ROSUVASTATIN CALCIUM: Package Insert and Label Information

ROSUVASTATIN CALCIUM- rosuvastatin calcium tablet
Lupin Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

1.3 Hypertriglyceridemia

Rosuvastatin calcium tablets are indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia.

1.4 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)

Rosuvastatin calcium tablets are indicated as an adjunct to diet for the treatment of adult patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia).

1.5 Adult Patients with Homozygous Familial Hypercholesterolemia

Rosuvastatin calcium tablets are indicated as adjunctive therapy to other lipid-lowering treatments (e.g., LDL apheresis) or alone if such treatments are unavailable to reduce LDL-C, Total-C, and ApoB in adult patients with homozygous familial hypercholesterolemia.

1.8 Limitations of Use

Rosuvastatin calcium tablets have not been studied in Fredrickson Type I and V dyslipidemias.

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

The dose range for rosuvastatin calcium tablet in adults is 5 to 40 mg orally once daily. The usual starting dose is 10 to 20 mg once daily. The usual starting dose in adult patients with homozygous familial hypercholesterolemia is 20 mg once daily.

The maximum rosuvastatin calcium tablet dose of 40 mg should be used only for those patients who have not achieved their LDL-C goal utilizing the 20 mg dose [see WARNINGS AND PRECAUTIONS (5.1)].

Rosuvastatin calcium tablets can be administered as a single dose at any time of day, with or without food. The tablet should be swallowed whole.

When initiating rosuvastatin calcium tablets therapy or switching from another HMG-CoA reductase inhibitor therapy, the appropriate rosuvastatin calcium tablets starting dose should first be utilized, and only then titrated according to the patient’s response and individualized goal of therapy.

After initiation or upon titration of rosuvastatin calcium tablets, lipid levels should be analyzed within 2 to 4 weeks and the dosage adjusted accordingly.

Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.3 Dosing in Asian Patients

In Asian patients, consider initiation of rosuvastatin calcium tablets therapy with 5 mg once daily due to increased rosuvastatin plasma concentrations. The increased systemic exposure should be taken into consideration when treating Asian patients not adequately controlled at doses up to 20 mg/day [see USE IN SPECIFIC POPULATIONS (8.8) and CLINICAL PHARMACOLOGY (12.3)].

2.4 Use with Concomitant Therapy

Patients taking cyclosporine

The dose of rosuvastatin calcium tablets should not exceed 5 mg once daily [see WARNINGS AND PRECAUTIONS (5.1), DRUG INTERACTIONS (7.1) and CLINICAL PHARMACOLOGY (12.3)].

Patients taking gemfibrozil

Avoid concomitant use of rosuvastatin calcium tablets with gemfibrozil. If concomitant use cannot be avoided, initiate rosuvastatin calcium tablets at 5 mg once daily. The dose of rosuvastatin calcium tablets should not exceed 10 mg once daily [see WARNINGS AND PRECAUTIONS (5.1), DRUG INTERACTIONS (7.2) and CLINICAL PHARMACOLOGY (12.3)].

Patients taking atazanavir and ritonavir, lopinavir and ritonavir, or simeprevir

Initiate rosuvastatin calcium tablets therapy with 5 mg once daily. The dose of rosuvastatin calcium tablets should not exceed 10 mg once daily [see WARNINGS AND PRECAUTIONS (5.1), DRUG INTERACTIONS (7.3) and CLINICAL PHARMACOLOGY (12.3)].

2.5 Dosing in Patients with Severe Renal Impairment

For patients with severe renal impairment (CL_cr <30 mL/min/1.73 m²) not on hemodialysis, dosing of rosuvastatin calcium tablets should be started at 5 mg once daily and not exceed 10 mg once daily [see USE IN SPECIFIC POPULATIONS (8.6) and CLINICAL PHARMACOLOGY (12.3)].

3 DOSAGE FORMS AND STRENGTHS

5 mg: Yellow, round, biconvex, film-coated tablets, debossed with “LU” on one side and “F61” on the other side.

10 mg: Pink, oval shaped, biconvex, film-coated tablets, debossed with “LU” on one side and “F62” on the other side.

