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Why is Crestor (Rosuvastatin) prescribed?
Crestor Composition
Each tablet contains 5 mg, 10 mg, 20 mg, or 40 mg of
rosuvastatin calcium.
Primary hypercholesterolemia (type IIa including heterozygous familial hypercholesterolemia) or mixed dyslipidaemia (type lIb) as an adjunct to diet when response to diet and other non-pharmacological treatments (e.g. exercise, weight reduction) is inadequate.
Homozygous familial hypercholesterolemia as an adjunct to diet and other lipid lowering treatments (e.g. LDL apheresis) or if such treatments are not appropriate.
Posology and method of administration
Before treatment initiation the patient should be placed
on a standard cholesterol-lowering diet that should
continue during treatment. The dose should be
individualised according to the goal of therapy and
patient response, using current consensus guidelines.
The recommended start dose is 5 or 10 mg once daily in
both statin naive patients or patients switched from
another HMG CoA reductase inhibitor. The choice of
starting dose should take into account the individual
patients cholesterol level and future cardiovascular
risk as well as the potential risk for adverse
reactions. A dose adjustment to 20 mg can be made after
2 to 4 weeks, if necessary (see Pharmacodynamic
properties). A doubling of the dose to 40 mg should only
be considered in patients with severe
hypercholesterolaemia at high cardiovascular risk (in
particular those with familial hypercholesterolaemia),
who do not achieve their treatment goal on 20 mg, and in
whom routine follow-up will be performed (see Special
warnings and precautions for use).
Crestor may be given at any time of day, with or without
food.
Paediatric use
Safety and efficacy have not been established in
children. Paediatric experience is limited to a
small number of children (aged 8 years or
above) with homozygous familial hypercholesterolaemia.
Therefore, Crestor is not recommended for paediatric use
at this time.
Use in the elderly
No dose adjustment is necessary.
Dosage in patients with renal insuffiecncy
No dose adjustment is necessary in patients with mild to
moderate renal impairment. The use of Crestor in
patients with severe renal impairment is contraindicated
(see Contraindications and Pharmacokinetic properties),
Dosage in patients with hepatic impairment
There was no increase in systemic exposure to
rosuvastatin in subjects with Child-Pugh scores of 7 or
below. However, increased systemic exposure has been
observed in subjects with Child-Pugh scores of 8 and 9
(see Pharmacokinetic properties), in
these patients an assessment of renal function should be
considered (see Special warnings and precautions
for use). There is no experience in subjects
with Child-Pugh scores above 9. Crestor is
contraindicated in patients with active liver disease
(see Contraindications).
Race
Increased plasma concentration of rosuvastatin has been
seen in Asian subjects (see Special
warnings and precautions for use
and Pharmacokinetic properties). The
increased systemic exposure should be taken into
consideration when treating Asian patients particularly
in those whose hypercholesterolemia is not adequately
controlled at doses up to 20 mg/daily.
CONTRAINDICATIONS
Crestor is contraindicated:
-
 in
patients with hypersensitivity to
rosuvastatin or to any of the excipients.
in
patients with active liver disease including
unexplained, persistant elevations of serum
transaminases
and any serum transaminase elevation exceeding 3 x
the upper limit of normal (ULN).
in
patients with severe renal impairment (creatinine
clearance <80 ml/rnin).
in
patients with myopathy.
in
patients receiving concomitant cyclosporin.
during
pregnancy and lactation and in women of childbearing
potential opt using appropriate contraceptive
measures.
SPECIAL WARNINGS AND PRECAUTIONS OF USE
Renal Effects
In the rosuvastatin clinincal 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 itwas generally transistentand was not
associated with worsening renal function. An assessment
ofrenal function should be considered during routine
follow-up of patients treated with a dose of 40 mg.
Skeletal Muscle Effects
As with other HMG-CoA reductase inhibitors, effects on
skeletal muscle e.g. uncomplicated myalgia, myopathy
and, rarely, rhabdomyolysis, have been reported in
patients treated with rosuvastatin. As with other
HMG-CoA reductase inhibitors, the reporting rate for
rhabdomyolysis in post-marketing use is higher at the
highest marketed dose.
