Rosuvastatin Calcium: Package Insert and Label Information

ROSUVASTATIN CALCIUM- rosuvastatin calcium tablet, film coated
A-S Medication Solutions

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 is indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia.

1.4 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)

Rosuvastatin is 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 is 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 has 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 tablets 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 tablets 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 therapy or switching from another HMG-CoA reductase inhibitor therapy, the appropriate rosuvastatin 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, 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 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 and darolutamide

The dose of rosuvastatin should not exceed 5 mg once daily [see Warnings and Precautions (5.1) , Drug Interactions (7.1), Drug Interactions (7.4) and Clinical Pharmacology (12.3)].

Patients taking gemfibrozil

Avoid concomitant use of rosuvastatin with gemfibrozil. If concomitant use cannot be avoided, initiate rosuvastatin at 5 mg once daily. The dose of rosuvastatin should not exceed 10 mg once daily [see Warnings and Precautions (5.1) , Drug Interactions (7.2) and Clinical Pharmacology (12.3) ].

Patients taking regorafenib

Concomitant use of rosuvastatin and regorafenib, the dose of rosuvastatin should not exceed 10 mg once daily. [see Warnings and Precautions (5.1) , Drug Interactions (7.5) and Clinical Pharmacology (12.3)].

Patients taking atazanavir and ritonavir, lopinavir and ritonavir, simeprevir or combination of dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir

Initiate rosuvastatin therapy with 5 mg once daily. The dose of rosuvastatin 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 (CLcr <30 mL/min/1.73 m2) not on hemodialysis, dosing of rosuvastatin 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: Pink, round, biconvex, coated tablets. Debossed as ‘CY’ on one side and ‘5’ on other side.

10 mg: Yellow, round, biconvex, coated tablets. Debossed as ‘CY’ on one side, and ‘10’ on other side.

20 mg: Yellow, round, biconvex, coated tablets. Debossed as ‘CY’ on one side, and ‘20’ on other side.

40 mg: Pink, round, biconvex, coated tablets. Debossed as ‘CY’ on one side, and ‘40’ on other side.

4 CONTRAINDICATIONS

Rosuvastatin 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 [see Adverse Reactions (6.1)].

• Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels [see Warnings and Precautions (5.3)].

• Pregnancy [see Use in Specific Populations (8.1, 8.3)].

• Lactation. Limited data indicate that rosuvastatin is present in human milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require rosuvastatin 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. These risks can occur at any dose level, but are increased at the highest dose (40 mg).

Rosuvastatin 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 may be increased with concurrent administration of gemfibrozil, some other lipid-lowering therapies (other fibrates or niacin), cyclosporine, darolutamide, regorafenib, atazanavir/ritonavir, lopinavir/ritonavir, simeprevir or combination of sofosbuvir/velpatasvir/voxilaprevir, dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, all combinations with ledipasvir (including ledipasvir/sofosbuvir) [see Dosage andAdministration (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 with colchicine [see Drug Interactions (7.9)].

Rosuvastatin therapy should be discontinued if markedly elevated creatine kinase levels occur or myopathy is diagnosed or suspected. Rosuvastatin 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).

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.

5.2 Immune-Mediated Necrotizing Myopathy

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; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.

5.3 Liver Enzyme Abnormalities

It is recommended that liver enzyme tests be performed before the initiation of rosuvastatin, 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. 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 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 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, promptly interrupt therapy. If an alternate etiology is not found, do not restart rosuvastatin.

Rosuvastatin 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 [see Contraindications (4)].

5.4 Concomitant Coumarin Anticoagulants

Caution should be exercised when anticoagulants are given in conjunction with rosuvastatin because of its potentiation of the effect of coumarin-type anticoagulants in prolonging the prothrombin time/INR. In patients taking coumarin anticoagulants and rosuvastatin concomitantly, INR should be determined before starting rosuvastatin and frequently enough during early therapy to ensure that no significant alteration of INR occurs [see Drug Interactions (7.6)].

5.5 Proteinuria and Hematuria

In the rosuvastatin calcium tablets clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among rosuvastatin treated patients. These findings were more frequent in patients taking rosuvastatin calcium tablets 40 mg, when compared to lower doses of rosuvastatin 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 therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.

5.6 Endocrine Effects

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. Based on clinical trial data with rosuvastatin, 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 alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if rosuvastatin calcium tablets are 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 (5.3)]

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 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 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 Reactions1 Reported in ≥ 2% of Patients Treated with Rosuvastatin and > Placebo in Placebo-Controlled Trials (% of Patients)

Adverse Reactions

Rosuvastatin 5 mg N = 291

Rosuvastatin 10 mg N = 283

Rosuvastatin 20 mg N = 64

Rosuvastatin 40 mg N = 106

Total Rosuvastatin 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

1 Adverse reactions by COSTART preferred term.

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 (5.5)] ; 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 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 Reactions1 Reported in ≥ 2% of Patients Treated with Rosuvastatin and > Placebo in a Trial (% of Patients)

Adverse Reactions

Rosuvastatin 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 2.2 0.7

1 Adverse reactions by MedDRA preferred term.

2 Frequency recorded as abnormal laboratory value.

In a clinical trial, 17,802 participants were treated with rosuvastatin 20 mg (n = 8,901) or placebo (n = 8,901) 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 (5.6) ].

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

Table 3. Adverse Reactions1 Reported in ≥ 2% of Patients Treated with Rosuvastatin and > Placebo in a Trial (% of Patients)

Adverse Reactions

Rosuvastatin 20 mg N = 8,901

Placebo N = 8,901

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

1 Treatment-emergent adverse reactions by MedDRA preferred term.

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