Nalecol

Overdose

In clinical studies, administration of Nalecol, 50 mg/day, to 15 healthy subjects for up to 14 days, or 40 mg/day to 18 patients with primary hypercholesterolaemia for up to 56 days, was generally well tolerated.

In animals, no toxicity was observed after single oral doses of 5,000 mg/kg of Nalecol in rats and mice and 3,000 mg/kg in dogs.

A few cases of overdose with Nalecol have been reported: most have not been associated with adverse experiences. Reported adverse experiences have not been serious. In the event of an overdose, symptomatic and supportive measures should be employed.

Nalecol price

Contraindications

When Nalecol is co-administered with a statin, please refer to the SmPC for that particular medicinal product.

Therapy with Nalecol co-administered with a statin is contraindicated during pregnancy and lactation.

Nalecol co-administered with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases.

Incompatibilities

Not applicable.

Undesirable effects

Tabulated list of adverse reactions (clinical studies and post-marketing experience)

In clinical studies of up to 112 weeks duration, Nalecol 10 mg daily was administered alone in 2396 patients, with a statin in 11,308 patients or with fenofibrate in 185 patients. Adverse reactions were usually mild and transient. The overall incidence of adverse reactions was similar between Nalecol and placebo. Similarly, the discontinuation rate due to adverse experiences was comparable between Nalecol and placebo.

Nalecol administered alone or co-administered with a statin:

The following adverse reactions were observed in patients treated with Nalecol (N=2396) and at a greater incidence than placebo (N=1159) or in patients treated with Nalecol co-administered with a statin (N=11308) and at a greater incidence than statin administered alone (N=9361). Post-marketing adverse reactions were derived from reports containing Nalecol either administered alone or with a statin.

Frequencies are defined as: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (> 1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data)

Nalecol co-administered with fenofibrate:

Gastrointestinal disorders: abdominal pain (common).

In a multicentre, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidaemia, 625 patients were treated for up to 12 weeks and 576 patients for up to 1 year. In this study, 172 patients treated with Nalecol and fenofibrate completed 12 weeks of therapy, and 230 patients treated with Nalecol and fenofibrate (including 109 who received Nalecol alone for the first 12 weeks) completed 1 year of therapy. This study was not designed to compare treatment groups for infrequent events. Incidence rates (95% CI) for clinically important elevations (>3 X ULN, consecutive) in serum transaminases were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for fenofibrate monotherapy and Nalecol co-administered with fenofibrate, respectively, adjusted for treatment exposure. Corresponding incidence rates for cholecystectomy were 0.6% (0.0, 3.1) and 1.7% (0.6, 4.0) for fenofibrate monotherapy and Nalecol co-administered with fenofibrate, respectively.

Paediatric (6 to 17 years of age) population

In a study involving paediatric (6 to 10 years of age) patients with heterozygous familial or non-familial hypercholesterolaemia (n = 138), elevations of ALT and/or AST (>3X ULN, consecutive) were observed in 1.1% (1 patient) of the Nalecol patients compared to 0% in the placebo group. There were no elevations of CPK (>10X ULN). No cases of myopathy were reported.

In a separate study involving adolescent (10 to 17 years of age) patients with heterozygous familial hypercholesterolaemia (n = 248), elevations of ALT and/or AST (> 3X ULN, consecutive) were observed in 3% (4 patients) of the Nalecol/simvastatin patients compared to 2% (2 patients) in the simvastatin monotherapy group; these figures were respectively 2% (2 patients) and 0% for elevation of CPK (> 10X ULN). No cases of myopathy were reported.

These trials were not suited for comparison of rare adverse reactions.

