A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Crestor Side Effects, and Drug Interactions - Rosuvastatin
Crestor Side Effects, and Drug Interactions - Rosuvastatin
SIDE EFFECTS
Rosuvastatin is generally well tolerated. Adverse reactions
have usually been mild and transient. In clinical studies of 10,275 patients,
3.7% were discontinued due to adverse experiences attributable to rosuvastatin.
The most frequent adverse events thought to be related to rosuvastatin were
myalgia, constipation, asthenia, abdominal pain, and nausea.
Clinical Adverse Experiences
Adverse experiences, regardless of causality assessment, reported
in ³2% of patients in placebo-controlled clinical
studies of rosuvastatin are shown in Table 6; discontinuations due to adverse
events in these studies of up to 12 weeks duration occurred in 3% of patients
on rosuvastatin and 5% on placebo.
|
Table 6. Adverse Events in Placebo-Controlled Studies
|
| |
Rosuvastatin
|
Placebo
|
|
Adverse Event
|
N=744
|
N=382
|
|
Pharyngitis
|
9.0
|
7.6
|
|
Headache
|
5.5
|
5.0
|
|
Diarrhea
|
3.4
|
2.9
|
|
Dyspepsia
|
3.4
|
3.1
|
|
Nausea
|
3.4
|
3.1
|
|
Myalgia
|
2.8
|
1.3
|
|
Asthenia
|
2.7
|
2.6
|
|
Back Pain
|
2.6
|
2.4
|
|
Flu syndrome
|
2.3
|
1.8
|
|
Urinary tract infection
|
2.3
|
1.6
|
|
Rhinitis
|
2.2
|
2.1
|
|
Sinusitis
|
2.0
|
1.8
|
In addition, the following adverse events were reported, regardless
of causality assessment, in ³1% of 10,275 patients
treated with rosuvastatin in clinical studies. The events in italics occurred
in ³2% of these patients.
Body as a Whole: Abdominal pain, accidental injury, chest pain,
infection, pain, pelvic pain, and neck pain.
Cardiovascular System: Hypertension, angina pectoris, vasodilatation,
and palpitation.
Digestive System: Constipation, gastroenteritis, vomiting,
flatulence, periodontal abscess, and gastritis.
Endocrine: Diabetes mellitus.
Hemic and Lymphatic System: Anemia and ecchymosis.
Metabolic and Nutritional Disorders: Peripheral edema.
Musculoskeletal System: Arthritis, arthralgia, and pathological
fracture.
Nervous System: Dizziness, insomnia, hypertonia, paresthesia,
depression, anxiety, vertigo and neuralgia.
Respiratory System: Bronchitis, cough increased, dyspnea, pneumonia,
and asthma.
Skin and Appendages: Rash and pruritus.
Laboratory Abnormalities: In the rosuvastatin clinical trial
program, dipstick-positive proteinuria and microscopic hematuria were observed
among rosuvastatin-treated patients, predominantly in patients dosed above the
recommended dose range (i.e., 80 mg). However, this finding was more frequent
in patients taking rosuvastatin 40 mg, when compared to lower doses of rosuvastatin
or comparator statins, though it was generally transient and was not associated
with worsening renal function. (See PRECAUTIONS,
Laboratory Tests.)
Other abnormal laboratory values reported were elevated creatinine
phosphokinase, transaminases, hyperglycemia, glutamyl transpeptidase, alkaline
phosphatase, bilirubin, and thyroid function abnormalities.
Other adverse events reported less frequently than 1% in the
rosuvastatin clinical study program, regardless of causality assessment, included
arrhythmia, hepatitis, hypersensitivity reactions (i.e., face edema, thrombocytopenia,
leukopenia, vesiculobullous rash, urticaria, and angioedema), kidney failure,
syncope, myasthenia, myositis, pancreatitis, photosensitivity reaction, myopathy,
and rhabdomyolysis.