Creatine Kinase Measurement
Creatine Kinase (CK) should not be measured following
strenuous exercise or in the presence of a plausible
alternative cause of CK increase which may confound
interpretation of the result. If CK levels are
significantly elevated at baseline (>5x Upper Limit of
Normal) a confirmatory test should be carried out within
5-7 days. If the repeat test confirms a baseline CK >5x
Upper Limit of Normal, treatment should not be started.
Before Treatment
Crestor, as with other HMG-CoA reductase inhibitors,
should be prescribed with caution in patients with
pre-disposing factors for rhabdomyolysis, such as,
renal
impairment
hypothyroidism
personal
or family history of hereditary muscular disorders
previous
history of muscular toxicity with another HMG-CoA
reductase inhibitor or fibrate
alcohol
abuse
age
>70 years
In such patients the risk of treatment should be
considered in relation to possible benefit and clinical
monitoring is recommended. If CK levels are
significantly elevated at baseline (>5x Upper Limit of
Normal) treatment should not be started.
Whilst on Treatment
Patients should be asked to report inexplicable muscle
pain, weakness or cramps immediately, particularly if
associated with malaise or fever. CK levels should be
measured in these patients. Therapy should be
discontinued if CK levels are markedly elevated (< 5x
Upper Limit of Normal) or if muscular symptoms are
severe and cause daily discomfort (even if CK levels
are s 5x Upper Limit of Normal). If symptoms
resolve and CK levels return to normal, then
consideration should be given to re-introducing Crestor
or an alternative HMG-CoA reductase inhibitor at the
lowest dose with close monitoring.
Routine monitoring of CK levels in asymptomatic patients
is not warranted.
In clinical trials there was no evidence of increased
skeletal muscle effects in the small number of patients
dosed with Crestor and concomitant therapy. However, an
increase in the incidence of myositis and myopathy has
been seen in patients receiving other HMG-CoA reductase
inhibitors together with fibric acid derivatives
including gemfibrozil, cyclosporin, nicotinic acid,
azole antifungals, protease inhibitors and macrolide
antibiotics. Gemfibrozil increases the risk of
myopathy when given concomitantly with some HMG-CoA
reductase inhibitors. , Therefore, the combination of
Crestor and gemfibrozil is not recommended. The benefit
of further alterations in lipid levels by the combined
use of Crestor with fibrates or niacin should be
carefully weighed against the potential risks of such
combinations. (See Interactions and Undesirable effects)
Crestor should be prescribed with caution in patients
with predisposing factors for myopathy, such as, renal
impairment, advanced age and hypothyroidism, or
situations where an increase in plasma levels may occur
(See Pharmacokinetic properties).
Crestor should not be used 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, major surgery,
trauma, severe metabolic, endocrine and electrolyte
disorders; or uncontrolled seizures).
Liver Effects
As with other HMG-CoA reductase inhibitors, Crestor
should be used with caution in patients who consume
excessive quantities of alcohol and/or have a history of
liver disease. It is recommended that liver function
tests be performed before and at 3 months following both
the initiation oi therapy and any elevation of dose, and
periodically thereafter. Crestor should be discontinued
or the dose reduced if the level of serum transaminases
is greater than 3 times the upper limit of normal.
In patients with secondary hypercholeserolaemia caused
by hypothyoroidism or nephrotic syndrome, the underlying
disease should be treated prior to initiating therapy
with Crestor
Race
Pharmacokinetic studies show an increase in exposure in
Asian subjects compared with Caucasians (see
Posology and Method of administration
and Pharmacokinetic properties)
INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND OTHER
FORMS OF INTERACTIONS
Cyclosporin: During concomitant
treatment with Crestor and cyclosporin, rosuvastatin AUC
values were on average seven times higher than those
observed in healthy volunteers (see
Contraindications).
Concomitant administration did not affect plasma
concentrations of cyclosporin.
Vitamin K antagonists:
As with other HMG-CoA reductase inhibitors, the
initiation of treatment or dosage up-titration of
Crestor in patients treated concomitantly with vitamin K
antagonists (e.g. warfarin) may result in an increase in
International Normalised Ratio (INR). Discontinuation or
down-titration of Crestor may result in a decrease in
INR. In such situations, appropriate monitoring of INR
is desirable.
Gemfibrozil:
As with other HMG-CoA reductase inhibitors, concomitant
use of Crestor and gemfibrozil resulted in a 2-fold
increase in rosuvastatin Cmax and AUC (see
Special warnings and precautions for use).
