ROSUVASTATIN: 36,332 Adverse Event Reports & Safety Profile

Rosuvastatin calcium is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)-reductase inhibitor. The chemical name for rosuvastatin calcium is bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt with the following structural formula: The molecular formula for rosuvastatin calcium is (C 22 H 27 FN 3 O 6 S) 2 · Ca and the molecular weight is 1,001.14. Rosuvastatin calcium is off-white to light yellow amorphous powder that is slightly soluble in water and methanol, and insoluble in ethanol. Rosuvastatin calcium is a hydrophilic compound with a partition coefficient (octanol/water) of 0.13 at pH of 7. Each rosuvastatin capsule for oral use contains 5 mg, 10 mg, 20 mg, or 40 mg of rosuvastatin (present as 5.198 mg, 10.395 mg, 20.790 mg, or 41.580 mg of rosuvastatin calcium) in the form of granules with the following inactive ingredients: crospovidone, ferric oxide, hypromellose, magnesium oxide, mannitol, microcrystalline cellulose, polyethylene glycol 4000, silicon dioxide, and sodium citrate. The capsule shells have the following inactive ingredients: gelatin, sodium lauryl sulfate, titanium dioxide, and water. Additionally following colorants are used in capsules: FD&C Red 40 (5 mg), FD&C Blue 1 (5 mg, 10 mg, 20 mg), D&C Red 28 (5 mg, 10 mg), FD&C Red 3 (20 mg), and FD&C Green 3 (40 mg). The imprinting black ink contains black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, and strong ammonia solution. spl-rosuvastatin-structure

AND USAGE Rosuvastatin tablets are an HMG Co-A reductase inhibitor indicated for:

• adult patients with primary hyperlipidemia and mixed dyslipidemia as an adjunct to diet to reduce elevated total-C, LDL-C, ApoB, nonHDL-C, and TG levels and to increase HDLC ( 1.1 )
• pediatric patients 8 to 17 years of age with heterozygous familial hypercholesterotemia (HeFH] to reduce elevated total-C, LDL-C and ApoB after failing an adequate trial of diet therapy ( 1.2 )
• adult patients with hypertriglyceridemia as an adjunct to diet ( 1.3 )
• adult patients with primary dysbetalipoproteinemia [Type III hyperlipoproteinemia) as an adjunct to diet ( 1.4 )
• adult patients with homozygous familial hypercholesterolemia (HoFH) to reduce LOL-G, total-G, and ApoB ( 1.5 )
• slowing the progression of atherosclerosis as part of a treatment strategy lo lower total-C and LDL-C as an adjunct to diet ( 1.6 )
• risk reduction of MI, stroke, and arterial revascularization procedures in patients without clinically evident CHD, but with multiple risk factors ( 1.7 ) Limitations of use ( 1.8 ): Rosuvastatin tablets have not been studied in Fredrickson Type I and V dyslipidemias.

1.1 Hyperlipidemia and Mixed Dyslipidemia Rosuvastatin tablets are indicated as adjunctive therapy to diet to reduce elevated Total-C, LDL-C, ApoB, nonHDL-C, and triglycerides and to increase HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and nonpharmacological interventions alone has been inadequate.

1.2 Pediatric Patients with Familial Hypercholesterolemia Rosuvastatin tablets are indicated as an adjunct to diet to:

• reduce Total-C, LDL-C and ApoB levels in children and adolescents 8 to 17 years of age with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: LDL-C >190 mg/dL, or >160 mg/dL along with a positive family history of premature cardiovascular disease (CVD) or two or more other CVD risk factors. Pediatric use information for patients 7 to 17 years of age with homozygous familial hypercholesterolemia (HoFH) is approved by 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 tablets are indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia.

1.4 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) Rosuvastatin 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 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.

1.6 Slowing of the Progression of Atherosclerosis Rosuvastatin tablets are indicated as adjunctive therapy to diet to slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower Total-C and LDL-C to target levels.

