Atorvastatin Sandoz

Specific treatment is not available for Atorvastatin Sandoz overdose. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required. Liver function tests should be performed and serum CK levels should be monitored. Due to extensive Atorvastatin Sandoz binding to plasma proteins, haemodialysis is not expected to significantly enhance Atorvastatin Sandoz clearance.

Pharmacotherapeutic group: Lipid modifying agents, HMG-CoA-reductase inhibitors, ATC code: C10AA05

Atorvastatin Sandoz is a selective, competitive inhibitor of HMG-CoA reductase, the rate- limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl- coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low-density lipoproteins (VLDL) and released into the plasma for delivery to peripheral tissues. Low-density lipoprotein (LDL) is formed from VLDL and is catabolized primarily through the receptor with high affinity to LDL (LDL receptor).

Atorvastatin Sandoz lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver and increases the number of hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL.

Atorvastatin Sandoz reduces LDL production and the number of LDL particles. Atorvastatin Sandoz produces a profound and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles. Atorvastatin Sandoz is effective in reducing LDL-C in patients with homozygous familial hypercholesterolaemia, a population that has not usually responded to lipid-lowering medicinal products.

Atorvastatin Sandoz has been shown to reduce concentrations of total-C (30% - 46%), LDL-C (41% - 61%), apolipoprotein B (34% - 50%), and triglycerides (14% - 33%) while producing variable increases in HDL-C and apolipoprotein A1 in a dose response study. These results are consistent in patients with heterozygous familial hypercholesterolaemia, nonfamilial forms of hypercholesterolaemia, and mixed hyperlipidaemia, including patients with noninsulin-dependent diabetes mellitus.

Reductions in total-C, LDL-C, and apolipoprotein B have been proven to reduce risk for cardiovascular events and cardiovascular mortality.

Homozygous familial hypercholesterolaemia

In a multicenter 8 week open-label compassionate-use study with an optional extension phase of variable length, 335 patients were enrolled, 89 of which were identified as homozygous familial hypercholesterolaemia patients. From these 89 patients, the mean percent reduction in LDL-C was approximately 20%. Atorvastatin Sandoz was administered at doses up to 80 mg/day.

Atherosclerosis

In the Reversing Atherosclerosis with Aggressive Lipid-Lowering Study (REVERSAL), the effect of intensive lipid lowering with Atorvastatin Sandoz 80 mg and standard degree of lipid lowering with pravastatin 40 mg on coronary atherosclerosis was assessed by intravascular ultrasound (IVUS), during angiography, in patients with coronary heart disease. In this randomised, double- blind, multicenter, controlled clinical trial, IVUS was performed at baseline and at 18 months in 502 patients. In the Atorvastatin Sandoz group (n=253), there was no progression of atherosclerosis.

The median percent change, from baseline, in total atheroma volume (the primary study criteria) was -0.4% (p=0.98) in the Atorvastatin Sandoz group and +2.7% (p=0.001) in the pravastatin group (n=249). When compared to pravastatin the effects of Atorvastatin Sandoz were statistically significant (p=0.02). The effect of intensive lipid lowering on cardiovascular endpoints (e. g. need for revascularisation, non fatal myocardial infarction, coronary death) was not investigated in this study.

In the Atorvastatin Sandoz group, LDL-C was reduced to a mean of 2.04 mmol/L ± 0.8 (78.9 mg/dl ± 30) from baseline 3.89 mmol/l ± 0.7 (150 mg/dl ± 28) and in the pravastatin group, LDL-C was reduced to a mean of 2.85 mmol/l ± 0.7 (110 mg/dl ± 26) from baseline 3.89 mmol/l ± 0.7 (150 mg/dl ± 26) (p<0.0001). Atorvastatin Sandoz also significantly reduced mean TC by 34.1% (pravastatin: -18.4%, p<0.0001), mean TG levels by 20% (pravastatin: -6.8%, p<0.0009), and mean apolipoprotein B by 39.1% (pravastatin: - 22.0%, p<0.0001). Atorvastatin Sandoz increased mean HDL-C by 2.9% (pravastatin: +5.6%, p=NS). There was a 36.4% mean reduction in CRP in the Atorvastatin Sandoz group compared to a 5.2% reduction in the pravastatin group (p<0.0001).