Patients with Coronary Heart Disease and ACS Event History

In the IMPROVE-IT study , involving 18,144 patients treated with either Nalecol/simvastatin 10/40 mg (n=9067; of whom 6% were uptitrated to Nalecol/simvastatin 10/80 mg) or simvastatin 40 mg (n=9077; of whom 27% were uptitrated to simvastatin 80 mg), the safety profiles were similar during a median follow-up period of 6.0 years. Discontinuation rates due to adverse experiences were 10.6% for patients treated with Nalecol/simvastatin and 10.1% for patients treated with simvastatin. The incidence of myopathy was 0.2% for Nalecol/simvastatin and 0.1% for simvastatin, where myopathy was defined as unexplained muscle weakness or pain with a serum CK >10 times ULN or two consecutive observations of CK >5 and <10 times ULN. The incidence of rhabdomyolysis was 0.1% for Nalecol/simvastatin and 0.2% for simvastatin, where rhabdomyolysis was defined as unexplained muscle weakness or pain with a serum CK >10 times ULN with evidence of renal injury, >5 times ULN and <10 times ULN on two consecutive occasions with evidence of renal injury or CK >10,000 IU/L without evidence of renal injury. The incidence of consecutive elevations of transaminases (>3 X ULN) was 2.5% for Nalecol/simvastatin and 2.3% for simvastatin. Gallbladder-related adverse effects were reported in 3.1% vs 3.5% of patients allocated to Nalecol/simvastatin and simvastatin, respectively. The incidence of cholecystectomy hospitalisations was 1.5% in both treatment groups. Cancer (defined as any new malignancy) was diagnosed during the trial in 9.4% vs 9.5%, respectively.

Patients with chronic kidney disease

In the Study of Heart and Renal Protection (SHARP) , involving over 9000 patients treated with a fixed dose combination of Nalecol 10 mg with simvastatin 20 mg daily (n=4650) or placebo (n=4620), the safety profiles were comparable during a median follow-up period of 4.9 years. In this trial, only serious adverse events and discontinuations due to any adverse events were recorded. Discontinuation rates due to adverse events were comparable (10.4% in patients treated with Nalecol combined with simvastatin, 9.8% in patients treated with placebo). The incidence of myopathy/rhabdomyolysis was 0.2% in patients treated with Nalecol combined with simvastatin and 0.1% in patients treated with placebo. Consecutive elevations of transaminases (>3X ULN) occurred in 0.7% of patients treated with Nalecol combined with simvastatin compared with 0.6% of patients treated with placebo. In this trial, there were no statistically significant increases in the incidence of pre-specified adverse events, including cancer (9.4% for Nalecol combined with simvastatin, 9.5% for placebo), hepatitis, cholecystectomy or complications of gallstones or pancreatitis.

Laboratory values

In controlled clinical monotherapy trials, the incidence of clinically important elevations in serum transaminases (ALT and/or AST > 3 X ULN, consecutive) was similar between Nalecol (0.5%) and placebo (0.3%). In co-administration trials, the incidence was 1.3% for patients treated with Nalecol co-administered with a statin and 0.4% for patients treated with a statin alone. These elevations were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment.

In clinical trials, CPK >10 X ULN was reported for 4 of 1,674 (0.2%) patients administered Nalecol alone vs 1 of 786 (0.1%) patients administered placebo, and for 1 of 917 (0.1%) patients co-administered Nalecol and a statin vs 4 of 929 (0.4%) patients administered a statin alone. There was no excess of myopathy or rhabdomyolysis associated with Nalecol compared with the relevant control arm (placebo or statin alone).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (www.mhra.gov.uk/yellowcard).

Preclinical safety data

Animal studies on the chronic toxicity of Nalecol identified no target organs for toxic effects. In dogs treated for four weeks with Nalecol (> 0.03 mg/kg/day) the cholesterol concentration in the cystic bile was increased by a factor of 2.5 to 3.5. However, in a one-year study on dogs given doses of up to 300 mg/kg/day no increased incidence of cholelithiasis or other hepatobiliary effects were observed. The significance of these data for humans is not known. A lithogenic risk associated with the therapeutic use of Nalecol cannot be ruled out.

In co-administration studies with Nalecol and statins the toxic effects observed were essentially those typically associated with statins. Some of the toxic effects were more pronounced than observed during treatment with statins alone. This is attributed to pharmacokinetic and pharmacodynamic interactions in co-administration therapy. No such interactions occurred in the clinical studies. Myopathies occurred in rats only after exposure to doses that were several times higher than the human therapeutic dose (approximately 20 times the AUC level for statins and 500 to 2,000 times the AUC level for the active metabolites).

In a series of in vivo and in vitro assays Nalecol, given alone or co-administered with statins, exhibited no genotoxic potential. Long-term carcinogenicity tests on Nalecol were negative.