1.7 Primary Prevention of Cardiovascular Disease In individuals without clinically evident coronary heart disease but with an increased risk of cardiovascular disease based on age ≥50 years old in men and >60 years old in women, hsCRP >2 mg/L, and the presence of at least one additional cardiovascular disease risk factor such as hypertension, low HDL-C, smoking, or a family history of premature coronary heart disease, rosuvastatin tablets are indicated to:

• reduce the risk of stroke
• reduce the risk of myocardial infarction
• reduce the risk of arterial revascularization procedures

1.8 Limitations of Use Rosuvastatin tablets have not been studied in Fredrickson Type I and V dyslipidemias.

AND ADMINISTRATION Take orally with or without food, at any time of day. (2.1) Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating EZALLOR SPRINKLE, and adjust dosage if necessary. (2.1) Adults: Recommended dosage range is 5 to 40 mg once daily. (2.1)

Pediatric

Patients with HeFH: Recommended dosage range is 5 to 10 mg once daily for patients aged 8 to less than 10 years of age, and 5 to 20 mg once daily for patients aged 10 years and older. (2.2)

Pediatric

Patients with HoFH: Recommended dosage is 20 mg once daily for patients aged 7 years and older. (2.2)

Asian

Patients: Initiate at 5 mg once daily. Consider risks and benefits of treatment if not adequately controlled at doses up to 20 mg once daily. (2.4) Patients with Severe Renal Impairment (not on hemodialysis): Initiate at 5 mg once daily; do not exceed 10 mg once daily. (2.5) See full prescribing information for EZALLOR SPRINKLE dosage and administration modifications due to drug interactions. (2.6)

2.1 General Dosage and Administration Information Administer EZALLOR SPRINKLE orally as a single dose at any time of day, with or without food. Swallow the capsules whole. Do not crush or chew. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating EZALLOR SPRINKLE, and adjust the dosage if necessary. If a dose is missed, advise patients not to take an extra dose. Resume treatment with the next dose. When taking EZALLOR SPRINKLE with an aluminum and magnesium hydroxide combination antacid, administer EZALLOR SPRINKLE at least 2 hours before the antacid <span class="opacity-50 text-xs">[see Drug Interactions (7.2)]</span>.

2.2 Recommended Dosage in Adult Patients The dosage range for EZALLOR SPRINKLE is 5 mg to 40 mg orally once daily. The recommended dose of EZALLOR SPRINKLE depends on a patient’s indication for usage, LDL-C, and individual risk for CV events.

2.3 Recommended Dosage in Pediatric Patients Dosage in Pediatric Patients 8 Years of Age and Older with HeFH The recommended dosage range is 5 mg to 10 mg orally once daily in patients aged 8 years to less than 10 years and 5 mg to 20 mg orally once daily in patients aged 10 years and older. Dosage in Pediatric Patients 7 Years of Age and Older with HoFH The recommended dosage is 20 mg orally once daily.

2.4 Recommended Dosage in Asian Patients Initiate EZALLOR SPRINKLE at 5 mg once daily due to increased rosuvastatin plasma concentrations. Consider the risks and benefits of EZALLOR SPRINKLE when treating Asian patients not adequately controlled at doses up to 20 mg once daily <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1), Use in Specific Populations (8.8), and Clinical Pharmacology (12.3)]</span>.

2.5 Recommended Dosage in Patients with Renal Impairment In patients with severe renal impairment (CLcr less than 30 mL/min/1.73 m 2 ) not on hemodialysis, the recommended starting dosage is 5 mg once daily and should not exceed 10 mg once daily <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]</span> . There are no dosage adjustment recommendations for patients with mild and moderate renal impairment.

2.6 Dosage Modifications Due to Drug Interactions Table 1 displays dosage modifications for EZALLOR SPRINKLE due to drug interactions <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) and Drug Interactions (7.1)]</span> .

Table

1: EZALLOR SPRINKLE Dosage Modifications Due to Drug Interactions Concomitantly Used Drug EZALLOR SPRINKLE Dosage Modifications Cyclosporine Do not exceed 5 mg once daily. Teriflunomide Do not exceed 10 mg once daily. Enasidenib Do not exceed 10 mg once daily. Capmatinib Do not exceed 10 mg once daily. Fostamatinib Do not exceed 20 mg once daily. Febuxostat Do not exceed 20 mg once daily.

Gemfibrozil

Avoid concomitant use. If used concomitantly, initiate at 5 mg once daily and do not exceed 10 mg once daily.

