Crestor Drug Information

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse reactions reported in ≥2% of patients in placebo-controlled clinical studies and at a rate greater than placebo are shown in Table 2. These studies had a treatment duration of up to 12 weeks. Table 2: Adverse Reactions Reported in ≥2% of Patients Treated with CRESTOR and > Placebo in Placebo-Controlled Trials Adverse Reactions Placebo N=382 % CRESTOR 5 mg N=291 % CRESTOR 10 mg N=283 % CRESTOR 20 mg N=64 % CRESTOR 40 mg N=106 % Total CRESTOR 5 mg ‑ 40 mg N=744 % Headache 5.0 5.5 4.9 3.1 8.5

Nausea 3.1 3.8 3.5 6.3 0 3.4 Myalgia 1.3 3.1 2.1 6.3

1.9

Asthenia 2.6 2.4 3.2 4.7 0.9 2.7 Constipation 2.4 2.1 2.1 4.7

2.8

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; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities. In the METEOR study, patients were treated with CRESTOR 40 mg (n=700) or placebo (n=281) with a mean treatment duration of 1.7 years.

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 CRESTOR and > Placebo in the METEOR Trial Adverse Reactions Placebo N=281 % CRESTOR 40 mg N=700 % Myalgia 12.1

Arthralgia 7.1 10.1 Headache 5.3 6.4 Dizziness 2.8 4.0 Increased

CPK 0.7

Abdominal pain 1.8 2.4

ALT greater than 3x ULN Frequency recorded as abnormal laboratory value. 0.7

In the

JUPITER study, patients were treated with CRESTOR 20 mg (n=8,901) or placebo (n=8,901) for a mean duration of 2 years. In JUPITER, there was a significantly higher frequency of diabetes mellitus reported in patients taking CRESTOR (2.8%) versus patients taking placebo (2.3%). Mean HbA1c was significantly increased by 0.1% in CRESTOR-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 CRESTOR-treated versus placebo-treated patients . Adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 4. Table 4: Adverse Reactions Reported in ≥2% of Patients Treated with CRESTOR and > Placebo in the JUPITER Trial Adverse Reactions Placebo N=8901 % CRESTOR 20 mg N=8901 % Myalgia 6.6

Pediatric Patients with HeFH

In a 12‑week controlled study in pediatric patients 10 to 17 years of age with HeFH with CRESTOR 5 mg to 20 mg daily , elevations in serum CK greater than 10 x ULN were observed more frequently in CRESTOR-treated patients compared with patients receiving placebo. Four of 130 (3%) patients treated with CRESTOR (2 treated with 10 mg and 2 treated with 20 mg) had increased CK greater than 10 x ULN, compared to 0 of 46 patients on placebo.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of CRESTOR. 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. Blood Disorders : thrombocytopenia Hepatobiliary Disorders : hepatitis, jaundice, fatal and non-fatal hepatic failure Musculoskeletal Disorders : arthralgia, rare reports of immune-mediated necrotizing myopathy associated with statin use Nervous System Disorders : peripheral neuropathy, rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, and confusion) associated with the use of 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). 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.

Psychiatric Disorders : depression, sleep disorders (including insomnia and nightmares) Reproductive System and Breast Disorders : gynecomastia Respiratory Disorders : interstitial lung disease Skin and Subcutaneous Tissue Disorders : drug reaction with eosinophilia and systemic symptoms (DRESS), lichenoid drug eruption