Nalecol had no effect on the fertility of male or female rats, nor was it found to be teratogenic in rats or rabbits, nor did it affect prenatal or postnatal development. Nalecol crossed the placental barrier in pregnant rats and rabbits given multiple doses of 1,000 mg/kg/day. The co-administration of Nalecol and statins was not teratogenic in rats. In pregnant rabbits a small number of skeletal deformities (fused thoracic and caudal vertebrae, reduced number of caudal vertebrae) were observed. The co-administration of Nalecol with lovastatin resulted in embryolethal effects.

Therapeutic indications

Primary hypercholesterolaemia

Nalecol, co-administered with an HMG-CoA reductase inhibitor (statin) is indicated as adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia who are not appropriately controlled with a statin alone.

Nalecol monotherapy is indicated as adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia in whom a statin is considered inappropriate or is not tolerated.

Prevention of Cardiovascular Events

Nalecol is indicated to reduce the risk of cardiovascular events in patients with coronary heart disease (CHD) and a history of acute coronary syndrome (ACS) when added to ongoing statin therapy or initiated concomitantly with a statin.

Homozygous Familial Hypercholesterolaemia (HoFH)

Nalecol co-administered with a statin, is indicated as adjunctive therapy to diet for use in patients with HoFH. Patients may also receive adjunctive treatments (e.g. LDL apheresis).

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Other lipid modifying agents, ATC code: C10A X09

Mechanism of action

Nalecol is in a new class of lipid-lowering compounds that selectively inhibit the intestinal absorption of cholesterol. Nalecol is orally active, and has a mechanism of action that differs from other classes of cholesterol-reducing compounds (e.g. statins, bile acid sequestrants [resins], fibric acid derivatives). The molecular target of Nalecol is the sterol transporter, Niemann- Pick C1-Like 1 (NPC1L1), which is responsible for the intestinal uptake of cholesterol.

Nalecol localises at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver; statins reduce cholesterol synthesis in the liver and together these distinct mechanisms provide complementary cholesterol reduction. In a 2-week clinical study in 18 hypercholesterolaemic patients, Nalecol inhibited intestinal cholesterol absorption by 54%, compared with placebo.

Pharmacodynamic effects

A series of preclinical studies was performed to determine the selectivity of Nalecol for inhibiting cholesterol absorption. Nalecol inhibited the absorption of [14C]-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or fat soluble vitamins A and D.

Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C.

Administration of Nalecol with a statin is effective in reducing the risk of cardiovascular events in patients with coronary heart disease and ACS event history.

Clinical efficacy and safety

In controlled clinical studies, Nalecol, either as monotherapy or co-administered with a statin significantly reduced total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG) and increased high-density lipoprotein cholesterol (HDL-C) in patients with hypercholesterolaemia.

Primary hypercholesterolaemia

In a double-blind, placebo-controlled, 8-week study, 769 patients with hypercholesterolaemia already receiving statin monotherapy and not at National Cholesterol Education Program (NCEP) LDL-C goal (2.6 to 4.1 mmol/L [100 to 160 mg/dL], depending on baseline characteristics) were randomised to receive either Nalecol 10 mg or placebo in addition to their on-going statin therapy.

Among statin-treated patients not at LDL-C goal at baseline (~82%), significantly more patients randomised to Nalecol achieved their LDL-C goal at study endpoint compared to patients randomised to placebo, 72% and 19% respectively. The corresponding LDL-C reductions were significantly different (25% and 4% for Nalecol versus placebo, respectively). In addition, Nalecol, added to on-going statin therapy, significantly decreased total-C, Apo B, TG and increased HDL-C, compared with placebo. Nalecol or placebo added to statin therapy reduced median C-reactive protein by 10% or 0% from baseline, respectively.

In two, double-blind, randomised placebo-controlled, 12-week studies in 1,719 patients with primary hypercholesterolaemia, Nalecol 10 mg significantly lowered total-C (13%), LDL-C (19%), Apo B (14%), and TG (8%) and increased HDL-C (3%) compared to placebo. In addition, Nalecol had no effect on the plasma concentrations of fat-soluble vitamins A, D, and E, no effect on prothrombin time, and, like other lipid-lowering agents, did not impair adrenocortical steroid hormone production.

In a multicenter, double-blind, controlled clinical study (ENHANCE), 720 patients with heterozygous familial hypercholesterolemia were randomized to receive Nalecol 10 mg in combination with simvastatin 80 mg (n = 357) or simvastatin 80 mg (n = 363) for 2 years. The primary objective of the study was to investigate the effect of the Nalecol/simvastatin combination therapy on carotid artery intima-media thickness (IMT) compared to simvastatin monotherapy. The impact of this surrogate marker on cardiovascular morbidity and mortality is still not demonstrated.

