Rosuvastatin Calcium Tablets

Rosuvastatin Calcium Tablets
Generic name: Rosuvastatin Calcium Tablets
Brand name: Softan
Composition:
The main ingredient of this product is Rosuvastatin Calcium.
Chemical name: calcium (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethan-3- ylsulfonamido)
pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate
Chemical structure:
Molecular formula: (C22H27FN3O6S)2 Ca
Molecular weight: 1001.14
Description:
This product is film-coated tablets, remove the coating was white or almost white.
Indications:
This product is suitable for primary hypercholesterolemia (type IIa) or mixed dyslipidemia (type IIb) that is not
adequately controlled by dyslipidemia due to dietary control and other non-medical treatments (eg exercise
therapy, weight loss).This product is also suitable for patients with homozygotic familial hypercholesterolemia
as adjuvant therapy for dietary control and other lipid-lowering measures such as LDL removal, or if
treatments are not appropriate.
Strength:(1) 5 mg (based on C22H27FN3O6S); (2) 5 mg (based on C22H27FN3O6S);
Dosage and 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, and considering patient's individual cholesterol levels, expected cardiovascular risk, and potential
risk of adverse reactions.Oral. This product commonly used initial dose of 5 mg, once daily. The initial dose
should be selected taking into account patient's individual cholesterol level, expected cardiovascular risk, and
the potential risk of adverse reactions. For those who need to lower LDL-C more strongly, consider 10 mg
once daily as the starting dose, which will control the level of blood lipids in most patients. If necessary, dose
levels up can be adjusted after 4 weeks of treatment. The daily maximum dose of this product is 20 mg.
This product can be administered at any time of the day, can be taken when eating or on an empty stomach.
Dosage in patients with renal insufficiency:
No need to adjust dose in patients with mild and moderate renal impairment. Patients with severe impairment
disable all doses of this product.
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.
In these patients an assessment of renal function should be considered. There is no experience in subjects
with Child-Pugh scores above 9. Rosuvastatin Calcium Tablets are contraindicated in patients with active liver
disease.
Race:
Asian subjects have been observed with increased systemic exposure.This factor should be considered when
deciding the dosage of a patient of Asian descent.
Contraindications:
Rosuvastatin Calcium Tablets are contraindicated:
- in patients with hypersensitivity to the active substance or any of the excipients of this product.
- in patients with active liver disease including unexplained, persistent 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 <30 mL/min).
- in patients with myopathy.
- in patients receiving concomitant ciclosporin.
- during pregnancy and lactation and in women of childbearing potential not using appropriate contraceptive
measures.
Precautions:
Renal Effects
Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated
with higher doses of rosuvastatin, in particular 40 mg, where it was transient or intermittent in most cases.
Skeletal Muscle Effects
Effects on skeletal muscle e.g. myalgia, myopathy and, , rhabdomyolysis have been reported in rosuvastatin-
treated patients with all doses and in particular with doses > 20 mg.
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 (>5xULN) a confirmatory test should be carried out within 5-7 days. If the repeat test
confirms a baseline CK >5xULN, treatment should not be started.
Before Treatment
Rosuvastatin, as with other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with
pre-disposing factors for myopathy/rhabdomyolysis.
Such factors include:
• 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
• situations where an increase in plasma levels may occur
• concomitant use of fibrates.
In such patients the risk of treatment should be considered in relation to possible benefit clinical monitoring is
recommended. If CK levels are significantly elevated at baseline (>5xULN) 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 patients. Therapy should be discontinued
if CK levels are markedly elevated (>5xULN) or if muscular symptoms are severe and cause daily discomfort
(even if CK levels are ≤ 5x ULN). If symptoms resolve and CK levels return to normal, then consideration
should be given to re-introducing rosuvastatin 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 rosuvastatin 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, ciclosporin, nicotinic acid, azole antifungals, protease inhibitors macrolide
antibiotics. Gemfibrozil increases the risk of myopathy when given concomitantly with some HMG-CoA
reductase inhibitors. Therefore, the combination of rosuvastatin and gemfibrozil is not recommended. The
benefit of further alterations in lipid levels by the combined use of rosuvastatin with fibrates or niacin should
be carefully weighed against the potential risks of such combinations.
