What is Zentasta used for?

Primary Hypercholesterolaemia Ezetimibe 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 nonfamilial) hypercholesterolaemia who are not appropriately controlled with a statin alone. Ezetimibe monotherapy is indicated as adjunctive therapy to diet for use in patients with primary (heterozygous familial and nonfamilial) hypercholesterolaemia in whom a statin is consi

What is the active ingredient in Zentasta?

Ezetimibum + Atorvastatinum (Atorvastatinum, Ezetimibum)

What pharmaceutical form is Zentasta available in?

Zentasta: Tabletki 10 mg + 10 mg (doustna)

Is Zentasta OTC or prescription only?

Zentasta requires a doctor's prescription.

What are the side effects of Zentasta?

Tabulated list of adverse reactions (clinical studies and postmarketing experience) In clinical studies of up to 112 weeks duration, Ezetimibe 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 side effects was similar between Ezetimibe and placebo. Similarly, the discontinuation rate due to adverse experiences was comparable betwee

Who should NOT take Zentasta?

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. When Ezetimibe is co-administered with a statin, please refer to the SPC for that particular medicinal product. Therapy with Ezetimibe co-administered with a statin is contraindicated during pregnancy and lactation. Ezetimibe co-administered with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases.

Does Zentasta interact with other medications?

In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 drug metabolising enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs known to be metabolised by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase. In clinical interaction studies, ezetimibe had no effect on the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipi

Can Zentasta be used during pregnancy?

Ezetimibe co-administered with a statin is contraindicated during pregnancy and lactation (see section 4.3), please refer to the SPC for that particular statin. Pregnancy Ezetimibe should be given to pregnant women only if clearly necessary. No clinical data are available on the use of ezetimibe during pregnancy. Animal studies on the use of ezetimibe in monotherapy have shown no evidence of direct or indirect harmful effects on pregnancy, embryofoetal development, birth or pos

What precautions should be taken with Zentasta?

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

What ATC class does Zentasta belong to?

Zentasta: ATC C10BA05. ATC is the WHO Anatomical Therapeutic Chemical classification — it groups drugs by organ system and pharmacological mechanism.

Zentasta

This information is for educational purposes only. It is not intended as medical advice. Always consult a qualified healthcare professional.