• See full prescribing information for details regarding concomitant use of CRESTOR with other drugs that increase the risk of myopathy and rhabdomyolysis. ( 7.1 ) Aluminum and Magnesium Hydroxide Combination Antacids : Administer CRESTOR at least 2 hours before the antacid. ( 7.2 ) Warfarin : Obtain INR prior to starting CRESTOR. Monitor INR frequently until stable upon initiation, dosage titration or discontinuation. ( 7.3 ) 7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with CRESTOR 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 CRESTOR 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 CRESTOR Sofosbuvir/velpatasvir/voxilaprevir or Ledipasvir/sofosbuvir Prevention or Management: Avoid concomitant use with CRESTOR. Mechanism and Clinical Effect(s): Rosuvastatin plasma levels were significantly increased with concomitant administration of many anti-viral drugs, which increases the risk of myopathy and rhabdomyolysis. Gemfibrozil Prevention or Management: Avoid concomitant use of gemfibrozil with CRESTOR. If use is unavoidable, initiate CRESTOR at 5 mg once daily and do not exceed a dosage of CRESTOR 10 mg once daily . Mechanism and Clinical Effect(s): Gemfibrozil significantly increased rosuvastatin exposure and gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Tafamidis Prevention or Management: Avoid concomitant use of tafamidis with CRESTOR. If use is unavoidable, initiate CRESTOR at 5 mg once daily and do not exceed a dosage of CRESTOR 20 mg once daily. Monitor for signs of myopathy and rhabdomyolysis if used concomitantly with CRESTOR . Mechanism and Clinical Effect(s): Tafamidis significantly increased rosuvastatin exposure and tafamidis may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Belumosudil Prevention or Management: In patients taking belumosudil, do not exceed a dosage of CRESTOR 5 mg once daily . Mechanism and Clinical Effect(s): Belumosudil increased rosuvastatin exposure more than 4.6-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Cyclosporine Prevention or Management: In patients taking cyclosporine, do not exceed a dosage of CRESTOR 5 mg once daily. Mechanism and Clinical Effect(s): Cyclosporine increased rosuvastatin exposure 7-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Darolutamide Prevention or Management: In patients taking darolutamide, do not exceed a dosage of CRESTOR 5 mg once daily . Mechanism and Clinical Effect(s): Darolutamide increased rosuvastatin exposure more than 5-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use . Additional Anti-Viral Medications Prevention or Management:
• Simeprevir
• Dasabuvir/ombitasvir/paritaprevir/ritonavir
• Elbasvir/grazoprevir
• Sofosbuvir/velpatasvir
• Glecaprevir/pibrentasvir
• Atazanavir/ritonavir
• Lopinavir/ritonavir Initiate with CRESTOR 5 mg once daily, and do not exceed a dosage of CRESTOR 10 mg once daily. Mechanism and Clinical Effect(s): Rosuvastatin plasma levels were significantly increased with concomitant administration of many anti-viral drugs, which increases the risk of myopathy and rhabdomyolysis. Capmatinib Prevention or Management: In patients taking capmatinib, do not exceed a dosage of CRESTOR 10 mg once daily . Mechanism and Clinical Effect(s): Capmatinib increased rosuvastatin exposure more than 2.1-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Enasidenib Prevention or Management: In patients taking enasidenib, do not exceed a dosage of CRESTOR 10 mg once daily . Mechanism and Clinical Effect(s): Enasidenib increased rosuvastatin exposure more than 3.4-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Momelotinib Prevention or Management: In patients taking momelotinib, do not exceed a dosage of CRESTOR 10 mg once daily. Mechanism and Clinical Effect(s): Momelotinib increased rosuvastatin exposure by 2.7-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Regorafenib Prevention or Management: In patients taking regorafenib, do not exceed a dosage of CRESTOR 10 mg once daily . Mechanism and Clinical Effect(s): Regorafenib increased rosuvastatin exposure and may increase the risk of myopathy and rhabdomyolysis. Teriflunomide Prevention or Management: In patients taking teriflunomide, do not exceed a dosage of CRESTOR 10 mg once daily . Mechanism and Clinical Effect(s): Teriflunomide increased rosuvastatin exposure more than 2.5-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Ticagrelor Prevention or Management: In patients taking ticagrelor, do not exceed a dosage of CRESTOR 20 mg once daily. In patients at increased risk for rhabdomyolysis [ see Warnings and Precautions (5.1) ], consider dosages less than 20 mg per day. Mechanism and Clinical Effect(s): Ticagrelor increased rosuvastatin exposure by 2.3-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Febuxostat Prevention or Management: In patients taking febuxostat, do not exceed a dosage of CRESTOR 20 mg once daily . Mechanism and Clinical Effect(s): Febuxostat increased rosuvastatin exposure more than 1.9-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Fostamatinib Prevention or Management: In patients taking fostamatinib, do not exceed a dosage of CRESTOR 20 mg once daily . Mechanism and Clinical Effect(s): Fostamatinib increased rosuvastatin exposure more than 2.0-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Fenofibrates (e.g., fenofibrate and fenofibric acid) Prevention or Management: Consider if the benefit of using fibrates concomitantly with CRESTOR 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 dosage titration of either drug. Mechanism and Clinical Effect(s): Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use. Colchicine Prevention or Management: Consider if the benefit of using colchicine concomitantly with CRESTOR 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 dosage titration of either drug. Mechanism and Clinical Effect(s): Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with CRESTOR. Niacin Prevention or Management: Consider if the benefit of using lipid-modifying dosages (≥1 g/day) of niacin concomitantly with CRESTOR 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 dosage titration of either drug. Mechanism and Clinical Effect(s): Cases of myopathy and rhabdomyolysis have occurred with concomitant use of lipid-modifying dosages (≥1 g/day) of niacin with CRESTOR. 7.2 Drug Interactions that Decrease the Efficacy of CRESTOR Table 6 presents drug interactions that may decrease the efficacy of CRESTOR and instructions for preventing or managing them. Table 6: Drug Interactions that Decrease the Efficacy of CRESTOR Antacids Prevention or Management: In patients taking an antacid, administer CRESTOR at least 2 hours before the antacid . Mechanism and Clinical Effect(s): Concomitant aluminum and magnesium hydroxide combination antacid administration decreased the mean exposure of rosuvastatin 50% [see Clinical Pharmacology (12.3) ]. 7.3 CRESTOR Effects on Other Drugs Table 7 presents CRESTOR’s effect on other drugs and instructions for preventing or managing them. Table 7: CRESTOR Effects on Other Drugs Warfarin Prevention or Management: In patients taking warfarin, obtain an INR before starting CRESTOR and frequently enough after initiation, dosage titration or discontinuation to ensure that no significant alteration in INR occurs. Once the INR is stable, monitor INR at regularly recommended intervals. Mechanism and Clinical Effect(s): Rosuvastatin significantly increased the INR in patients receiving warfarin [see Clinical Pharmacology (12.3) ].