20 mg: Pink, round, biconvex, film-coated tablets, debossed with “LU” on one side and “F63” on the other side.

40 mg: Pink, oval shaped, biconvex, film-coated tablets, debossed with “LU” on one side and “F64” on the other side.

4 CONTRAINDICATIONS

Rosuvastatin calcium is contraindicated in the following conditions:

• Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema have been reported with rosuvastatin calcium [see ADVERSE REACTIONS (6.1)].
• Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels [see WARNINGS AND PRECAUTIONS (5.2)].
• Pregnancy [see USE IN SPECIFIC POPULATIONS (8.1, 8.3)].
• Lactation. Limited data indicate that rosuvastatin calcium is present in human milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require rosuvastatin calcium treatment should not breastfeed their infants [see USE IN SPECIFIC POPULATIONS (8.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Skeletal Muscle Effects

Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including rosuvastatin calcium. These risks can occur at any dose level, but are increased at the highest dose (40 mg).

Rosuvastatin calcium should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age ≥ 65 years, inadequately treated hypothyroidism, renal impairment).

The risk of myopathy during treatment with rosuvastatin calcium may be increased with concurrent administration of some other lipid-lowering therapies (fibrates or niacin), gemfibrozil, cyclosporine, atazanavir/ritonavir, lopinavir/ritonavir, or simeprevir [see DOSAGE AND ADMINISTRATION (2) and DRUG INTERACTIONS (7)]. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing rosuvastatin calcium with colchicine [see DRUG INTERACTIONS (7.7)].

Rosuvastatin calcium therapy should be discontinued if markedly elevated creatine kinase levels occur or myopathy is diagnosed or suspected. Rosuvastatin calcium therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.

All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing rosuvastatin calcium.

5.2 Liver Enzyme Abnormalities

It is recommended that liver enzyme tests be performed before the initiation of rosuvastatin calcium, and if signs or symptoms of liver injury occur.

Increases in serum transaminases [AST (SGOT) or ALT (SGPT)] have been reported with HMG-CoA reductase inhibitors, including rosuvastatin calcium. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were two cases of jaundice, for which a relationship to rosuvastatin calcium therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials.

In a pooled analysis of placebo-controlled trials, increases in serum transaminases to >3 times the upper limit of normal occurred in 1.1% of patients taking rosuvastatin calcium versus 0.5% of patients treated with placebo.

There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with rosuvastatin calcium, promptly interrupt therapy. If an alternate etiology is not found, do not restart rosuvastatin calcium tablets.

Rosuvastatin calcium should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease [see CLINICAL PHARMACOLOGY (12.3)]. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of rosuvastatin calcium [see CONTRAINDICATIONS (4)].

5.3 Concomitant Coumarin Anticoagulants

Caution should be exercised when anticoagulants are given in conjunction with rosuvastatin calcium because of its potentiation of the effect of coumarin-type anticoagulants in prolonging the prothrombin time/INR. In patients taking coumarin anticoagulants and rosuvastatin calcium concomitantly, INR should be determined before starting rosuvastatin calcium and frequently enough during early therapy to ensure that no significant alteration of INR occurs [see DRUG INTERACTIONS (7.4)].

5.4 Proteinuria and Hematuria

In the rosuvastatin calcium clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among rosuvastatin calcium treated patients. These findings were more frequent in patients taking rosuvastatin calcium 40 mg, when compared to lower doses of rosuvastatin calcium or comparator HMG-CoA reductase inhibitors, though it was generally transient and was not associated with worsening renal function. Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients on rosuvastatin calcium therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.

5.5 Endocrine Effects

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including rosuvastatin calcium. Based on clinical trial data with rosuvastatin calcium, in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus [see ADVERSE REACTIONS (6.1)].

