Rozact

Rozact

rosuvastatin

Manufacturer:

Amarox
Full Prescribing Info
Contents
Rosuvastatin Ca.
Description
ROZACT Film coated tablet 10 mg, each film coated tablet contains: Rosuvastatin Calcium equivalent to Rosuvastatin 10 mg.
ROZACT Film coated tablet 20 mg, each film coated tablet contains: Rosuvastatin Calcium equivalent to Rosuvastatin 20 mg.
ROZACT Film coated tablet 40 mg, each film coated tablet contains: Rosuvastatin Calcium equivalent to Rosuvastatin 40 mg.
Action
Pharmacotherapeutic group: HMG-CoA reductase inhibitors.
Pharmacology: Pharmacodynamics: 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 of 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.
Pharmacokinetics: This study was designed as a randomized, single blind, two period, single dose, cross-over study with two weeks washout period in 25 healthy subjects under fasting condition. The study was conducted following an oral administration of one tablet 40 mg of the test drug or one tablet 40 mg of the reference drug.
Based on the pharmacokinetic parameters of Rosuvastatin (N = 25), mean ± SD for Test Drug and Reference Drug showed: Cmax values were 87.20 (46.27) and 96.98 (73.21) ng.mL-1, respectively; AUCt values were 699.40 (308.74) and 794.39 (408.08) h.ng.mL-1, respectively; AUCinf values were 723.29 (333.20) and 811.93 (415.65) h.ng.mL-1, respectively; Tmax values were 2.46 (1.13) and 2.42 (1.29) hours, respectively; T½ values were 13.70 (6.02) and 13.86 (5.00) hours, respectively.
Results from bioequivalence study for Test Drug and Reference Drug were as following: 90.00% Confidence Intervals of geometric means ratio of the two bioavailability parameters of Rosuvastatin were 81.45 - 108.95% for Cmax and 80.10 - 101.51% for AUCt. Intra subject CV (%) of Cmax and AUCt for Rosuvastatin were 29.97 and 24.42%, respectively.
Conclusion: These results showed that 40 mg Rosuvastatin film coated tablet was bioequivalent to the reference product.
Special populations: Age and sex: There was no relevant effect of age or sex on the pharmacokinetics of Rosuvastatin in adults.
Race: Pharmacokinetic studies show an approximate 2-fold elevation in median AUC in Asian subjects compared with Caucasians. A population pharmacokinetic analysis revealed no relevant differences in pharmacokinetics among Caucasian, Hispanic and Black or Afro-Caribbean groups.
Renal insufficiency: In subjects with varying degrees of renal impairment, mild to moderate renal disease had no influence on plasma concentrations of Rosuvastatin. However, subjects with severe impairment (CrCl < 30 mL/minute) had a 3-fold increase in plasma concentration compared to 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 other than in the 2 subjects with the most severe liver disease (Child-Pugh scores of 8 and 9). In these subjects systemic exposure was increased by at least 2-fold compared to subjects with lower Child-Pugh scores. There is no experience in subjects with Child-Pugh scores above 9.
Genetic polymorphisms: Disposition of HMG-CoA reductase inhibitors, including Rosuvastatin, involves OATP1B1 and BCRP transporter proteins. In patients with SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) genetic polymorphisms there is a risk of increased Rosuvastatin exposure. Individual polymorphisms of SLCO1B1 c.521CC and ABCG2 c.421AA are associated with an approximate 1.7-fold higher Rosuvastatin exposure (AUC) or 2.4-fold higher exposure, respectively, compared to the SLCO1B1 c.521TT or ABCG2 c.421CC genotypes. This specific genotyping is not established in clinical practice, but for patients who are known to have these types of polymorphisms, a lower daily dose of Rosuvastatin is recommended.
Indications/Uses
Patients with primary hypercholesterolaemia, (type IIa, including heterozygous familial hypercholesterolaemia) or mixed dyslipidaemia (type IIb) as an adjunct to diet when response to diet and exercise is inadequate.