Study results were obtained with the 80 mg dose strength. Therefore, they cannot be extrapolated to the lower dose strengths.

The safety and tolerability profiles of the two treatment groups were comparable.

The effect of intensive lipid lowering on major cardiovascular endpoints was not investigated in this study. Therefore, the clinical significance of these imaging results with regard to the primary and secondary prevention of cardiovascular events is unknown.

Acute coronary syndrome

In the MIRACL study, Atorvastatin Sandoz 80 mg has been evaluated in 3,086 patients (Atorvastatin Sandoz n=1,538; placebo n=1,548) with an acute coronary syndrome (non Q-wave MI or unstable angina).

Prevention of cardiovascular disease

The effect of Atorvastatin Sandoz on fatal and non-fatal coronary heart disease was assessed in a randomized, double-blind, placebo-controlled study, the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA). Patients were hypertensive, 40- 79 years of age, with no previous myocardial infarction or treatment for angina, and with TC levels ≤ 6.5 mmol/l (251 mg/dl). All patients had at least 3 of the pre-defined cardiovascular risk factors: male gender, age > 55 years, smoking, diabetes, history of CHD in a first-degree relative, TC:HDL-C > 6, peripheral vascular disease, left ventricular hypertrophy, prior cerebrovascular event, specific ECG abnormality, proteinuria/albuminuria. Not all included patients were estimated to have a high risk for a first cardiovascular event.

Patients were treated with anti-hypertensive therapy (either amlodipine or atenolol- based regimen) and either Atorvastatin Sandoz 10 mg daily (n=5,168) or placebo (n=5,137).

The absolute and relative risk reduction effect of Atorvastatin Sandoz was as follows:

¹ Based on difference in crude events rates occurring over a median follow-up of 3.3 years.

CHD = coronary heart disease; MI = myocardial infarction.

Total mortality and cardiovascular mortality were not significantly reduced (185 vs. 212 events, p=0.17 and 74 vs. 82 events, p=0.51). In the subgroup analyses by gender (81% males, 19% females), a beneficial effect of Atorvastatin Sandoz was seen in males but could not be established in females possibly due to the low event rate in the female subgroup. Overall and cardiovascular mortality were numerically higher in the female patients (38 vs. 30 and 17 vs. 12), but this was not statistically significant. There was significant treatment interaction by antihypertensive baseline therapy. The primary endpoint (fatal CHD plus non-fatal MI) was significantly reduced by Atorvastatin Sandoz in patients treated with amlodipine (HR 0.47 (0.32-0.69), p=0.00008), but not in those treated with atenolol (HR 0.83 (0.59-1.17), p=0.287).

The effect of Atorvastatin Sandoz on fatal and non-fatal cardiovascular disease was also assessed in a randomized, double-blind, multicenter, placebo-controlled trial, the Collaborative Atorvastatin Sandoz Diabetes Study (CARDS) in patients with type 2 diabetes, 40-75 years of age, without prior history of cardiovascular disease, and with LDL-C ≤ 4.14 mmol/l (160 mg/dl) and TG ≤ 6.78 mmol/l (600 mg/dl). All patients had at least 1 of the following risk factors: hypertension, current smoking, retinopathy, microalbuminuria or macroalbuminuria.

Patients were treated with either Atorvastatin Sandoz 10 mg daily (n=1,428) or placebo (n=1,410) for a median follow-up of 3.9 years.

The absolute and relative risk reduction effect of Atorvastatin Sandoz was as follows:

¹ Based on difference in crude events rates occurring over a median follow-up of 3.9 years.

AMI = acute myocardial infarction; CABG = coronary artery bypass graft; CHD = coronary heart disease; MI = myocardial infarction; PTCA = percutaneous transluminal coronary angioplasty.

There was no evidence of a difference in the treatment effect by patient's gender, age, or baseline LDL-C level. A favourable trend was observed regarding the mortality rate (82 deaths in the placebo group vs. 61 deaths in the Atorvastatin Sandoz group, p=0.0592).