Pharmacotherapeutic group: Other lipid modifying agents, ATC code: C10A X09 Mechanism of action Ezetimibe is in a new class of lipid-lowering compounds that selectively inhibit the intestinal absorption of cholesterol and related plant sterols.‍‍‍‍‍‍‍‍ ezetimibe is orally active and has a mechanism of action that differs from other classes of cholesterolreducing compounds (e.g., statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols).The molecular target of ezetimibe is the sterol transporter, Niemann-Pick C1-Like1 (NPC1L1), which is responsible for the intestinal uptake of cholesterol and phytosterols. Ezetimibe 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, ezetimibe inhibited intestinal cholesterol absorption by 54 %, compared with placebo. Pharmacodynamic effects A series of preclinical studies was performed to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. ezetimibe inhibited the absorption of [ 14 C]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 ezetimibe 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, ezetimibe 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 ezetimibe 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 ezetimibe 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 ezetimibe versus placebo, respectively). In addition, ezetimibe, added to ongoing statin therapy, significantly decreased total-C, Apo B, TG and increased HDL-C, compared with placebo. ezetimibe 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 1719 patients with primary hypercholesterolaemia, ezetimibe 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, ezetimibe 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, doubleblind, controlled clinical study (ENHANCE), 720 patients with heterozygous familial hypercholesterolemia were randomised to receive ezetimibe 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 ezetimibe/simvastatin combination therapy on carotid artery intimamedia 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 ezetimibe 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. Ezetimibe 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 ezetimibe 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 ezetimibe 10 mg or placebo for 12 weeks. At week 12, Ezetimibe 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 randomised to either ezetimibe 10 mg co-administered with simvastatin (10, 20 or 40 mg) or simvastatin (10, 20 or 40 mg) alone for 6 weeks, co-administered ezetimibe and 40 mg simvastatin or 40 mg simvastatin alone for the next 27 weeks, and open-label coadministered. Ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter. At Week 6, ezetimibe coadministered 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 ezetimibe 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 ezetimibe coadministered 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 ezetimibe coadministered with simvastatin have not been studied in paediatric patients < 10 years of age. The long-term efficacy of therapy with ezetimibe 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 lipidlowering 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 ezetimibe/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 ezetimibe/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 ezetimibe 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 ezetimibe-simvastatin group and 2742 of 9077 patients (7-year KM rate 34.67%) in the simvastatin alone group. (See Figure 1 and Table 2.) This incremental benefit is expected to be similar with coadministration 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 2). There was an overall benefit for all strokes; however there was a small nonsignificant increase in haemorrhagic stroke in the ezetimibe-simvastatin group compared with simvastatin alone (see Table 2). The risk of haemorrhagic stroke for ezetimibe co-administered with higher potency statins in long-term outcome studies has not been evaluated. The treatment effect of ezetimibe-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 Ezetimibe/Simvastatin on the Primary Composite Endpoint of Cardiovascular Death, Major Coronary Event, or Non-fatal Stroke Table 2 Major Cardiovascular Events by Treatment Group in All Randomised Patients in IMPROVE-IT Outcome Ezetimibe/Simvastatin 10/40 mg a (n=9067) Simvastatin 40 mg b (n=9077) Hazard Ratio (95% CI) p-value n K-M% c n K-M% c Primary Composite Efficacy Endpoint (CV death, Major Coronary Events and non-fatal stroke) 2572 32.72% 2742 34.67% 0.936 (0.887, 0.988) 0.016 Secondary Composite Efficacy Endpoints CHD death, nonfatal MI, urgent coronary revascularisation after 30 days 1322 17.52% 1448 18.88% 0.912 (0.847, 0.983) 0.016 MCE, non-fatal stroke, death (all causes) 3089 38.65% 3246 40.25% 0.948 (0.903, 0.996) 0.035 CV death, non-fatal MI, unstable angina requiring hospitalisation, Any revascularisation, nonfatal stroke 2716 34.49% 2869 36.20% 0.945 (0.897, 0.996) 0.035 Components of Primary Composite Endpoint and Select Efficacy Endpoints (first occurrences of specified event at any time) Cardiovascular death 537 6.89% 538 6.84% 1.000 (0.887, 1.127) 0.997 Major Coronary Event: Non-fatal MI 945 12.77% 1083 14.41% 0.871 (0.798, 0.950) 0.002 Unstable angina requiring hospitalisation 156 2.06% 148 1.92% 1.059 (0.846, 1.326) 0.618 Coronary revascularisation after 30 days 1690 21.84% 1793 23.36% 0.947 (0.886, 1.012) 0.107 Non-fatal stroke 245 3.49% 305 4.24% 0.802 (0.678, 0.949) 0.010 All MI (fatal and nonfatal) 977 13.13% 1118 14.82% 0.872 (0.800, 0.950) 0.002 All stroke (fatal and nonfatal) 296 4.16% 345 4.77% 0.857 (0.734, 1.001) 0.052 Non-hemorrhagic stroke d 242 3.48% 305 4.23% 0.793 (0.670, 0.939) 0.007 Hemorrhagic stroke 59 0.77% 43 0.59% 1.377 (0.930, 2.040) 0.110 Death from any cause 1215 15.36% 1231 15.28% 0.989 (0.914, 1.070) 0.782 a 6% were uptitrated to ezetimibe/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, randomised, 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 ezetimibe 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 m 2 . 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 ezetimibe 10 mg combined with simvastatin 20 mg. The SHARP protocol-specified primary comparison was an intentiontotreat analysis of "major vascular events" (MVE; defined as nonfatal MI or cardiac death, stroke, or any revascularisation procedure) in only those patients initially randomised to the ezetimibe combined with simvastatin (n=4193) or placebo (n=4191) groups. Secondary analyses included the same composite analyzed for the full cohort randomised (at study baseline or at year 1) to ezetimibe combined with simvastatin (n=4650) or placebo (n=4620) as well as the components of this composite. The primary endpoint analysis showed that ezetimibe combined with simvastatin significantly reduced the risk of major vascular events (749 patients with events in the placebo group vs. 639 in the ezetimibe 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 ezetimibe to efficacy to significantly reduce the risk of major vascular events in patients with CKD. The individual components of MVE in all randomised patients are presented in Table 3. Ezetimibe combined with simvastatin significantly reduced the risk of stroke and any revascularisation, with non-significant numerical differences favouring Ezetimibe combined with simvastatin for nonfatal MI and cardiac death. Table 3 Major Vascular Events by Treatment Group in all randomised patients in SHARP a Outcome Ezetimibe 10 mg combined with simvastatin 20 mg (n=4650) Placebo (n=4620) Risk Ratio (95% CI) P-value Major Vascular Events 701 (15.1%) 814 (17.6%) 0.85 (0.77-0.94) 0.001 Nonfatal MI 134 (2.9%) 159 (3.4%) 0.84 (0.66-1.05) 0.12 Cardiac Death 253 (5.4%) 272 (5.9%) 0.93 (0.78-1.10) 0.38 Any Stroke 171 (3.7%) 210 (4.5%) 0.81 (0.66-0.99) 0.038 Non-hemorrhagic Stroke 131 (2.8%) 174 (3.8%) 0.75 (0.60-0.94) 0.011 Hemorrhagic Stroke 45 (1.0%) 37 (0.8%) 1.21 (0.78-1.86) 0.40 Any Revascularisation 284 (6.1%) 352 (7.6%) 0.79 (0.68-0.93) 0.004 Major Atherosclerotic Events (MAE) b 526 (11.3%) 619 (13.4%) 0.83 (0.74-0.94) 0.002 a Intention-to-treat analysis on all SHARP patients randomised to Ezetimibe combined with simvstatin or placebo either at baseline or year 1 b MAE; defined as the composite of nonfatal myocardial infarction, coronary death, non-hemorrhagic stroke, or any revascularization. The absolute reduction in LDL cholesterol achieved with ezetimibe 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. Ezetimibe coadministered 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 Ezetimibe 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 randomised 1:1 to receive placebo or co-administered ezetimibe 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, ezetimibe/simvastatin 10/40 mg did not significantly reduce the risk of MCE. The primary outcome occurred in 333 patients (35.3%) in the ezetimibe / simvastatin group and in 355 patients (38.2%) in the placebo group (hazard ratio in the ezetimibe / 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 ezetimibe / 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 ezetimibe / 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 ezetimibe / 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 ezetimibe/ 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 ezetimibe/simvastatin group versus 863 in the simvastatin group) did not differ significantly and therefore the finding of SEAS trial could not be confirmed by SHARP or IMPROVE-IT.

Zentasta

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