Rosuvastatin reduces elevated LDL-cholesterol, total cholesterol, triglycerides and ApoB, and increases HDL-cholesterol.
Patients with homozygous familial hypercholesterolemia as an adjunct to diet and other lipid lowering treatments (e.g. LDL aphaeresis).
Dosage/Direction for Use
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.
Rosuvastatin may be given at any time of day, with or without food.
The recommended start dose is 5 or 10 mg orally once daily in both Statin naïve or patients switched from another HMG CoA reductase inhibitor. The choice of start dose should take into account the individual patient's cholesterol level and future cardiovascular risk as well as the potential risk for adverse reactions. A dose adjustment to the next dose level can be made after 4 weeks, if necessary. In light of the increased reporting rate of adverse reactions with the 40 mg dose compared to lower doses, a final titration to the maximum dose of 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. Specialist supervision is recommended when the 40 mg dose is initiated.
Use in children: 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 hypercholesterolemia. Therefore, Rosuvastatin is not recommended for paediatric use at this time.
Use in the elderly: A start dose of 5 mg is recommended in patients > 70 years. No other dose adjustment is necessary in relation to age.
Dosage in patients with renal insufficiency: No dose adjustment is necessary in patients with mild to moderate renal impairment. For patients with severe renal impairment (CLcr < 30 mL/minute/1.73 m2) not on haemodialysis, dosing of Rosuvastatin should be started at 5 mg once daily and not to exceeded 10 mg once daily.
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 and the dose of Rosuvastatin should not exceed 20 mg once daily. There is no experience in subjects with Child-Pugh scores above 9. Rosuvastatin is contraindicated in patients with active liver disease.
Race: A 5 mg starting dose of Rosuvastatin should be considered for Asian patients. Increased plasma concentration of Rosuvastatin has been seen in Asian subjects. The increased systemic exposure should be taken into consideration when treating Asian patients whose hypercholesterolaemia is not adequately controlled at doses up to 20 mg daily.
Dosage in patients with pre-disposing factors to myopathy: The recommended start dose is 5 mg in patients with predisposing factors to myopathy.
Concomitant therapy: Rosuvastatin is a substrate of various transporter proteins (e.g. OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) is increased when Rosuvastatin is administered concomitantly with certain medicinal products that may increase the plasma concentration of Rosuvastatin due to interactions with these transporter proteins (e.g. Ciclosporin and certain protease inhibitors including combinations of Ritonavir with Atazanavir, Lopinavir, and/or Tipranavir (see PRECAUTIONS and INTERACTIONS). Whenever possible, alternative medications should be considered, and if necessary, consider temporarily discontinuing Rosuvastatin therapy. In situations where co-administration of these medicinal products with Rosuvastatin is unavoidable, the benefit and the risk of concurrent treatment and Rosuvastatin dosing adjustments should be carefully considered (see INTERACTIONS).
Overdosage
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 in unlikely to be of benefit.
Contraindications
Patient with hypersensitivity to Rosuvastatin or to any of excipients.
Patient with active liver disease including unexplained, persistent elevations of serum transaminase and any serum transaminase elevation exceeding 3x the upper limit of normal (ULN).
Patient with myopathy.
Receiving concomitant Cyclosporine.
During pregnancy and lactation and in women of childbearing potential not using appropriate contraceptive measures.
Special 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. Proteinuria has not been shown to be predictive of acute or progressive renal disease. An assessment of renal 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. myalgia, myopathy and, rarely, rhabdomyolysis have been reported in Rosuvastatin in use is higher at the 40 mg dose.
Creatine kinase measurement: Creatine Kinase (CK) should be measured following strenuous exercise or in the presence of a plausible alternative cause of CK increase which may comfound interpretation of the result. If CK levels are significantly elevated at baseline (> 5 x ULN) a confirmatory test should be carried out within 5 - 7 days. If the repeat test confirms a baseline CK > 5 x ULN, 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 as 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 (see Pharmacology: Pharmacokinetics under Actions, Dosage & Administration and Interactions); Concomitant use of Fibrates.