The primary endpoint, the change in the mean IMT of all six carotid segments, did not differ significantly (p=0.29) between the two treatment groups as measured by B-mode ultrasound. With Nalecol 10 mg in combination with simvastatin 80 mg or simvastatin 80 mg alone, intima-medial thickening increased by 0.0111 mm and 0.0058 mm, respectively, over the study's 2 year duration (baseline mean carotid IMT 0.68 mm and 0.69 mm respectively).

Nalecol 10 mg in combination with simvastatin 80 mg lowered LDL-C, total-C, Apo B, and TG significantly more than simvastatin 80 mg. The percent increase in HDL-C was similar for the two treatment groups. The adverse reactions reported for Nalecol 10 mg in combination with simvastatin 80 mg were consistent with its known safety profile.

Paediatric population

In a multicentre, double-blind, controlled study, 138 patients (59 boys and 79 girls) 6 to 10 years of age (mean age 8.3 years) with heterozygous familial or non-familial hypercholesterolaemia (HeFH) with baseline LDL-C levels between 3.74 and 9.92 mmol/L were randomised to either Nalecol 10 mg or placebo for 12 weeks.

At week 12, Nalecol significantly reduced total-C (-21% vs. 0%), LDL-C (-28% vs. -1%), Apo-B (-22% vs. -1%), and non-HDL-C (-26% vs. 0%) compared to placebo. Results for the two treatment groups were similar for TG and HDL-C (-6% vs. +8%, and +2% vs. +1%, respectively).

In a multicentre, double-blind, controlled study, 142 boys (Tanner stage II and above) and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years) with heterozygous familial hypercholesterolaemia (HeFH) with baseline LDL-C levels between 4.1 and 10.4 mmol/L were randomized to either Nalecol 10 mg co-administered with simvastatin (10, 20 or 40 mg) or simvastatin (10, 20 or 40 mg) alone for 6 weeks, co-administered Nalecol and 40 mg simvastatin or 40 mg simvastatin alone for the next 27 weeks, and open-label co-administered Nalecol and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter.

At Week 6, Nalecol co-administered with simvastatin (all doses) significantly reduced total-C (38 % vs 26 %), LDL-C (49 % vs 34 %), Apo B (39 % vs 27 %), and non-HDL-C (47 % vs 33 %) compared to simvastatin (all doses) alone. Results for the two treatment groups were similar for TG and HDL-C (-17 % vs -12 % and +7 % vs +6 %, respectively). At Week 33, results were consistent with those at Week 6 and significantly more patients receiving Nalecol and 40 mg simvastatin (62 %) attained the NCEP AAP ideal goal (< 2.8 mmol/L [110 mg/dL]) for LDL-C compared to those receiving 40 mg simvastatin (25 %).

At Week 53, the end of the open label extension, the effects on lipid parameters were maintained.

The safety and efficacy of Nalecol co-administered with doses of simvastatin above 40 mg daily have not been studied in paediatric patients 10 to 17 years of age. The safety and efficacy of Nalecol co-administered with simvastatin have not been studied in paediatric patients <10 years of age. The long-term efficacy of therapy with Nalecol in patients below 17 years of age to reduce morbidity and mortality in adulthood has not been studied.

Prevention of Cardiovascular Events

The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) was a multicenter, randomised, double-blind, active-control study of 18,144 patients enrolled within 10 days of hospitalisation for acute coronary syndrome (ACS; either acute myocardial infarction [MI] or unstable angina [UA]). Patients had an LDL-C ≤125 mg/dL (≤3.2 mmol/L) at the time of presentation with ACS if they had not been taking lipid-lowering therapy, or ≤100 mg/dL (≤2.6 mmol/L) if they had been receiving lipid-lowering therapy. All patients were randomised in a 1:1 ratio to receive either Nalecol/simvastatin 10/40 mg (n=9067) or simvastatin 40 mg (n=9077) and followed for a median of 6.0 years.

