Rosuvastatin (Page 2 of 7)

5.3 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 (7.4)].

5.4 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 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.

5.5 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.

5.6 Risk of Allergic Reactions due to Tartrazine

This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

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 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-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 (5.4)]; 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 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 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

4.0

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=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 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

3.0

Diabetes mellitus

2.8

2.3

Nausea

2.4

2.3

1 Treatment-emergent adverse reactions by MedDRA preferred term.

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