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 (> 5 x ULN) 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 (> 5 x ULN) or if muscular symptoms are severe and cause daily discomfort (even if CK levels are ≤ 5 x 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.
There have been very rare reports of an immune-mediated necrotizing myopathy clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase during treatment or following discontinuation of Statins, including Rosuvastatin. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required.
There are increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitor together with fibric acid derivatives including Gemfibrozil, Ciclosporin, Nicotinic acid, Azole antifungals, protease inhibitors and Macrolide antibiotics. Gemfibrozil increases the risk of myopathy when given concomitantly with some HMG-CoA reductase inhibitors. 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. The 40 mg dose is contraindicated with concomitant use of a Fibrate (see INTERACTIONS and ADVERSE REACTIONS).
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 hypercholesterolemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with Rosuvastatin.
Diabetes mellitus: As with other HMG-CoA reductase inhibitors, increases in HbA1c and serum glucose levels have been observed in patients treated with Rosuvastatin.
Race: Pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasians.
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 pharmacodynamics 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.
Use In Pregnancy & Lactation
Pregnancy and lactation: Rosuvastatin is contraindicated during pregnancy or lactation as the safety of Rosuvastatin during pregnancy and whilst breast-feeding has not been established. 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. If a patient becomes pregnant during the use of this product, treatment should be discontinued immediately.
There are no data with respect to excretion in milk in humans.
Adverse Reactions
The frequencies of adverse events are ranked according to the following: Common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000), very rare (< 1/10000), not known (cannot be estimated from the available data).
Immune system disorders: Rare: Hypersensitivity reactions including angioedema.
Endocrine disorders: Common: Diabetes mellitus*.
Nervous system disorders: Common: Headache, dizziness.
Gastrointestinal disorders: Common: Constipation, nausea, abdominal pain.
Rare: Pancreatitis.
Skin and subcutaneous tissue disorders: Uncommon: Pruritus, rash and urticaria.
Musculoskeletal, connective tissue and bone disorders: Common: Myalgia.
Rare: Myopathy (including myositis) and rhabdomyolysis.
General disorders: Common: Asthenia.
Note: *Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol/L, BMI > 30 kg/m2, raised triglycerides, history of hypertension).
As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions tends to be dose dependent.
Renal effects: Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with Rosuvastatin. A minor increase in shift from none or trace to ++ or more were seen in < 1% of patients at some time during treatment with 10 and 20 mg and in approximately 3% of patients treated with 40 mg. A minor increase in shift from none or trace to + was observed with the 20 mg dose. In most cases, proteinuria decreases or disappears spontaneously on continued therapy and is not predictive acute or progressive renal disease.
Skeletal muscle effects: Rare cases of rhabdomyolysis which were occasionally associated with the impairment of renal function have been reported with Rosuvastatin and with other marketed Statins.
Laboratory effects: As with other HMG-CoA reductase inhibitors, a dose-related increase in transaminases and CK have been observed in a small number of patients taking Rosuvastatin; the majority of cases were mild, asymptomatic and transient. If CK levels are elevated (> 5 x ULN), treatment should be discontinued. Increases in HbA1c have also been observed in patients treated with Rosuvastatin.
Post Marketing experience: In addition to above, the following adverse event have been reported with Rosuvastatin and with other marketed Statins.
Haematological disorders: Frequency unknown: Thrombocytopenia.
Hepatobiliary disorders: Very rare: Jaundice, hepatitis.
Rare: Increased hepatic transaminases.
Musculoskeletal disorders: Frequency unknown: Immune-mediated necrotizing myopathy.
Very rare: Arthralgia.
Nervous system disorders: Very rare: Polyneuropathy, memory loss.
Psychiatric disorders: Frequency unknown: Depression, sleep disorders (including insomnia and nightmares).
Reproductive system and breast disorders: Frequency unknown: Gynaecomastia.