DRUG INTERACTIONS
Cyclosporine: When rosuvastatin 10 mg was co-administered
with cyclosporine in cardiac transplant patients, rosuvastatin mean Cmax
and mean AUC were increased 11-fold and 7-fold, respectively, compared with
healthy volunteers. These increases are considered to be clinically significant
and require special consideration in the dosing of rosuvastatin to patients
taking concomitant cyclosporine (see WARNINGS,
Myopathy/Rhabdomyolysis, and DOSAGE AND ADMINISTRATION).
Warfarin: Coadministration of rosuvastatin to patients
on stable warfarin therapy resulted in clinically significant rises in INR (>4,
baseline 2-3). 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.
Once a stable INR time has been documented, INR can be monitored at the intervals
usually recommended for patients on coumarin anticoagulants. If the dose of
rosuvastatin is changed, the same procedure should be repeated. Rosuvastatin
therapy has not been associated with bleeding or with changes in INR in patients
not taking anticoagulants.
Gemfibrozil: Coadministration of a single rosuvastatin
dose to healthy volunteers on gemfibrozil (600 mg twice daily) resulted in 2.2-
and 1.9-fold, respectively, increase in mean Cmax and mean AUC of
rosuvastatin (see DOSAGE AND ADMINISTRATION).
Endocrine Function
Although clinical studies have shown that rosuvastatin alone
does not reduce basal plasma cortisol concentration or impair adrenal reserve,
caution should be exercised if any HMG-CoA reductase inhibitor or other agent
used to lower cholesterol levels is administered concomitantly with drugs that
may decrease the levels or activity of endogenous steroid hormones such as ketoconazole,
spironolactone, and cimetidine.
CNS Toxicity
CNS vascular lesions, characterized by perivascular hemorrhages,
edema, and mononuclear cell infiltration of perivascular spaces, have been observed
in dogs treated with several other members of this drug class. A chemically
similar drug in this class produced dose-dependent optic nerve degeneration
(Wallerian degeneration of retinogeniculate fibers) in dogs, at a dose that
produced plasma drug levels about 30 times higher than the mean drug level in
humans taking the highest recommended dose. Edema, hemorrhage, and partial necrosis
in the interstitium of the choroid plexus was observed in a female dog sacrificed
moribund at day 24 at 90 mg/kg/day by oral gavage (systemic exposures 100 times
the human exposure at 40 mg/day based on AUC comparisons). Corneal opacity was
seen in dogs treated for 52 weeks at 6 mg/kg/day by oral gavage (systemic exposures
20 times the human exposure at 40 mg/day based on AUC comparisons). Cataracts
were seen in dogs treated for 12 weeks by oral gavage at 30 mg/kg/day (systemic
exposures 60 times the human exposure at 40 mg/day based on AUC comparisons).
Retinal dysplasia and retinal loss were seen in dogs treated for 4 weeks by
oral gavage at 90 mg/kg/day (systemic exposures 100 times the human exposure
at 40 mg/day based on AUC). Doses =30 mg/kg/day (systemic exposures =60 times
the human exposure at 40 mg/day based on AUC comparisons) following treatment
up to one year, did not reveal retinal findings.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104-week carcinogenicity study in rats at dose levels
of 2, 20, 60, or 80 mg/kg/day by oral gavage, the incidence of uterine stromal
polyps was significantly increased in females at 80 mg/kg/day at systemic exposure
20 times the human exposure at 40 mg/day based on AUC. Increased incidence of
polyps was not seen at lower doses.
In a 107-week carcinogenicity study in mice given 10, 60, 200
mg/kg/day by oral gavage, an increased incidence of hepatocellular adenoma/carcinoma
was observed at 200 mg/kg/day at systemic exposures 20 times human exposure
at 40 mg/day based on AUC. An increased incidence of hepatocellular tumors was
not seen at lower doses.