Patients had a mean age of 63.6 years; 76% were male, 84% were Caucasian, and 27% were diabetic. The average LDL-C value at the time of study qualifying event was 80 mg/dL (2.1 mmol/L) for those on lipid-lowering therapy (n=6390) and 101 mg/dL (2.6 mmol/L) for those not on previous lipid-lowering therapy (n=11594). Prior to the hospitalisation for the qualifying ACS event, 34% of the patients were on statin therapy. At one year, the average LDL-C for patients continuing on therapy was 53.2 mg/dL (1.4 mmol/L) for the Nalecol/simvastatin group and 69.9 mg/dL (1.8 mmol/L) for the simvastatin monotherapy group. Lipid values were generally obtained for patients who remained on study therapy.

The primary endpoint was a composite consisting of cardiovascular death, major coronary events (MCE; defined as non-fatal myocardial infarction, documented unstable angina that required hospitalisation, or any coronary revascularisation procedure occurring at least 30 days after randomised treatment assignment) and non-fatal stroke. The study demonstrated that treatment with Nalecol when added to simvastatin provided incremental benefit in reducing the primary composite endpoint of cardiovascular death, MCE, and non-fatal stroke compared with simvastatin alone (relative risk reduction of 6.4%, p=0.016). The primary endpoint occurred in 2572 of 9067 patients (7-year Kaplan-Meier [KM] rate 32.72%) in the Nalecol/simvastatin group and 2742 of 9077 patients (7-year KM rate 34.67%) in the simvastatin alone group (see Figure 1 and Table 1.) This incremental benefit is expected to be similar with co-administration of other statins shown to be effective in reducing the risk of cardiovascular events. Total mortality was unchanged in this high risk group (see Table 1).

There was an overall benefit for all strokes; however there was a small non-significant increase in haemorrhagic stroke in the Nalecol-simvastatin group compared with simvastatin alone (see Table 1). The risk of haemorrhagic stroke for Nalecol co-administered with higher potency statins in long-term outcome studies has not been evaluated.

The treatment effect of Nalecol/simvastatin was generally consistent with the overall results across many subgroups, including sex, age, race, medical history of diabetes mellitus, baseline lipid levels, prior statin therapy, prior stroke, and hypertension.

Figure 1: Effect of Nalecol/Simvastatin on the Primary Composite Endpoint of Cardiovascular Death, Major Coronary Event, or Non-fatal Stroke

Table 1

Major Cardiovascular Events by Treatment Group in All Randomised Patients in IMPROVE-IT

a 6% were uptitrated to Nalecol/simvastatin 10/80 mg.

b 27% were uptitrated to simvastatin 80 mg.

c Kaplan-Meier estimate at 7 years.

d includes ischemic stroke or stroke of undetermined type.

Prevention of Major Vascular Events in Chronic Kidney Disease (CKD)

The Study of Heart and Renal Protection (SHARP) was a multi-national, randomized, placebo-controlled, double-blind study conducted in 9438 patients with chronic kidney disease, a third of whom were on dialysis at baseline. A total of 4650 patients were allocated to a fixed dose combination of Nalecol 10 mg with simvastatin 20 mg and 4620 to placebo, and followed for a median of 4.9 years. Patients had a mean age of 62 and 63 % were male, 72 % Caucasian, 23 % diabetic and, for those not on dialysis, the mean estimated glomerular filtration rate (eGFR) was 26.5 mL/min/1.73 m2. There were no lipid entry criteria. Mean LDL-C at baseline was 108 mg/dL. After one year, including patients no longer taking study medication, LDL-C was reduced 26 % relative to placebo by simvastatin 20 mg alone and 38 % by Nalecol 10 mg combined with simvastatin 20 mg.

The SHARP protocol-specified primary comparison was an intention-to-treat analysis of "major vascular events" (MVE; defined as nonfatal MI or cardiac death, stroke, or any revascularization procedure) in only those patients initially randomized to the Nalecol combined with simvastatin (n=4193) or placebo (n=4191) groups. Secondary analyses included the same composite analyzed for the full cohort randomized (at study baseline or at year 1) to Nalecol combined with simvastatin (n=4650) or placebo (n=4620) as well as the components of this composite.

The primary endpoint analysis showed that Nalecol combined with simvastatin significantly reduced the risk of major vascular events (749 patients with events in the placebo group vs. 639 in the Nalecol combined with simvastatin group) with a relative risk reduction of 16 % (p=0.001).

Nevertheless, this study design did not allow for a separate contribution of the monocomponent Nalecol to efficacy to significantly reduce the risk of major vascular events in patients with CKD.