Drug Interactions
Effect of co-administered medicinal products on Rosuvastatin: Transporter protein inhibitors: In vitro and in vivo data indicate that Rosuvastatin has no clinically significant cytochrome P450 interactions (as a substrare, inhibitor or inducer). Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter proteins. Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of Rosuvastatin with medicinal products that are inhibitors of these transporter proteins may result in increased Rosuvastatin plasma concentrations and an increased risk of myopathy (see DOSAGE AND ADMINISTRATIONS).
Ciclosporin: Rosuvastatin is contraindicated in patients receiving concomitant Ciclosporin. Concomitant administration did not affect plasma concentrations of Ciclosporin.
Protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase Rosuvastatin exposure. The concomitant use of Rosuvastatin and some protease inhibitor combinations may be considered after careful consideration of Rosuvastatin dose adjustments based on the expected increase in Rosuvastatin exposure.
Gemfibrozil and other lipid-lowering products: Concomitant use of Rosuvastatin and Gemfibrozil resulted in a 2-fold increase in Rosuvastatin Cmax and AUC. Gemfibrozil, Fenofibrate, other Fibrates and lipid lowering doses (> or equal to 1 g/day) of Niacin (Nicotinic acid) increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone. The 40 mg dose is contraindicated with concomitant use of a Fibrate. These patients should also start with the 5 mg dose.
Ezetimibe: Concomitant use of Rosuvastatin and Ezetimibe resulted in no change to AUC for either drug when administered to healthy volunteers. There was a 1.2 fold increase in AUC of Rosuvastatin when 10 mg Rosuvastatin and 10 mg Ezetimibe was administered in hypercholesterolaemic subjects. A pharmacodynamic interaction, in terms of adverse effects, between Rosuvastatin and Ezetimibe cannot be ruled out.
Antacid: The simultaneous dosing of Rosuvastatin 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 Rosuvastatin.
Erythromycin: Concomitant use of Rosuvastatin and Erythromycin resulted in a 20% decrease in AUC and a 30% decrease in Cmax of Rosuvastatin. This interaction may be caused by the increase in gut motility caused by Erythromycin.
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 in a poor substrate for these isoenzymes. Therefore, drug interactions resulting from cytochrome P450-mediated metabolism are not expected. 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).
Interactions requiring Rosuvastatin dose adjustments: When it is necessary to co-administer Rosuvastatin with other medicinal products known to increase exposure to Rosuvastatin, doses of Rosuvastatin should be adjusted. Start with a 5 mg once daily dose of Rosuvastatin if the expected increase in exposure (AUC) is approximately 2-fold or higher. The maximum daily dose of Rosuvastatin should be adjusted so that the expected Rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of Rosuvastatin taken without interacting medicinal products, for example a 20 mg dose of Rosuvastatin with Gemfibrozil (1.9-fold increase), and a 10 mg dose of Rosuvastatin with combination Ritonavir/Atazanavir (3.1-fold increase). (See table.)


Click on icon to see table/diagram/image


Effect of Rosuvastatin on co-administered medicinal products: Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, the initiation of treatment or dosage up-titration of Rosuvastatin in patients treated concomitantly with vitamin K antagonists (e.g. Warfarin or another Coumarin anticoagulant) may result in an increase in International Normalised Ratio (INR). Discontinuation or down-titration of Rosuvastatin may result in a decrease in INR. In such situations, appropriate monitoring of INR is desirable.
Oral contraceptive/hormone replacement therapy (HRT): Concomitant use of Rosuvastatin and an oral contraceptive resulted in an increase in Ethinyl estradiol and Norgestrel. These increased plasma levels should be considered when selecting oral contraceptives doses.
Genetic polymorphisms: Genotypes of SLCOB1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA have been shown to be associated with an increase in Rosuvastatin exposure (AUC) compared to SLCO1B1 c.521TT and ABCG2 c.421CC. For patients known to have the c.521CC or c.421AA genotype, a maximum once daily dose of 20 mg of Rosuvastatin is recommended.
Storage
Store below 30°C.
ATC Classification
C10AA07 - rosuvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.
Presentation/Packing
FC tab 10 mg x 3 x 10's. 20 mg x 3 x 10's. 40 mg x 3 x 10's.
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