Although clinical studies have shown that rosuvastatin calcium alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if rosuvastatin calcium is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy (including myositis) [see WARNINGS AND PRECAUTIONS (5.1)]
• Liver enzyme abnormalities [see WARNINGS AND PRECAUTIONS (5.2)]

6.1 Clinical Studies 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 clinical practice.

In the rosuvastatin calcium controlled clinical trials database (placebo or active-controlled) of 5394 patients with a mean treatment duration of 15 weeks, 1.4% of patients discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were:

• myalgia
• abdominal pain
• nausea

The most commonly reported adverse reactions (incidence ≥2%) in the rosuvastatin calcium controlled clinical trial database of 5394 patients were:

• headache
• myalgia
• abdominal pain
• asthenia
• nausea

Adverse reactions reported in ≥2% of patients in placebo-controlled clinical studies and at a rate greater than placebo are shown in Table 1. These studies had a treatment duration of up to 12 weeks.

Table 1. Adverse Reactions *Reported in ≥2% of Patients Treated with Rosuvastatin Calcium and > Placebo in Placebo-Controlled Trials (% of Patients)

* Adverse reactions by COSTART preferred term.
Adverse Reactions	Rosuvastatin Calcium 5 mg N = 291	Rosuvastatin Calcium 10 mg N = 283	Rosuvastatin Calcium 20 mg N = 64	Rosuvastatin Calcium 40 mg N = 106	Total Rosuvastatin Calcium 5 mg to 40 mg N = 744	Placebo N = 382
Headache	5.5	4.9	3.1	8.5	5.5	5.0
Nausea	3.8	3.5	6.3	0	3.4	3.1
Myalgia	3.1	2.1	6.3	1.9	2.8	1.3
Asthenia	2.4	3.2	4.7	0.9	2.7	2.6
Constipation	2.1	2.1	4.7	2.8	2.4	2.4

Other adverse reactions reported in clinical studies were abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria, and angioedema) and pancreatitis. The following laboratory abnormalities have also been reported: dipstick-positive proteinuria and microscopic hematuria [see WARNINGS AND PRECAUTIONS (5.4)]; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities.

In a clinical trial, involving 981 participants treated with rosuvastatin 40 mg (n=700) or placebo (n=281) with a mean treatment duration of 1.7 years, 5.6% of subjects treated with rosuvastatin calcium versus 2.8% of placebo-treated subjects discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: myalgia, hepatic enzyme increased, headache, and nausea.

Adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 2.

Table 2. Adverse Reactions *Reported in ≥2% of Patients Treated with Rosuvastatin Calcium and > Placebo in a Trial (% of Patients)

* Adverse reactions by MedDRA preferred term. † Frequency recorded as abnormal laboratory value.
Adverse Reactions	Rosuvastatin Calcium 40 mg N = 700	Placebo N = 281
Myalgia	12.7	12.1
Arthralgia	10.1	7.1
Headache	6.4	5.3
Dizziness	4.0	2.8
Increased CPK	2.6	0.7
Abdominal pain	2.4	1.8
ALT > 3x ULN †	2.2	0.7

In a clinical trial, 17,802 participants were treated with rosuvastatin 20 mg (n=8901) or placebo (n=8901) for a mean duration of 2 years. A higher percentage of rosuvastatin-treated patients versus placebo-treated patients, 6.6% and 6.2%, respectively, discontinued study medication due to an adverse event, irrespective of treatment causality. Myalgia was the most common adverse reaction that led to treatment discontinuation.

There was a significantly higher frequency of diabetes mellitus reported in patients taking rosuvastatin (2.8%) versus patients taking placebo (2.3%). Mean HbA1c was significantly increased by 0.1% in rosuvastatin-treated patients compared to placebo-treated patients. The number of patients with a HbA1c > 6.5% at the end of the trial was significantly higher in rosuvastatin-treated versus placebo-treated patients [see WARNINGS AND PRECAUTIONS (5.5)].

Adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 3.

Table 3. Adverse Reactions *Reported in ≥2% of Patients Treated with Rosuvastatin Calcium and > Placebo in a Trial (% of Patients)

* Treatment-emergent adverse reactions by MedDRA preferred term.
Adverse Reactions	Rosuvastatin Calcium 20 mg N = 8901	Placebo N = 8901
Myalgia	7.6	6.6
Arthralgia	3.8	3.2
Constipation	3.3	3.0
Diabetes mellitus	2.8	2.3
Nausea	2.4	2.3