Antacid:
The simultaneous dosing of Crestor with an antacid
suspension containing aluminium and magnesium hydroxide
resulted in a decrease in rosuvastatin plasma
concentration of approximately 50%. This effect was
mitigated when the antacid was dosed 2 hours after
Crestor. The clinical relevance of this interaction has
not been studied.
Erythromycin:
Concomitant use of Crestor and erythromycin resulted in
a 20% decrease in AUC (0-t) and a 30% decrease in Cmax
of rosuvastatin. This interaction may be caused by the
increase in gut motility caused by erythromycin
Oral contraceptive/hormone replacement therapy (HRT):
Concomitant use of Crestor and an oral contraceptive
resulted in an increase in ethinyl oestradiol and
norgestrel AUC of 26% and 34%, respectively. These
increased plasma levels should be considered when
selecting oral contraceptive doses. There are no
pharmacokinetic data available in subjects taking
concomitant Crestor and HRT and therefore a similar
effect cannot be excluded. However, the combination has
been extensively used in women in clinical trials and
was well tolerated.
Other medicinal products:
Based on data from specific interaction studies no
clinically relevant interactions with digoxin or
fenofibrate are expected. Gemfibrozil, other fibrates
and lipid lowering doses (> or equal to fg/day)
of niacin (nicotinic acid) increase the risk of myopathy
when given concomitantly with some HMG-CoA reductase
inhibitors, probably because they can produce myopathy
when given alone (see Special warnings and
precautions for use).
Cytochrome P450 enzymes:
Results from in vitro and in vivo
studies show that rosuvastatin is neither an inhibitor
nor an inducer of cytochrome P450 isoenzymes. In
addition, rosuvastatin is a poor substrate for these
isoenzymes. No clinically relevant interactions have
been observed between rosuvastatin and either
fluconazole (an inhibitor of CYP2C9 and CYP3A4) or
ketoconazole (an inhibitor of CYP2A6 and CYP3A4).
Concomitant administration of itraconazole (an inhibitor
of CYP3A4) and rosuvastatin resulted in a 28% increase
in AUC of rosuvastatin. This small increase is not
considered clinically significant. Therefore, drug
interactions resulting from cytochrome P45Q-mediated
metabolism are not expected
PREGNANCY AND LACTATION
Crestor is contraindicated in pregnancy and lactation.
Women of child bearing potential should use appropriate
contraceptive measures.
Since cholesterol and other products of cholesterol
biosynthesis are essential for the development of the
foetus, the potential risk from inhibition of HMG-CoA
reductase outweighs the advantage of treatment during
pregnancy. Animal studies provide limited evidence of
reproductive toxicity (see Preclinical safety data). If
a patient becomes pregnant during use of this product,
treatment should be discontinued immediately.
Rosuvastatin is excreted in the milk of rats. There are
no data with respect to excretion in milk in humans (see
Contraindications).
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
Studies to determine the effect of Crestor on the
ability to drive and use machines have not been
conducted. However, based on its pharmacodynamic
properties, Crestor is unlikely to affect this ability.
When driving vehicles or operating machines, it should
be taken into account that dizziness may occur during
treatment.
UNDESIRABLE EFFECTS
The adverse events seen with Crestor are generally mild
and transient. In controlled clinical trials, less than
4% of Crestor-treated patients were withdrawn due to
adverse events.
The frequencies of adverse events are ranked
according to the following:
Common (>1/100, <1/10); Uncommon (>1/1000, 1/100 );
Rare (>1>10.000, <1/1000);
Nervous system disorders
Common: headache, dizziness
Gastrointestinal disorders
Common: constipation, nausea, abdominal pain
Musculoskeletal, connective tissue and bone
disorders
Common: myalgia
Rare: myopathy (including myositis) and rhabdomyolysis
Skin disorders
Uncommon: Pruritus, rash and urticaria
Hypersensitivity
Rare: hypersensitivity reactions including angioedema
General disorders
Common: asthenia
As with other HMG-CoA reductase inhibitors, the
incidence of adverse drug reactions tends to be dose
dependent.
Renal Effects:
Refer to "Special warnings and precautions for
use"
Skeletal muscle effects:
As with other HMG-CoA reductase inhibitors, effects on
skeletal muscle e.g. uncomplicated myalgia and myopathy
(including myositis), have been reported in Crestor-treated
patients Rare cases of rhabdomyolysis, which were
occasionally associated with impairment of renal
function, have been reported with rosuvastatin and with
other marketed statins.