Rosuvastatin was not mutagenic or clastogenic with or without
metabolic activation in the Ames test with Salmonella typhimurium and Escherichia
coli, the mouse lymphoma assay, and the chromosomal aberration assay in Chinese
hamster lung cells. Rosuvastatin was negative in the in vivo mouse micronucleus
test.
In rat fertility studies with oral gavage doses of 5, 15, 50
mg/kg/day, males were treated for 9 weeks prior to and throughout mating and
females were treated 2 weeks prior to mating and throughout mating until gestation
day 7. No adverse effect on fertility was observed at 50 mg/kg/day (systemic
exposures up to 10 times human exposure at 40 mg/day based on AUC comparisons).
In testicles of dogs treated with rosuvastatin at 30 mg/kg/day for one month,
spermatidic giant cells were seen. Spermatidic giant cells were observed in
monkeys after 6-month treatment at 30 mg/kg/day in addition to vacuolation of
seminiferous tubular epithelium. Exposures in the dog were 20 times and in the
monkey 10 times human exposure at 40 mg/day based on body surface area comparisons.
Similar findings have been seen with other drugs in this class.
Pregnancy
Pregnancy Category X
See CONTRAINDICATIONS.
Rosuvastatin may cause fetal harm when administered to a pregnant
woman. Rosuvastatin is contraindicated in women who are or may become pregnant.
Safety in pregnant women has not been established. There are no adequate and
well-controlled studies of rosuvastatin in pregnant women. Rosuvastatin crosses
the placenta 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. A higher fetal tissue distribution
(25% maternal plasma concentration) was observed in rabbits after a single oral
gavage dose of 1 mg/kg on gestation day 18. If this drug is administered to
a woman with reproductive potential, the patient should be apprised of the potential
hazard to a fetus.
In female rats given oral gavage doses of 5, 15, 50 mg/kg/day
rosuvastatin before mating and continuing through day 7 postcoitus results in
decreased fetal body weight (female pups) and delayed ossification at the high
dose (systemic exposures 10 times human exposure at 40 mg/day based on AUC comparisons).
In pregnant rats given oral gavage doses of 2, 20, 50 mg/kg/day
from gestation day 7 through lactation day 21 (weaning), decreased pup survival
occurred in groups given 50 mg/kg/day, systemic exposures ³12
times human exposure at 40 mg/day based on body surface area comparisons.
In pregnant rabbits given oral gavage doses of 0.3, 1, 3 mg/kg/day
from gestation day 6 to lactation day 18 (weaning), exposures equivalent to
human exposure at 40 mg/day based on body surface area comparisons, decreased
fetal viability and maternal mortality was observed.
Rosuvastatin was not teratogenic in rats at £25
mg/kg/day or in rabbits £3 mg/kg/day (systemic exposures
equivalent to human exposure at 40 mg/day based on AUC or body surface comparison,
respectively).
Nursing Mothers
It is not known whether rosuvastatin is excreted in human milk.
Studies in lactating rats have demonstrated that rosuvastatin is secreted into
breast milk at levels 3 times higher than that obtained in the plasma following
oral gavage dosing. Because many drugs are excreted in human milk and because
of the potential for serious adverse reactions in nursing infants from rosuvastatin,
a decision should be made whether to discontinue nursing or administration of
rosuvastatin taking into account the importance of the drug to the lactating
woman.
Pediatric Use
The safety and effectiveness in pediatric patients have not
been established. Treatment experience with rosuvastatin in a pediatric
population is limited to 8 patients with homozygous FH. None of these patients
was below 8 years of age.
Geriatric Use
Of the 10,275 patients in clinical studies with rosuvastatin,
3,159 (31%) were 65 years and older, and 698 (6.8%) were 75 years and older.
The overall frequency of adverse events and types of adverse events were similar
in patients above and below 65 years of age. (See WARNINGS,
Myopathy/Rhabdomyolysis.)
The efficacy of rosuvastatin in the geriatric population (³65
years of age) was comparable to the efficacy observed in the non-elderly.
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