The individual components of MVE in all randomized patients are presented in Table 2. Nalecol combined with simvastatin significantly reduced the risk of stroke and any revascularization, with non-significant numerical differences favouring Nalecol combined with simvastatin for nonfatal MI and cardiac death.

Table 2

Major Vascular Events by Treatment Group in all randomized patients in SHARPa

aIntention-to-treat analysis on all SHARP patients randomized to Nalecol combined with simvastatin or placebo either at baseline or year 1

bMAE; defined as the composite of nonfatal myocardial infarction, coronary death, non-haemorrhagic stroke, or any revascularization

The absolute reduction in LDL cholesterol achieved with Nalecol combined with simvastatin was lower among patients with a lower baseline LDL-C (<2.5 mmol/L) and patients on dialysis at baseline than the other patients, and the corresponding risk reductions in these two groups were attenuated.

Homozygous Familial Hypercholesterolaemia (HoFH)

A double-blind, randomised, 12-week study enrolled 50 patients with a clinical and/or genotypic diagnosis of HoFH, who were receiving atorvastatin or simvastatin (40 mg) with or without concomitant LDL apheresis. Nalecol co-administered with atorvastatin (40 or 80 mg) or simvastatin (40 or 80 mg), significantly reduced LDL-C by 15% compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to 80 mg.

Aortic Stenosis

The Simvastatin and Nalecol for the Treatment of Aortic Stenosis (SEAS) study was a multi-center, double-blind, placebo-controlled study with a median duration of 4.4 years conducted in 1873 patients with asymptomatic aortic stenosis (AS), documented by Doppler-measured aortic peak flow velocity within the range of 2.5 to 4.0 m/s. Only patients who were considered not to require statin treatment for purposes of reducing atherosclerotic cardiovascular disease risk were enrolled. Patients were randomized 1:1 to receive placebo or co-administered Nalecol 10 mg and simvastatin 40 mg daily.

The primary endpoint was the composite of major cardiovascular events (MCE) consisting of cardiovascular death, aortic valve replacement (AVR) surgery, congestive heart failure (CHF) as a result of progression of AS, nonfatal myocardial infarction, coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), hospitalization for unstable angina, and nonhaemorrhagic stroke. The key secondary endpoints were composites of subsets of the primary endpoint event categories.

Compared to placebo, Nalecol/simvastatin 10/40 mg did not significantly reduce the risk of MCE. The primary outcome occurred in 333 patients (35.3%) in the Nalecol / simvastatin group and in 355 patients (38.2%) in the placebo group (hazard ratio in the Nalecol / simvastatin group, 0.96; 95% confidence interval, 0.83 to 1.12; p = 0.59). Aortic valve replacement was performed in 267 patients (28.3%) in the Nalecol / simvastatin group and in 278 patients (29.9%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; p = 0.97). Fewer patients had ischemic cardiovascular events in the Nalecol / simvastatin group (n=148) than in the placebo group (n=187) (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; p = 0.02), mainly because of the smaller number of patients who underwent coronary artery bypass grafting.

Cancer occurred more frequently in the Nalecol/simvastatin group (105 versus 70, p = 0.01). The clinical relevance of this observation is uncertain as in the bigger SHARP trial the total number of patients with any incident cancer (438 in the Nalecol/simvastatin versus 439 placebo group) did not differ. In addition, in the IMPROVE-IT trial the total number of patients with any new malignancy (853 in the Nalecol/simvastatin group versus 863 in the simvastatin group) did not differ significantly and therefore the finding of the SEAS trial could not be confirmed by SHARP or IMPROVE-IT.

Pharmacokinetic properties

Absorption

After oral administration, Nalecol is rapidly absorbed and extensively conjugated to a pharmacologically-active phenolic glucuronide (Nalecol-glucuronide). Mean maximum plasma concentrations (Cmax) occur within 1 to 2 hours for Nalecol-glucuronide and 4 to 12 hours for Nalecol.

The absolute bioavailability of Nalecol cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection.

Concomitant food administration (high fat or non-fat meals) had no effect on the oral bioavailability of Nalecol when administered as Nalecol 10 mg tablets. Nalecol can be administered with or without food.

Distribution

Nalecol and Nalecol-glucuronide are bound 99.7% and 88 to 92% to human plasma proteins, respectively.