Rosuvastatin 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, rosuvastatin 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 carried out prior to, and 3 months following, the initiation of treatment. Rosuvastatin 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 hypercholesterolaemia caused by hypothyroidism or nephrotic
syndrome, the underlying disease should be treated prior to initiating therapy with rosuvastatin.
Race
Pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasians.
Protease inhibitors
The concomitant use with protease inhibitors is not recommended.
Effects on ability to drive and use machines
Studies to determine the effect of rosuvastatin on the ability to drive and use machines have not been
conducted. However, based on its pharmacodynamic properties, rosuvastatin is unlikely to affect this ability.
When driving vehicles or operating machines, it should be taken into account that dizziness may occur during
treatment.
Pharmacology and toxicology:
Pharmacology
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.
In patients with homozygous and heterozygous familial hypercholesterolemia, non-familial hypercholesterole
mia, mixed dyslipidemia, rosuvastatin can reduce total cholesterol, LDL-C, ApoB, non-HDL-C levels.
Rosuvastatin also lowers TG and increases HDL-C levels. Rosuvastatin can reduce total cholesterol, LDL-C,
VLDL-C, ApoB, non-HDL-C, TG levels and increase HDL-C levels hypertriglyceridemic patients. The impact
of rosuvastatin on the morbidity and mortality of cardiovascular disease has not been established.
Toxicology
Central nervous system toxicity
Several dog trials of similar drugs found CNS vascular injury, showing perivascular hemorrhage, edema,
perivascular mononuclear cell infiltration. A drug similar in structure to this class of drugs appears to have a
dose-dependent optic nerve degeneration (retinal-kinetochore Wallerian degeneration) at doses of dog
plasma drug concentrations higher than the 30-fold average concentration of the human plasma.
1 female dog orally administered rosuvastatin 90 mg/kg/day (calculated by AUC, systemic expose equivalent
to 100 times the human 40 mg/day exposure), euthanasia was applied to this dog at the 24th day because it's
dying, we can see choroid plexus edema, hemorrhage and partial necrosis. Administration of rosuvastatin
6 mg/kg/day (calculated by AUC, systemic exposure equivalent to 20 times the human 40 mg/day exposure)
for 52 weeks, corneal turbidity can be seen. Dog oral administration of rosuvastatin 30 mg/kg/day (calculated
according to AUC, systemic exposure equivalent to 60 times the human 40 mg/day exposure) for 12
consecutive weeks, visible cataract. Dog oral administration of rosuvastatin 90 mg/kg/day (calculated by AUC
, systemic exposure equivalent to 100 times the human 40 mg/day exposure) for 4 weeks, showing retinal
dysplasia and retinal detachment. Dog at dose ≤30 mg/kg/day (calculated by AUC, systemic exposure
equivalent to 60 times the human 40 mg/day exposure), continuous administration of 1 year, no effect on the
retina.
Genetic toxicity
In the Ames test, mouse lymphoma test, CHL cell chromosome aberration test, and mouse micronucleus test,
the results of rosuvastatin were all negative.
Reproductive toxicity
In the rat fertility test, male rats were orally administered 5, 15 and 50 mg/kg/day from 9 weeks before mating
to mating, and female rats were orally administered 5, 15 and 50 mg/kg/day from 2 weeks before mating to 7
days of gestation. At the highest dose (calculated by AUC, systemic exposure equivalent to 10 times the
human 40 mg/day exposure), no adverse effects on fertility. Dogs were orally administered rosuvastatin 30
mg/kg/day for 1 month, the giant sperm cells (Spermatidic giant cell) were found in the testes. The monkey
orally administered rosuvastatin 30 mg/kg/day for 6 months, showing giant sperm cells, vas deferens
epithelial vacuoles. The above dose of dog and monkey estimated by body surface area equivalent to
20 times and 10 times the human 40 mg/day exposure, respectively. Similar drugs can also see a similar
phenomenon.