Tafamidis

Avoid concomitant use. If used concomitantly, initiate at 5 mg once daily and do not exceed 20 mg once daily.

Antiviral Medications

Sofosbuvir/velpatasvir/voxilaprevir Ledipasvir/sofosbuvir Concomitant use not recommended.

Simeprevir

Dasabuvir/ombitasvir/paritaprevir/ritonavir Elbasvir/Grazoprevir Sofosbuvir/Velpatasvir Glecaprevir/Pibrentasvir Atazanavir/Ritonavir Lopinavir/Ritonavir Initiate at 5 mg once daily. Do not exceed 10 mg once daily. Darolutamide Do not exceed 5 mg once daily. Regorafenib Do not exceed 10 mg once daily.

2.7 Preparation and Administration Instructions EZALLOR SPRINKLE capsule should be swallowed whole. For patients unable to swallow an intact capsule, consider the following instructions based on the route of administration and refer to the accompanying Instructions for Use for complete administration instructions: Oral Administration Carefully open the capsule and sprinkle the entire contents of the capsule onto at least one teaspoonful (5 mL) of room temperature applesauce or chocolate/vanilla flavored pudding. Stir the mixture for 10 to 15 seconds. Swallow the entire mixture within 60 minutes of mixing. Do not chew the mixture. Do not save the mixture for later use. Discard the unused portion immediately.

Nasogastric

Tube (≥16 French)

Administration

Carefully open the capsule and empty the intact granules emptied into a 60 mL catheter tipped syringe barrel and add 40 mL of water. Do not use with liquids other than water. Replace the plunger and shake the syringe vigorously for 15 seconds. The granules in EZALLOR SPRINKLE capsule may start dissolving which is acceptable. Attach the syringe to a nasogastric tube (≥16-French) and deliver the contents of the syringe through the nasogastric tube into the stomach. Flush the nasogastric tube should with 20 mL of additional water after administering the mixture. Do not save the mixture for later use. Discard the unused portion immediately.

Rosuvastatin calcium tablets are 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 tablets [ Error! Hyperlink reference not valid. )].
• Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels [ Error! Hyperlink reference not valid. )].
• Pregnancy [ see Use in Specific Populations (8.1, Error! Hyperlink reference not valid. )].
• 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 tablets treatment should not breastfeed their infants Error! Hyperlink reference not valid. )].
• Known hypersensitivity to product components ( Error! Hyperlink reference not valid. )
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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 )] Most frequent adverse reactions (rate ≥2%) are headache, myalgia, abdominal pain, asthenia, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

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 Reactions

1 Reported in ≥ 2% of Patients Treated with Rosuvastatin and > Placebo in Placebo to Controlled Trials (% of Patients) 1 Adverse reactions by COSTART preferred term.

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 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.5 )]</span>; 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.8 )]</span>. Adverse reactions reported in ≥ 2% of patients and at a rate greater than placebo are shown in Table 2.

Table

2.

Adverse Reactions

1 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

2.8 Increased CPK 2.6

0.7 Abdominal pain 2.4

1.8 ALT &gt;3 x ULN 2 2.2 0.7 1 Adverse reactions by MedDRA preferred term. 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 &gt; 6.5% at the end of the trial was significantly higher in rosuvastatin-treated versus placebo-treated patients <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.6 ) and Clinical Studies ( 14.9 )]</span>. Adverse reactions reported in ≥ 2% of patients and at a rate greater than placebo are shown in Table 3.

Table

3.

Adverse Reactions

1 Reported in ≥ 2% of Patients Treated with Rosuvastatin and > Placebo in a Trial (% of Patients)

Adverse Reactions Rosuvastatin

20 mg N=8901 Placebo N=8901 Myalgia 7.6

6.6 Arthralgia 3.8

3.2 Constipation 3.3 3 Diabetes mellitus 2.8

2.3 Nausea 2.4 2.3 1 Treatment-emergent adverse reactions by MedDRA preferred term.

Pediatric

Patients with Heterozygous Familial Hypercholesterolemia In a 12-week controlled study in boys and postmenarcheal girls 10 to 17 years of age with heterozygous familial hypercholesterolemia with rosuvastatin 5 to 20 mg daily [see U se in Specific Populations (8.4 ) and Clinical Studies ( 14.7 )], elevations in serum creatine phosphokinase (CK) >10 x ULN were observed more frequently in rosuvastatin compared with placebo-treated children. Four of 130 (3%) children treated with rosuvastatin (2 treated with 10 mg and 2 treated with 20 mg) had increased CK >10 x ULN, compared to 0 of 46 children on placebo.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of rosuvastatin: arthralgia, fatal and non-fatal hepatic failure, hepatitis, jaundice, thrombocytopenia, depression, sleep disorders (including insomnia and nightmares), peripheral neuropathy, interstitial lung disease and gynecomastia. 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. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span>. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, and confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