Biotransformation

Nalecol is metabolised primarily in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated. Nalecol and Nalecol-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20 % and 80 to 90 % of the total drug in plasma, respectively. Both Nalecol and Nalecol-glucuronide are slowly eliminated from plasma with evidence of significant enterohepatic recycling. The half-life for Nalecol and Nalecol-glucuronide is approximately 22 hours.

Elimination

Following oral administration of 14C-Nalecol (20 mg) to human subjects, total Nalecol accounted for approximately 93% of the total radioactivity in plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the faeces and urine, respectively, over a 10-day collection period. After 48 hours, there were no detectable levels of radioactivity in the plasma.

Special populations:

Paediatric population

The pharmacokinetics of Nalecol are similar between children >6 years and adults. Pharmacokinetic data in the paediatric population <6 years of age are not available. Clinical experience in paediatric and adolescent patients includes patients with HoFH or HeFH.

Elderly

Plasma concentrations for total Nalecol are about 2-fold higher in the elderly (>65 years) than in the young (18 to 45 years). LDL-C reduction and safety profile are comparable between elderly and young subjects treated with Nalecol. Therefore, no dosage adjustment is necessary in the elderly.

Hepatic impairment

After a single 10 mg dose of Nalecol, the mean AUC for total Nalecol was increased approximately 1.7-fold in patients with mild hepatic impairment (Child Pugh score 5 or 6), compared to healthy subjects. In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic impairment (Child Pugh score 7 to 9), the mean AUC for total Nalecol was increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. No dosage adjustment is necessary for patients with mild hepatic impairment. Due to the unknown effects of the increased exposure to Nalecol in patients with moderate or severe (Child Pugh score>9) hepatic impairment, Nalecol is not recommended in these patients.

Renal impairment

After a single 10-mg dose of Nalecol in patients with severe renal disease (n=8; mean CrCl ≤ 30 mL/min/1.73m2), the mean AUC for total Nalecol was increased approximately 1.5-fold, compared to healthy subjects (n=9). This result is not considered clinically significant. No dosage adjustment is necessary for renal impaired patients.

An additional patient in this study (post-renal transplant and receiving multiple medicinal products, including ciclosporin) had a 12-fold greater exposure to total Nalecol.

Gender

Plasma concentrations for total Nalecol are slightly higher (approximately 20%) in women than in men.

LDL-C reduction and safety profile are comparable between men and women treated with Nalecol. Therefore, no dosage adjustment is necessary on the basis of gender.

Qualitative and quantitative composition

Special warnings and precautions for use

When Nalecol is co-administered with a statin, please refer to the SmPC for that particular medicinal product.

Liver enzymes

In controlled co-administration trials in patients receiving Nalecol with a statin, consecutive transaminase elevations (> 3 X the upper limit of normal [ULN]) have been observed. When Nalecol is co-administered with a statin, liver function tests should be performed at initiation of therapy and according to the recommendations of the statin.

In the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), 18,144 patients with coronary heart disease and ACS event history were randomised to receive Nalecol/simvastatin 10/40 mg daily (n=9067) or simvastatin 40 mg daily (n=9077). During a median follow-up of 6.0 years, the incidence of consecutive elevations of transaminases (>3 X ULN) was 2.5% for Nalecol/simvastatin and 2.3% for simvastatin.

In a controlled clinical study in which over 9000 patients with chronic kidney disease were randomized to receive Nalecol 10 mg combined with simvastatin 20 mg daily (n=4650) or placebo (n=4620), (median follow-up period of 4.9 years), the incidence of consecutive elevations of transaminases (>3 X ULN) was 0.7% for Nalecol combined with simvastatin and 0.6% for placebo.

Skeletal muscle

In post-marketing experience with Nalecol, cases of myopathy and rhabdomyolysis have been reported.

Most patients who developed rhabdomyolysis were taking a statin concomitantly with Nalecol. However, rhabdomyolysis has been reported very rarely with Nalecol monotherapy and very rarely with the addition of Nalecol to other agents known to be associated with increased risk of rhabdomyolysis. If myopathy is suspected based on muscle symptoms or is confirmed by a creatine phosphokinase (CPK) level>10 times the ULN, Nalecol, any statin, and any of these other agents that the patient is taking concomitantly should be immediately discontinued. All patients starting therapy with Nalecol should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness.

