Specific treatment is not available for Ateroz 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 Ateroz binding to plasma proteins, haemodialysis is not expected to significantly enhance Ateroz clearance.
Not applicable.
In the Ateroz placebo-controlled clinical trial database of 16,066 (8755 Ateroz vs. 7311 placebo) patients treated for a mean period of 53 weeks, 5.2% of patients on Ateroz discontinued due to adverse reactions compared to 4.0% of the patients on placebo.
Based on data from clinical studies and extensive post-marketing experience, the following table presents the adverse reaction profile for Ateroz.
Estimated frequencies of reactions are ranked according to the following convention:
common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000).
Infections and infestations:
Common: nasopharyngitis.
Blood and lymphatic system disorders
Rare: thrombocytopenia.
Immune system disorders
Common: allergic reactions.
Very rare: anaphylaxis.
Metabolism and nutrition disorders
Common: hyperglycaemia.
Uncommon: hypoglycaemia, weight gain, anorexia.
Psychiatric disorders
Uncommon: nightmare, insomnia.
Nervous system disorders
Common: headache.
Uncommon: dizziness, paraesthesia, hypoesthesia, dysgeusia, amnesia.
Rare: peripheral neuropathy.
Eye disorders
Uncommon: vision blurred.
Rare: visual disturbance.
Ear and labyrinth disorders
Uncommon: tinnitus
Very rare: hearing loss.
Respiratory, thoracic and mediastinal disorders:
Common: pharyngolaryngeal pain, epistaxis.
Gastrointestinal disorders
Common: constipation, flatulence, dyspepsia, nausea, diarrhoea.
Uncommon: vomiting, abdominal pain upper and lower, eructation, pancreatitis.
Hepatobiliary disorders
Uncommon: hepatitis.
Rare: cholestasis.
Very rare: hepatic failure.
Skin and subcutaneous tissue disorders
Uncommon: urticaria, skin rash, pruritus, alopecia.
Rare: angioneurotic oedema, dermatitis bullous including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders
Common: myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain.
Uncommon: neck pain, muscle fatigue.
Rare: myopathy, myositis, rhabdomyolysis, tendonopathy, sometimes complicated by rupture.
Reproductive system and breast disorders
Very rare: gynecomastia.
General disorders and administration site conditions
Uncommon: malaise, asthenia, chest pain, peripheral oedema, fatigue, pyrexia.
Investigations
Common: liver function test abnormal, blood creatine kinase increased.
Uncommon: white blood cells urine positive.
As with other HMG-CoA reductase inhibitors elevated serum transaminases have been reported in patients receiving Ateroz. These changes were usually mild, transient, and did not require interruption of treatment. Clinically important (> 3 times upper normal limit) elevations in serum transaminases occurred in 0.8% patients on Ateroz. These elevations were dose related and were reversible in all patients.
Elevated serum creatine kinase (CK) levels greater than 3 times upper limit of normal occurred in 2.5% of patients on Ateroz, similar to other HMG-CoA reductase inhibitors in clinical trials. Levels above 10 times the normal upper range occurred in 0.4% Ateroz-treated patients.
Class Effects
− Sexual dysfunction.
− Depression.
− Exceptional cases of interstitial lung disease, especially with long-term therapy
− Diabetes Mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood glucose > 5.6 mmol/L, BMI>30kg/m2, raised triglycerides, history of hypertension).
Paediatric Population
The clinical safety database includes safety data for 249 paediatric patients who received Ateroz, among which 7 patients were < 6 years old, 14 patients were in the age range of 6 to 9, and 228 patients were in the age range of 10 to 17.
Nervous system disorders
Common: headache.
Gastrointestinal disorders
Common: abdominal pain.
Investigations
Common: alanine aminotransferase increased, blood creatine phosphokinase increased.
Based on the data available, frequency, type and severity of adverse reactions in children are expected to be the same as in adults. There is currently limited experience with respect to long-term safety in the paediatric population.
Ateroz was negative for mutagenic and clastogenic potential in a battery of 4 in vitro tests and 1 in vivo assay. Ateroz was not found to be carcinogenic in rats, but high doses in mice (resulting in 6-11 fold the AUC0-24h 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 Ateroz 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 Ateroz. In rats, there is evidence of placental transfer. In rats, plasma concentrations of Ateroz are similar to those in milk. It is not known whether Ateroz or its metabolites are excreted in human milk.
Pharmacotherapeutic group: Lipid modifying agents, HMG-CoA-reductase inhibitors, ATC code: C10AA05
Ateroz 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).
Ateroz 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.