Pregnancy Risk Summary Discontinue CRESTOR when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. CRESTOR decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, CRESTOR may cause fetal harm when administered to pregnant patients based on the mechanism of action . In addition, treatment of hypercholesterolemia is not generally necessary during pregnancy.

Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with CRESTOR use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data). In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered rosuvastatin during the period of organogenesis at doses that resulted in systemic exposures equivalent to human exposures at the maximum recommended human dose (MRHD) of 40 mg/day, based on AUC and body surface area (mg/m2), respectively (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data A Medicaid cohort linkage study of 1,152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus.

There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births.

Animal Data In female rats given 5, 15 and 50 mg/kg/day before mating and continuing through to gestation day 7 resulted in decreased fetal body weight (female pups) and delayed ossification at 50 mg/kg/day (10 times the human exposure at the MRHD of 40 mg/day based on AUC). In pregnant rats given 2, 10 and 50 mg/kg/day of rosuvastatin from gestation day 7 through lactation day 21 (weaning), decreased pup survival occurred at 50 mg/kg/day (dose equivalent to 12 times the MRHD of 40 mg/day based body surface area). In pregnant rabbits given 0.3, 1, and 3 mg/kg/day of rosuvastatin from gestation day 6 to day 18, decreased fetal viability and maternal mortality was observed at 3 mg/kg/day (dose equivalent to the MRHD of 40 mg/day based on body surface area). Rosuvastatin crosses the placenta in rats and rabbits and is found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats. In rabbits, fetal tissue distribution was 25% of maternal plasma concentration after a single oral gavage dose of 1 mg/kg on gestation day 18.

Pediatric Use The safety and effectiveness of CRESTOR as an adjunct to diet to reduce LDL-C have been established in pediatric patients 8 years of age and older with HeFH. Use of CRESTOR for this indication is based on one 12-week controlled trial with a 40-week open-label extension period in 176 pediatric patients 10 years of age and older with HeFH and one 2‑year open-label, uncontrolled trial in 175 pediatric patients 8 years of age and older with HeFH . In the 1-year trial with a 12-week controlled phase, there was no detectable effect of CRESTOR on growth, weight, BMI (body mass index), or sexual maturation in patients aged 10 to 17 years. The safety and effectiveness of CRESTOR as an adjunct to other LDL-C-lowering therapies to reduce LDL-C have been established in pediatric patients 7 years of age and older with HoFH. Use of CRESTOR for this indication is based on a randomized, placebo-controlled, cross-over study in 14 pediatric patients 7 years of age and older with HoFH . The safety and effectiveness of CRESTOR have not been established in pediatric patients younger than 8 years of age with HeFH, younger than 7 years of age with HoFH, or in pediatric patients with other types of hypercholesterolemia (other than HeFH or HoFH).

• is contraindicated in patients with:
• Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3) ] .
• Hypersensitivity to rosuvastatin or any excipients in CRESTOR. Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema have been reported with CRESTOR [see Adverse Reactions (6.1) ] . Acute liver failure or decompensated cirrhosis. ( 4 ) Hypersensitivity to rosuvastatin or any excipients in CRESTOR. ( 4 )

No specific antidotes for CRESTOR are known. Hemodialysis does not significantly enhance clearance of rosuvastatin. In the event of overdose, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.