In IMPROVE-IT, 18,144 patients with coronary heart disease and ACS event history were randomised to receive Nalecol/simvastatin 10/40 mg daily (n=9067) or simvastatin 40 mg daily (n=9077). During a median follow-up of 6.0 years, the incidence of myopathy was 0.2% for Nalecol/simvastatin and 0.1% for simvastatin, where myopathy was defined as unexplained muscle weakness or pain with a serum CK >10 times ULN or two consecutive observations of CK >5 and <10 times ULN. The incidence of rhabdomyolysis was 0.1% for Nalecol/simvastatin and 0.2% for simvastatin, where rhabdomyolysis was defined as unexplained muscle weakness or pain with a serum CK >10 times ULN with evidence of renal injury, >5 times ULN and <10 times ULN on two consecutive occasions with evidence of renal injury or CK >10,000 IU/L without evidence of renal injury.

In a clinical trial in which over 9000 patients with chronic kidney disease were randomized to receive Nalecol 10 mg combined with simvastatin 20 mg daily (n=4650) or placebo (n=4620) (median follow-up 4.9 years), the incidence of myopathy/rhabdomyolysis was 0.2% for Nalecol combined with simvastatin and 0.1% for placebo.

Hepatic impairment

Due to the unknown effects of the increased exposure to Nalecol in patients with moderate or severe hepatic impairment, Nalecol is not recommended.

Paediatric population

Efficacy and safety of Nalecol in patients 6 to 10 years of age with heterozygous familial or non-familial hypercholesterolemia have been evaluated in a 12-week placebo-controlled clinical trial. Effects of Nalecol for treatment periods >12 weeks have not been studied in this age group.

Nalecol has not been studied in patients younger than 6 years of age.

Efficacy and safety of Nalecol co-administered with simvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys (Tanner stage II or above) and in girls who were at least one year post-menarche.

In this limited controlled study, there was generally no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. However, the effects of Nalecol for a treatment period > 33 weeks on growth and sexual maturation have not been studied.

The safety and efficacy of Nalecol co-administered with doses of simvastatin above 40 mg daily have not been studied in paediatric patients 10 to 17 years of age.

The safety and efficacy of Nalecol co-administered with simvastatin have not been studied in paediatric patients <10 years of age.

The long-term efficacy of therapy with Nalecol in patients below 17 years of age to reduce morbidity and mortality in adulthood has not been studied.

Fibrates

The safety and efficacy of Nalecol administered with fibrates have not been established.

If cholelithiasis is suspected in a patient receiving Nalecol and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued.

Ciclosporin

Caution should be exercised when initiating Nalecol in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving Nalecol and ciclosporin.

Anticoagulants

If Nalecol is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored.

Excipient

Nalecol contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported.

Dosage (Posology) and method of administration

Posology

The patient should be on an appropriate lipid lowering diet and should continue on this diet during treatment with Nalecol.

Route of administration is oral. The recommended dose is one Nalecol 10 mg tablet daily. Nalecol can be administered at any time of the day, with or without food.

When Nalecol is added to a statin, either the indicated usual initial dose of that particular statin or the already established higher statin dose should be continued. In this setting, the dosage instructions for that particular statin should be consulted.

Use in Patients with Coronary Heart Disease and ACS Event History

For incremental cardiovascular event reduction in patients with coronary heart disease and ACS event history, Nalecol 10 mg may be administered with a statin with proven cardiovascular benefit.

Co-administration with bile acid sequestrants

Dosing of Nalecol should occur either > 2 hours before or > 4 hours after administration of a bile acid sequestrant.

Elderly

No dosage adjustment is required for elderly patients.

Paediatric population

Initiation of treatment must be performed under review of a specialist.

Children and adolescents >6 years: The safety and efficacy of Nalecol in children aged 6 to 17 years has not been established.8, 5.1 and 5.2 but no recommendation on a posology can be made.

When Nalecol is administered with a statin, the dosage instructions for the statin, in children should be consulted.

Children <6 years: The safety and efficacy of Nalecol in children aged <6 years has not been established. No data are available.

Hepatic impairment

No dosage adjustment is required in patients with mild hepatic impairment (Child-Pugh score 5 to 6).

Treatment with Nalecol is not recommended in patients with moderate (Child-Pugh score 7 to 9) or severe (Child-Pugh score>9) liver dysfunction.

Renal impairment

No dosage adjustment is required for renal impaired patients.

Special precautions for disposal and other handling

No special requirements.