SIMVASTATIN: Package Insert and Label Information

SIMVASTATIN — simvastatin tablet, film coated
Lupin Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

Simvastatin tablets USP 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.
• 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.

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Information

• Take simvastatin tablets USP orally once daily in the evening.
• ​ The maximum recommended dosage is simvastatin tablets USP 40 mg once daily [see DOSAGE AND ADMINISTRATION (2.2, 2.3)]. The simvastatin tablets USP 80 mg daily dosage is restricted to patients who have been taking simvastatin tablets USP 80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see WARNINGS AND PRECAUTIONS (5.1)].
• For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving simvastatin tablets USP 40 mg daily, prescribe alternative LDL-C-lowering treatment.
• Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating simvastatin tablets USP, and adjust the dosage if necessary.

2.2 Recommended Dosage in Adult Patients

​ The recommended dosage range of simvastatin tablets USP is 20 mg to 40 mg once daily

2.3 Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HeFH

​ The recommended dosage range of simvastatin tablets USP is 10 mg to 40 mg daily.

2.4 Recommended Dosage in Patients with Renal Impairment

​ 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)]. Simvastatin tablets USP is not available in a 5 mg strength. Use another simvastatin product to initiate dosing in such patients.

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

2.5 Dosage Modifications Due to Drug Interactions

Concomitant use of simvastatin tablets USP with the following drugs requires dosage modification of simvastatin tablets USP [see WARNINGS AND PRECAUTIONS (5.1) AND DRUG INTERACTIONS (7.1)].

Patients taking Lomitapide

Reduce the dosage of simvastatin tablets USP by 50%. Do not exceed simvastatin tablets USP 20 mg once daily (or 40 mg once daily for patients who have previously taken simvastatin tablets USP 80 mg daily chronically while taking lomitapide) [see DOSAGE AND ADMINISTRATION (2.1)].

Patients taking Verapamil, Diltiazem, or Dronedarone

Do not exceed simvastatin tablets USP 10 mg once daily.

Patients taking Amiodarone, Amlodipine, or Ranolazine

Do not exceed simvastatin tablets USP 20 mg once daily.

3 DOSAGE FORMS AND STRENGTHS

• Simvastatin tablets 5 mg are tan colored, round, biconvex, film-coated tablets debossed with ‘LL’ on one side and ‘C01’ on the other side.
• Simvastatin tablets 10 mg are peach colored, oval shaped, biconvex, film-coated tablets debossed with ‘LL’ on one side and ‘C02’ on the other side.
• Simvastatin tablets 20 mg are tan colored, oval shaped, biconvex, film-coated tablets debossed with ‘LL’ on one side and ‘C03’ on the other side.
• Simvastatin tablets 40 mg are brick red colored, round shaped, biconvex, film-coated tablets debossed with ‘LL’ on one side and ‘C04’ on the other side.
• Simvastatin tablets 80 mg are brick red colored, capsule shaped, biconvex, film-coated tablets debossed with ‘LL’ on one side and ‘C05’ on the other side.

4 CONTRAINDICATIONS

Simvastatin 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 simvastatin tablets USP. Hypersensitivity reactions, including anaphylaxis, angioedema and Stevens-Johnson syndrome, have been reported [see ADVERSE REACTIONS (6.2)]

5 WARNINGS AND PRECAUTIONS

5.1 Myopathy and Rhabdomyolysis

​ Simvastatin 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 simvastatin.
In clinical studies of 24,747 simvastatin -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 simvastatin 20 mg, 40 mg, and 80 mg daily, respectively. In another clinical study of 12,064 simvastatin -treated patients (with a history of myocardial infarction) with a mean follow-up of 6.7 years, the incidences of myopathy in patients taking simvastatin 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 simvastatin 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 simvastatin dosage; Chinese patients on simvastatin 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 simvastatin 80 mg daily compared with patients taking lower simvastatin 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 simvastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is required, temporarily suspend simvastatin during the duration of strong CYP3A4 inhibitor treatment. The concomitant use of simvastatin with gemfibrozil, cyclosporine, or danazol is also contraindicated [see CONTRAINDICATIONS (4) AND DRUG INTERACTIONS (7.1)].

Simvastatin dosage modifications are recommended for patients taking lomitapide, verapamil, diltiazem, dronedarone, amiodarone, amlodipine or ranolazine [see DOSAGE AND ADMINISTRATION (2.5)]. Simvastatin 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 simvastatin 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 simvastatin 80 mg are prescribed an interacting drug that increases the risk for myopathy and rhabdomyolysis, switch to an alternate statin [SEE DRUG INTERACTIONS (7.1)].

Discontinue simvastatin if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK increases may resolve if simvastatin is discontinued. Temporarily discontinue simvastatin 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 simvastatin dosage and advise patients receiving simvastatin 80 mg 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.

5.2 Immune-Mediated Necrotizing Myopathy

​ 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 simvastatin if IMNM is suspected

5.3 Hepatic Dysfunction

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

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 simvastatin initiation and when clinically indicated thereafter. Simvastatin 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 simvastatin.

5.4 Increases in HbA1c and Fasting Serum Glucose Levels

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

6 ADVERSE REACTIONS

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)]

6.1 Clinical Trials Experience

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 simvastatin with a median duration of follow-up of approximately 18 months. The most commonly reported adverse reactions (incidence ≥5%) in these simvastatin clinical studies were: upper respiratory infections (9%), headache (7%), abdominal pain (7%), constipation (7%), and nausea (5%). Overall, 1.4% of patients discontinued simvastatin 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 simvastatin 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.

Table 1 : Adverse Reactions Reported ≥2% of Patients Treated with Simvastatin and Greater than Placebo in Study 4S

	% Placebo	% Simvastatin
	(N = 2,223)	(N = 2,221)
Bronchitis	6.3	6.6
Abdominal pain	5.8	5.9
Atrial fibrillation	5.1	5.7
	3.9	4.9
Gastritis
Eczema	3.0	4.5
Vertigo	4.2	4.5
Diabetes mellitus	3.6	4.2
Insomnia	3.8	4.0
Myglia	3.2	3.7
Urinary tract infection	3.1	3.2
Edema/swelling	2.3	2.7
Headache	2.1	2.5
Sinusitis	1.8	2.3
Constipation	1.6	2.2

Myopathy/Rhabdomyolysis

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

Elevations in Liver Enzyme Tests

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

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