Recurrent stroke

In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, the effect of Atorvastatin Sandoz 80 mg daily or placebo on stroke was evaluated in 4731 patients who had a stroke or transient ischemic attack (TIA) within the preceding 6 months and no history of coronary heart disease (CHD). Patients were 60% male, 21- 92 years of age (average age 63 years), and had an average baseline LDL of 133 mg/dL (3.4 mmol/L). The mean LDL-C was 73 mg/dL (1.9 mmol/L) during treatment with Atorvastatin Sandoz and 129 mg/dL (3.3 mmol/L) during treatment with placebo. Median follow-up was 4.9 years.

Atorvastatin Sandoz 80 mg reduced the risk of the primary endpoint of fatal or non-fatal stroke by 15% (HR 0.85; 95% CI, 0.72-1.00; p=0.05 or 0.84; 95% CI, 0.71-0.99; p=0.03 after adjustment for baseline factors) compared to placebo. All cause mortality was 9.1% (216/2365) for Atorvastatin Sandoz versus 8.9% (211/2366) for placebo.

In a post-hoc analysis, Atorvastatin Sandoz 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% vs. 274/2366, 11.6%, p=0.01) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%, p=0.02) compared to placebo.

− The risk of hemorrhagic stroke was increased in patients who entered the study with prior hemorrhagic stroke (7/45 for Atorvastatin Sandoz versus 2/48 for placebo; HR 4.06; 95% CI, 0.84-19.57), and the risk of ischemic stroke was similar between groups (3/45 for Atorvastatin Sandoz versus 2/48 for placebo; HR 1.64; 95% CI, 0.27-9.82).

− The risk of hemorrhagic stroke was increased in patients who entered the study with prior lacunar infarct (20/708 for Atorvastatin Sandoz versus 4/701 for placebo; HR 4.99; 95% CI, 1.71-14.61), but the risk of ischemic stroke was also decreased in these patients (79/708 for Atorvastatin Sandoz versus 102/701 for placebo; HR 0.76; 95% CI, 0.57-1.02). It is possible that the net risk of stroke is increased in patients with prior lacunar infarct who receive Atorvastatin Sandoz 80 mg/day.

All cause mortality was 15.6% (7/45) for Atorvastatin Sandoz versus 10.4% (5/48) in the subgroup of patients with prior hemorrhagic stroke. All cause mortality was 10.9% (77/708) for Atorvastatin Sandoz versus 9.1% (64/701) for placebo in the subgroup of patients with prior lacunar infarct.

Paediatric Population

Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 6-17 years old

An 8-week, open-label study to evaluate pharmacokinetics, pharmacodynamics, and safety and tolerability of Atorvastatin Sandoz was conducted in children and adolescents with genetically confirmed heterozygous familial hypercholesterolemia and baseline LDL-C > 4 mmol/L. A total of 39 children and adolescents, 6 to 17 years of age, were enrolled. Cohort A included 15 children, 6 to 12 years of age and at Tanner Stage 1. Cohort B included 24 children, 10 to 17 years of age and at Tanner Stage > 2.

The initial dose of Atorvastatin Sandoz was 5 mg daily of a chewable tablet in Cohort A and 10 mg daily of a tablet formulation in Cohort B. The Atorvastatin Sandoz dose was permitted to be doubled if a subject had not attained target LDL-C of < 3.35 mmol/L at Week 4 and if Atorvastatin Sandoz was well tolerated.

Mean values for LDL-C, TC, VLDL-C, and Apo B decreased by Week 2 among all subjects. For subjects whose dose was doubled, additional decreases were observed as early as 2 weeks, at the first assessment, after dose escalation. The mean percent decreases in lipid parameters were similar for both cohorts, regardless of whether subjects remained at their initial dose or doubled their initial dose. At Week 8, on average, the percent change from baseline in LDL-C and TC was approximately 40% and 30%, respectively, over the range of exposures.

Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 10-17 years old

In a double-blind, placebo controlled study followed by an open-label phase, 187 boys and postmenarchal girls 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (FH) or severe hypercholesterolaemia were randomised to Atorvastatin Sandoz (n=140) or placebo (n=47) for 26 weeks and then all received Atorvastatin Sandoz for 26 weeks.).

Absorption

Atorvastatin Sandoz is rapidly absorbed after oral administration; maximum plasma concentrations (C_max) occur within 1 to 2 hours. Extent of absorption increases in proportion to Atorvastatin Sandoz dose. After oral administration, Atorvastatin Sandoz film-coated tablets are 95% to 99% bioavailable compared to the oral solution. The absolute bioavailability of Atorvastatin Sandoz is approximately 12% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism

Distribution

Mean volume of distribution of Atorvastatin Sandoz is approximately 381 l. Atorvastatin Sandoz is > 98% bound to plasma proteins.