AND PRECAUTIONS

• Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with use of 40 mg dose, advanced age (≥65), hypothyroidism, renal impairment, and combination use with cyclosporine, darolutamide, regorafenib, certain anti-viral medicines or their combinations. Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness and discontinue rosuvastatin tablets if signs or symptoms appear. ( 5.1 , 7.4 , 7.5 , 7.7 , 7.8 )
• Immune-Mediated Necrotizing Myopathy (IMNM): There have been rare reports of 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. (5.2)
• Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Perform liver enzyme tests before initiating therapy and as clinically indicated thereafter. (5.3)

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 tablets should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age ≥ 65 years, inadequately treated hypothyroidism, renal impairment). Rosuvastatin tablets 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 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 tablets with colchicine <span class="opacity-50 text-xs">[see Drug Interactions (7.9) ]</span>. 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).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). 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. 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 tablets. 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 tablets.

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 tablets, 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 &gt;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 tablets. Rosuvastatin tablets 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 clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among rosuvastatin treated patients. These findings were more frequent in patients taking rosuvastatin tablets 40 mg, when compared to lower doses of rosuvastatin tablets 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 is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.

INTERACTIONS See full prescribing information for details regarding concomitant use of rosuvastatin tablets with other drugs that increase the risk of myopathy and rhabdomyolysis. ( 7.1 ) Aluminum and Magnesium Hydroxide Combination Antacids : Administer rosuvastatin tablets at least 2 hours before the antacid. ( 7.2 ) Warfarin : Obtain INR prior to starting rosuvastatin tablets. Monitor INR frequently until stable upon initiation, dose titration or discontinuation. ( 7.3 )

7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Rosuvastatin Tablets Rosuvastatin is a substrate of CYP2C9 and transporters (such as OATP1B1, BCRP). Rosuvastatin plasma levels can be significantly increased with concomitant administration of inhibitors of CYP2C9 and transporters.

Table

5 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with rosuvastatin tablets and instructions for preventing or managing them [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] .

Table

5: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Rosuvastatin Tablets Cyclosporine Clinical Impact: Cyclosporine increased rosuvastatin exposure 7-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with rosuvastatin tablets. Intervention: If used concomitantly, do not exceed a dose of rosuvastatin tablets 5 mg once daily.

Teriflunomide Clinical

Impact: Teriflunomide increased rosuvastatin exposure more than 2.5-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Intervention: In patients taking teriflunomide, do not exceed a dose of rosuvastatin tablets 10 mg once daily.

Enasidenib Clinical

Impact: Enasidenib increased rosuvastatin exposure more than 2.4-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Intervention: In patients taking enasidenib, do not exceed a dose of rosuvastatin tablets 10 mg once daily.

Capmatinib Clinical

Impact: Capmatinib increased rosuvastatin exposure more than 2.1-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Intervention: In patients taking capmatinib, do not exceed a dose of rosuvastatin tablets 10 mg once daily.

Fostamatinib Clinical

Impact: Fostamatinib increased rosuvastatin exposure more than 2.0-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Intervention: In patients taking fostamatinib, do not exceed a dose of rosuvastatin tablets 20 mg once daily.

Febuxostat Clinical

Impact: Febuxostat increased rosuvastatin exposure more than 1.9-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Intervention: In patients taking febuxostat, do not exceed a dose of rosuvastatin tablets 20 mg once daily.

Gemfibrozil Clinical

Impact: Gemfibrozil significantly increased rosuvastatin exposure and gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of gemfibrozil with rosuvastatin tablets. Intervention: Avoid concomitant use of gemfibrozil with rosuvastatin tablets. If used concomitantly, initiate rosuvastatin tablets at 5 mg once daily and do not exceed a dose of rosuvastatin tablets 10 mg once daily.