Ateroz reduces LDL production and the number of LDL particles. Ateroz produces a profound and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles. Ateroz is effective in reducing LDL-C in patients with homozygous familial hypercholesterolaemia, a population that has not usually responded to lipid-lowering medicinal products.
Ateroz 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%. Ateroz 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 Ateroz 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 Ateroz 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 Ateroz group and +2.7% (p=0.001) in the pravastatin group (n=249). When compared to pravastatin the effects of Ateroz 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 Ateroz 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). Ateroz 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). Ateroz increased mean HDL-C by 2.9% (pravastatin: +5.6%, p=NS). There was a 36.4% mean reduction in CRP in the Ateroz 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, Ateroz 80 mg has been evaluated in 3,086 patients (Ateroz 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 Ateroz 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 Ateroz 10 mg daily (n=5,168) or placebo (n=5,137).
The absolute and relative risk reduction effect of Ateroz was as follows:
| Event | Relative Risk Reduction (%) | No. of Events (Ateroz vs Placebo) | Absolute Risk Reduction 1 (%) | p-value |
| Fatal CHD plus non-fatal MI Total cardiovascular events and revascularization procedures Total coronary events | 36% 20% 29% | 100 vs. 154 389 vs. 483 178 vs 247 | 1.1% 1.9% 1.4% | 0.0005 0.0008 0.0006 |
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 Ateroz 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 Ateroz 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 Ateroz on fatal and non-fatal cardiovascular disease was also assessed in a randomized, double-blind, multicenter, placebo-controlled trial, the Collaborative Ateroz 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 Ateroz 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 Ateroz was as follows:
| Event | Relative Risk Reduction (%) | No. of Events (Ateroz vs Placebo) | Absolute Risk Reduction1 (%) | p- value |
| Major cardiovascular events (fatal and non-fatal AMI, silent MI, acute CHD death, unstable angina, CABG, PTCA, revascularization, stroke) MI (fatal and non-fatal AMI, silent MI) Strokes (Fatal and non- fatal) | 37%
42% 48% | 83 vs. 127
38 vs 64 21 vs. 39 | 3.2%
1.9% 1.3% | 0.0010
0.0070 0.0163 |
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 Ateroz group, p=0.0592).
Recurrent stroke
In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, the effect of Ateroz 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 Ateroz and 129 mg/dL (3.3 mmol/L) during treatment with placebo. Median follow-up was 4.9 years.
Ateroz 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 Ateroz versus 8.9% (211/2366) for placebo.
In a post-hoc analysis, Ateroz 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 Ateroz 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 Ateroz 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 Ateroz 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 Ateroz 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 Ateroz 80 mg/day.
All cause mortality was 15.6% (7/45) for Ateroz versus 10.4% (5/48) in the subgroup of patients with prior hemorrhagic stroke. All cause mortality was 10.9% (77/708) for Ateroz 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 Ateroz 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 Ateroz was 5 mg daily of a chewable tablet in Cohort A and 10 mg daily of a tablet formulation in Cohort B. The Ateroz 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 Ateroz 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 Ateroz (n=140) or placebo (n=47) for 26 weeks and then all received Ateroz for 26 weeks.).
Absorption
Ateroz is rapidly absorbed after oral administration; maximum plasma concentrations (Cmax) occur within 1 to 2 hours. Extent of absorption increases in proportion to Ateroz dose. After oral administration, Ateroz film-coated tablets are 95% to 99% bioavailable compared to the oral solution. The absolute bioavailability of Ateroz 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 Ateroz is approximately 381 l. Ateroz is > 98% bound to plasma proteins.
Biotransformation
Ateroz 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 Ateroz. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.
Excretion
Ateroz is eliminated primarily in bile following hepatic and/or extrahepatic metabolism. However, Ateroz does not appear to undergo significant enterohepatic recirculation. Mean plasma elimination half-life of Ateroz 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 Ateroz 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 Ateroz tablets once daily, respectively. Body weight was the only significant covariate in Ateroz population PK model.
Apparent oral clearance of Ateroz 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 Ateroz and o-hydroxyAteroz exposures.
Gender: Concentrations of Ateroz and its active metabolites in women differ from those in men (Women: approx. 20% higher for Cmax 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 Ateroz and its active metabolites.
Hepatic insufficiency: Plasma concentrations of Ateroz and its active metabolites are markedly increased (approx. 16-fold in Cmax 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 Ateroz, involves the OATP1B1 transporter. In patients with SLCO1B1 polymorphism there is a risk of increased exposure of Ateroz, 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 Ateroz exposure (AUC) than in individuals without this genotype variant (c.521TT). A genetically impaired hepatic uptake of Ateroz is also possible in these patients. Possible consequences for the efficacy are unknown.
No special requirements