A dose-related increase in CK levels has been observed
in a small number of patients taking rosuvastatin; the
majority of cases were mild, asymptomatic and transient.
If CK levels are elevated (>5x Upper Limit of Normal),
treatment should be temporarily discontinued (see
Special warnings and precautions for use).
Liver effects:
As with other HMG-CoA reductase Inhibitors, a
dose-related increase in transaminases has been observed
in a small number of patients taking rosuvastatin; the
majority of cases were mild, asymptomatic and transient.
Post Marketing Experience:
In addition to the above, the following adverse events
have been reported during post marketing experience for
Creator.
Skeletal Muscle Effects:
As with other HMG-CoA reductase inhibitors, the
reporting rate for rhabdomyolysis in post-marketing use
is higher at the highest marketed dose.
Hepatobiliary disorders:
Very rare: Jaundice, hepatitis;
Rare: Increased hepatic transaminases.
OVERDOSE
There is no specific treatment in the event of overdose.
In the event of overdose, the patient should be treated
symptomatically and supportive measures instituted as
required. Liver function and CK levels should be
monitored. Haemodialysis is unlikely to be of benefit.
PHARMACODYNAMIC PROPERTIES
Pharmacotherapeutic group: HMG-CoA reductase inhibitors
Mechanism of action:
Rosuvastatin is a selective and competitive inhibitor of
HMG-CoA reductase, the rate-limiting enzyme that
converts 3-hydroxy-3-methylglutaryl coenzyme A to
mevalonate, a precursor for cholesterol The primary site
of action of rosuvastatin is the liver, the target organ
for cholesterol lowering.
Rosuvastatin increases the number of hepatic LDL
receptors on the cell-surface, enhancing uptake and
catabolism of LDL and it inhibits the hepatic synthesis
of VLDL, thereby reducing the total number of VLDL and
LDL particles.
Pharmacodynamic effects
Crestor reduces elevated LDL-cholesterol, total
cholesterol and triglycerides and increases HDL
cholesterol It also lowers ApoB, nonHOL-C, VLDL-C, VLDL-TG
and increases ApoA-l (see Table 1) Crestor also lowers
LOL-C/WDL-C, total C/HDL-C and nonHDL-C/HDL-C and the
ApoB/ApoA-l ratios.
Table 1: Dose response in patients with primary
hypercholesterolemia (type Ha and lib) (adjusted mean
percent change from baseline)
A therapeutic effect is obtained within 1 week
following treatment initiation and 90% of maximum
response is achieved in 2 weeks. The maximum response is
usually achieved by 4 weeks and is maintained after
that.
Clinical efficacy
Crestor is effective in adults with
hyporcholesterolaemia, with and without
hypertriglyceridaemia, regardless of race, sex, or age
and in special populations such as diabetics, or
patients with familial hyporcholesterolaemia.
From pooled phase III data, Crestor has
been shown to be effective at treating the majority of
patients with type Ha and lib hypercholesterolaemia
(mean baseline LDL-C about 4.8 mmol/l) to recognised
European Atherosclerosis Society (EAS; 1998) guideline
targets; about 80% of patients treated with 10 mg
reached the EAS targets for LDL-C levels (<3 mmol/l).
In a large study, 435 patients with heterozygous
familial hypercholesterolaemia were given Crestor from
20 mg to 80 mg in a force-titration design. All doses
showed a beneficial effect on lipid parameters and
treatment to target goals. Following titration to a
daily dose of 40 mg (12 weeks of treatment), LDL-C was
reduced by 53%. 33% of patients reached EAS guidelines
for LDL-C levels (<3 mmol/l).
In a force-titration, open label trial, 42 patients with
homozygous familial hypercholesterolaemia were evaluated
for their response, to Crestor 20 - 40 mg. In the
overall population, the mean LDL-C reduction was 22%.
In clinical studies with a limited number of patients,
Crestor has been shown to have additive efficacy in
lowering triglycerides when used in combination with
fenofibrate and in increasing HDL- C levels when used in
combination with niacin (see Special warnings
and precautions for use).