Tafamidis Clinical

Impact: Tafamidis significantly increased rosuvastatin exposure and tafamidis may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of tafamidis with rosuvastatin tablets. Intervention: Avoid concomitant use of tafamidis with rosuvastatin tablets. If used concomitantly, initiate rosuvastatin tablets at 5 mg once daily and do not exceed a dose of rosuvastatin tablets 20 mg once daily. Monitor for signs of myopathy and rhabdomyolysis if used concomitantly with rosuvastatin tablets. Anti-Viral Medications Clinical Impact: Rosuvastatin plasma levels were significantly increased with concomitant administration of many anti-viral drugs, which increases the risk of myopathy and rhabdomyolysis. Intervention:

• Sofosbuvir/velpatasvir/voxilaprevir
• Ledipasvir/sofosbuvir Avoid concomitant use with rosuvastatin tablets.
• Simeprevir
• Dasabuvir/ombitasvir/paritaprevir/ritonavir
• Elbasvir/grazoprevir
• Sofosbuvir/velpatasvir
• Glecaprevir/pibrentasvir
• Atazanavir/ritonavir
• Lopinavir/ritonavir Initiate with rosuvastatin tablets 5 mg once daily, and do not exceed a dose of rosuvastatin tablets 10 mg once daily.

Darolutamide Clinical

Impact: Darolutamide increased rosuvastatin exposure more than 5-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Intervention: In patients taking darolutamide, do not exceed a dose of rosuvastatin tablets 5 mg once daily.

Regorafenib Clinical

Impact: Regorafenib increased rosuvastatin exposure and may increase the risk of myopathy. Intervention: In patients taking regorafenib, do not exceed a dose of rosuvastatin tablets 10 mg once daily. Fenofibrates (e.g., fenofibrate and fenofibric acid)

Clinical

Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with rosuvastatin tablets. Intervention: Consider if the benefit of using fibrates concomitantly with rosuvastatin tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.

Niacin Clinical

Impact: Cases of myopathy and rhabdomyolysis have occurred with concomitant use of lipid-modifying doses (≥1 g/day) of niacin with rosuvastatin tablets. Intervention: Consider if the benefit of using lipid-modifying doses (≥1 g/day) of niacin concomitantly with rosuvastatin tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.

Colchicine Clinical

Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with rosuvastatin tablets. Intervention: Consider if the benefit of using colchicine concomitantly with rosuvastatin tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.

Ticagrelor Clinical

Impact: Concomitant use of rosuvastatin tablets and ticagrelor has been shown to increase rosuvastatin concentrations, which may result in increased risk of myopathy. Cases of myopathy and rhabdomyolysis have been reported in patients using both products concomitantly. Cases have occurred more frequently in patients taking 40 mg of rosuvastatin. Intervention: In patients taking concomitant ticagrelor, especially those with additional risk factors for myopathy and rhabdomyolysis, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of rosuvastatin tablets.

7.2 Drug Interactions that Decrease the Efficacy of Rosuvastatin Tablets Table 6 presents drug interactions that may decrease the efficacy of rosuvastatin tablets and instructions for preventing or managing them.

Table

6: Drug Interactions that Decrease the Efficacy of Rosuvastatin Tablets Antacids Clinical Impact: Concomitant aluminum and magnesium hydroxide combination antacid administration decreased the mean exposure of rosuvastatin 50% [see Clinical Pharmacology (12.3) ] . Intervention: In patients taking antacid, administer rosuvastatin tablets at least 2 hours before the antacid .

7.3 Rosuvastatin Tablets Effects on Other Drugs Table 7 presents rosuvastatin tablets’s effect on other drugs and instructions for preventing or managing them.

Table

7: Rosuvastatin Tablets Effects on Other Drugs Warfarin Clinical Impact: Rosuvastatin significantly increased the INR in patients receiving warfarin [see Clinical Pharmacology (12.3) ] . Intervention: In patients taking warfarin, obtain an INR before starting rosuvastatin tablets and frequently enough after initiation, dose titration or discontinuation to ensure that no significant alteration in INR occurs. Once the INR is stable, monitor INR at regularly recommended intervals.