Biotransformation

Atorvastatin Sandoz is metabolized by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta-oxidation products. Apart from other pathways these products are further metabolized via glucuronidation. In vitro, inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of Atorvastatin Sandoz. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.

Excretion

Atorvastatin Sandoz is eliminated primarily in bile following hepatic and/or extrahepatic metabolism. However, Atorvastatin Sandoz does not appear to undergo significant enterohepatic recirculation. Mean plasma elimination half-life of Atorvastatin Sandoz in humans is approximately 14 hours. The half-life of inhibitory activity for HMG-CoA reductase is approximately 20 to 30 hours due to the contribution of active metabolites.

Special populations

Elderly: Plasma concentrations of Atorvastatin Sandoz and its active metabolites are higher in healthy elderly subjects than in young adults while the lipid effects were comparable to those seen in younger patient populations.

Paediatric: In an open-label, 8-week study, Tanner Stage 1 (N=15) and Tanner Stage > 2 (N=24) paediatric patients (ages 6-17 years) with heterozygous familial hypercholesterolemia and baseline LDL-C > 4 mmol/L were treated with 5 or 10 mg of chewable or 10 or 20 mg of film-coated Atorvastatin Sandoz tablets once daily, respectively. Body weight was the only significant covariate in Atorvastatin Sandoz population PK model.

Apparent oral clearance of Atorvastatin Sandoz in paediatric subjects appeared similar to adults when scaled allometrically by body weight. Consistent decreases in LDL-C and TC were observed over the range of Atorvastatin Sandoz and o-hydroxyAtorvastatin Sandoz exposures.

Gender: Concentrations of Atorvastatin Sandoz and its active metabolites in women differ from those in men (Women: approx. 20% higher for C_max and approx. 10% lower for AUC). These differences were of no clinical significance, resulting in no clinically significant differences in lipid effects among men and women.

Renal insufficiency: Renal disease has no influence on the plasma concentrations or lipid effects of Atorvastatin Sandoz and its active metabolites.

Hepatic insufficiency: Plasma concentrations of Atorvastatin Sandoz and its active metabolites are markedly increased (approx. 16-fold in C_max and approx. 11-fold in AUC) in patients with chronic alcoholic liver disease (Child-Pugh B).

SLCO1B1 polymorphism: Hepatic uptake of all HMG-CoA reductase inhibitors including Atorvastatin Sandoz, involves the OATP1B1 transporter. In patients with SLCO1B1 polymorphism there is a risk of increased exposure of Atorvastatin Sandoz, which may lead to an increased risk of rhabdomyolysis. Polymorphism in the gene encoding OATP1B1 (SLCO1B1 c.521CC) is associated with a 2.4-fold higher Atorvastatin Sandoz exposure (AUC) than in individuals without this genotype variant (c.521TT). A genetically impaired hepatic uptake of Atorvastatin Sandoz is also possible in these patients. Possible consequences for the efficacy are unknown.

Atorvastatin Sandoz was negative for mutagenic and clastogenic potential in a battery of 4 in vitro tests and 1 in vivo assay. Atorvastatin Sandoz was not found to be carcinogenic in rats, but high doses in mice (resulting in 6-11 fold the AUC_0-24h reached in humans at the highest recommended dose) showed hepatocellular adenomas in males and hepatocellular carcinomas in females.

There is evidence from animal experimental studies that HMG-CoA reductase inhibitors may affect the development of embryos or fetuses. In rats, rabbits and dogs Atorvastatin Sandoz had no effect on fertility and was not teratogenic, however, at maternally toxic doses fetal toxicity was observed in rats and rabbits. The development of the rat offspring was delayed and post-natal survival reduced during exposure of the dams to high doses of Atorvastatin Sandoz. In rats, there is evidence of placental transfer. In rats, plasma concentrations of Atorvastatin Sandoz are similar to those in milk. It is not known whether Atorvastatin Sandoz or its metabolites are excreted in human milk.

Not applicable.

No special requirements