Rosuvastatin has not been proven to prevent the
associated complications of lipid abnormalities, such as
coronary heart disease as mortality and morbidity
studies with Crestor have not yet been completed
PHARMACOKINETIC PROPERTIES
Absorption: Maximum rosuvastatin plasma
concentrations are achieved approximately 5 hours after
oral administration. The absolute bioavailability is
approximately 20%.
Distribution: Rosuvastatin is taken up
extensively by the liver which is the primary site of
cholesterol synthesis and LDL-C clearance. The volume of
distribution of rosuvastatin is approximately 134 L.
Approximately 90% of rosuvastatin is bound to plasma
proteins, mainly to albumin.
Metabolism: Rosuvastatin undergoes
limited metabolism, (approximately 10%). In vitro
metabolism studies using human hepatocytes indicate that
rosuvastatin is a poor substrate for cytochrome
P450-based metabolism. CYP2C9 was the principal
isoenzyme involved, with 2C19, 3A4 and 2D6 involved to a
lesser extent. The main metabolites identified are the
N-desmethyl and lactone metabolites. The N-desmethyl
metabolite is approximately 50% less active than
rosuvastatin whereas the lactone form is considered
clinically inactive. Rosuvastatin accounts for greater
than 90% of the circulating HMG-CoA reductase Inhibitor
activity.
Excretion: Approximately 90% of the
rosuvastatin dose is excreted unchanged in the faeces
(consisting of absorbed and non-absorbed active
substance) and the remaining part is excreted in urine.
Approximately 5% is excreted unchanged In urine. The
plasma elimination half-life is approximately 19 hours.
The elimination half-life does not Increase at higher
doses. The geometric mean plasma clearance is
approximately 60 litres/hour (coefficient of variation
21.7%). As with other HMQ-CoA reductase inhibitors, the
hepatic uptake of rosuvastatin involves the membrane
transporter OATP-C. This transporter is Important in the
hepatic elimination of rosuvastatin.
Linearity: Systemic exposure of
rosuvastatin increases In proportion to dose. There are
no changes in pharmacokinetic parameters following
multiple dally doses
Special populations:
Age and sex: There was no clinically
relevant effect of age or on the pharmacokinetics of
rosuvastatin.
Race: Pharmacokinetic studies show an
approximate 2-fold elevation in median AUC and Cmax in
Asian subjects compared with Caucasians. A population
pharmacokinetic analysis revealed no clinically relevant
differences in pharmacokinetic among Caucasian, Hispanic
and Black or Afro-Caribbean groups
Renal Insufficiency: In a study in
subjects with varying degrees of renal impairment, mild
to moderate renal disease had no influence on plasma
concentration of rosuvastatin or the M-desmethyl
metabolite. Subjects with severe impairment (CrCl <30
ml/min) had a 3-fold increase in plasma concentration
and a 9-fold increase in the N-desmethyl metabolite
concentration compared to healthy volunteers.
Steady-state plasma concentrations of rosuvastatin in
subjects undergoing haemodialysis were approximately 50%
greater compared to healthy volunteers.
Hepatic Insufficiency: In a study with
subjects with varying degrees of hepatic impairment
there was no evidence of increased exposure to
rosuvastatin in subjects with Child-Pugh scores of 7 or
below. However, two subjects with Child-Pugh scores of 8
and 9 showed an increase in systemic exposure of at
least 2-fold compared to subjects with lower Child-Pugh
scores. There is no experience in subjects with
Child-Pugh scores above 9.
Preclinical safety data:
Preclinical data reveal no special hazard for humans
based on conventional studies of safety pharmacology,
repeated dose toxicity, genotoxicity and carcinogenicity
potential. In a rat pre-and postnatal study,
reproductive toxicity was evident from reduced liner
sizes, litter weight and pup survival. These effects
were observed at maternotoxic doses at systemic
exposures several times above the therapeutic exposure
level
List of excipients
Tablet core
Lactose monohydrate
Microcrystalline cellulose
Calcium phosphate
Crospovidone
Magnesium stearate
Tablet coat
Lactose monohydrate
Hypromellose
Glycerol triacetate
Titanium dioxide (E171)
Ferric oxide, red (E172)
Incompatibilities
Not applicable.
Shelf-life
Please refer to expiry date on outer carton.
Special precautions for storage
Do not store above 30°C. Store in the original package
Pack Size
Please refer to outer carton for pack size.
Instructions for use and handling
No special requirements.
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