marked persistent increases of hepatic transaminases have also occurred with ZOCOR. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including ZOCOR.

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 ZOCOR initiation and when clinically indicated thereafter. ZOCOR 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 ZOCOR.

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

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)]

Most common adverse reactions (incidence ≥5%) are upper respiratory infection, headache, abdominal pain, constipation, and nausea. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Organon LLC, a subsidiary of Organon & Co., at 1-844-674-3200 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 ZOCOR with a median duration of follow-up of approximately 18 months. The most commonly reported adverse reactions (incidence ≥5%) in these ZOCOR clinical studies were: upper respiratory infections (9%), headache (7%), abdominal pain (7%), constipation (7%), and nausea (5%). Overall, 1.4% of patients discontinued ZOCOR 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 35-71 years, 19% women, 100% Caucasians) were treated with 20-40 mg per day of ZOCOR 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.

Myopathy/Rhabdomyolysis

In clinical studies with a median follow-up of at least 4 years, in which 24,747 patients received ZOCOR , 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 ZOCOR 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 ZOCOR (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 ZOCOR 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 ZOCOR 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 ZOCOR 40 mg per day (mean follow-up of 5 years), the incidence of myopathy/rhabdomyolysis was <0.1% in patients treated with ZOCOR.

Elevations in Liver Enzyme Tests

Moderate (less than 3xULN) elevations of serum transaminases have been reported with use of ZOCOR.

Persistent increases to more than 3xULN in serum transaminases have occurred in approximately 1% of patients receiving ZOCOR in clinical studies. Marked persistent increases of hepatic transaminases have occurred with ZOCOR. 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 ZOCOR 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 ZOCOR compared with 0.6% in patients taking placebo. Elevated transaminases leading to discontinuation of study treatment occurred in 0.4% of patients taking ZOCOR 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 ZOCOR (10-40 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)].

The following adverse reactions have been identified during post-approval use of ZOCOR. 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, vomiting

Hepatic and Pancreatic Disorders: 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, polymyalgia rheumatica, arthritis

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: 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