Female rats oral administration of 5,15,50 mg/kg/day from pre-mating to 7 days after mating, high-dose group
(calculated by AUC, body exposure equivalent to 10 times the human 40 mg/day exposure) shows fetal body
weight reduce and ossification delay.
The rats were orally administered with 2, 10, 50 mg/kg/day from the 7th day of pregnancy to the 21st day of
lactation (ablactation) and the high dose group (calculated by body surface area, body exposure equivalent to
12 times the human 40 mg/day exposure or more) shows survival rates of cub is reduced. Rabbits orally were
administered 0.3,1,3 mg/kg/day from the 6th day of pregnancy to the 18th day of lactation (ablactation), and
the high dose group ((calculated by body surface area, body exposure equivalent to the human 40 mg/day
exposure) shows reduced fetal survival rates of cub and maternal animals death. When dose of rosuvastatin
was ≤25 mg/kg/day in rats ≤3 mg/kg/day in rabbits. No teratogenicity was observed (equivalent to a human
exposure of 40 mg/day, calculated by AUC and body surface area, respectively).
Carcinogenicity
In a 104-week carcinogenicity test in rats, the oral dose was 2, 20, 60, 80 mg/kg/day. 80 mg/kg/day dose
group (calculated according to AUC, systemic exposure equivalent to 20 times the human 40 mg/day
exposure) of female animals showed a significant increase in the incidence of uterine polyps, no increase in
the low doses.In a 107-week carcinogenicity test in mice, the dose was orally administered at 10, 60, 200 mg
/kg/day. 200 mg/kg/day dose group (calculated according to AUC, systemic exposure equivalent to 20 times
the human 40 mg/day exposure) of animals showed increased incidence of hepatocellular adenoma/cancer,
no increase in the low doses.
Pharmacokinetics:
The pharmacokinetics of rosuvastatin in caucasian people showed that:
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.
Biotransformation: 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 lactone form is considered clinically
inactive.
Rosuvastatin accounts for greater than 90% of the circulating HMG-CoA reductase inhibitor activity.
Elimination: 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 50 litres/hour (coefficient of variation 21.7%).
As with other HMG-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 daily doses.
only about 10% of rosuvastatin is metabolized at the oral dose, mainly N-bit demethylation.
Special populations:
Age and sex: Age or sex did not have a clinically significant effect on rosuvastatin pharmacokinetics.
Renal impairment: 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 N-desmethyl metabolite. Subjects
with severe impairment (CrCl <30 mL/min) had a 3-fold increase in plasma concentration and a 9increase in
the N-desmethyl metabolite concentration compared healthy volunteers. Steady-state plasma concentrations
of rosuvastatin in subjects undergoing haemodialysis were approximately 50% greater compared to healthy
volunteers.
Hepatic impairment: 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.
Race: Pharmacokinetic studies show an approximate 2-fold elevation in median AUC and Cmax in Asian
subjects (Japanese, Chinese, Filipino, Vietnamese and Koreans) compared with Caucasians. A population
pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics between Caucasian
and Black groups.
Studies have shown that: Chinese single-dose administration of healthy volunteers, tmax median range of
2.5-5 hours, followed by an exponential decline. The half-life (t1/2) is about 11 to 12 hours. The third day of
multiple administrations. Blood concentration reached steady state. After repeated administration, drug
accumulation is small, and has nothing to do with the dose.
Storage:Protect from light, and seal up.
Packs:Package material: Blister packaging;5 mg: 7 tablets/blister, 10 tablets/blister, 12 tablets/blister;
10 mg: 7 tablets/blister, 10 tablets/blister, 12 tablets/blister, 7 tablets/blister x 2 blisters/box, 7 tablets/blister
x 4 blisters/box.
Shelf-life:24 months