Page 4 - P4304.1-V90_PS-Magazine-October 2023 - PRINT

Ezetimibe / Simvastatin Tablets confirm the results. Before the treatment: All patients starting therapy physicians contemplating combined therapy with simvastatin and mmol/L, BMI >30 kg/m2, raised triglycerides, hypertension) should be
with Ezetimibe/Simvastatin, or whose dose is being increased, should lipid-modifying doses (≥1 g/day) of niacin (nicotinic acid) or products monitored clinically and biochemically. Paediatric population: Efficacy
be advised of the risk of myopathy and told to report promptly any containing niacin should carefully weigh the potential benefits and risks and safety of ezetimibe co-administered with simvastatin in patients 10
unexplained muscle pain, tenderness or weakness. Caution should be and should carefully monitor patients for any signs and symptoms of to 17 years of age with heterozygous familial hypercholesterolemia
10mg/20mg, 10mg/40mg & 10mg/80mg exercised in patients with pre-disposing factors for rhabdomyolysis. In muscle pain, tenderness, or weakness, particularly during the initial have been evaluated in a controlled clinical trial in adolescent boys
order to establish a reference baseline value, a CK level should be months of therapy and when the dose of either medicinal product is (Tanner stage II or above) and in girls who were at least one year post-
measured before starting treatment in the following situations: Elderly increased. Additionally, the incidence of myopathy was approximately menarche. In this limited controlled study, there was generally no
(age ≥65 years); Female gender; Renal impairment; Uncontrolled 0.24 % for Chinese patients on simvastatin 40 mg or ezetimibe/ detectable effect on growth or sexual maturation in the adolescent boys
hypothyroidism; Personal or familial history of hereditary muscular simvastatin 10/40 mg compared with 1.24 % for Chinese patients on or girls, or any effect on menstrual cycle length in girls. However, the
disorders; Previous history of muscular toxicity with a statin or fibrate; simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg co-administered effects of ezetimibe for a treatment period >33 weeks on growth and
Alcohol abuse. In such situations, the risk of treatment should be with modified-release nicotinic acid/ laropiprant 2000 mg/40 mg. sexual maturation have not been studied. The safety and efficacy of
considered in relation to possible benefit, and clinical monitoring is Because the incidence of myopathy is higher in Chinese than in non- ezetimibe co-administered with doses simvastatin above 40 mg daily
recommended. If a patient has previously experienced a muscle Chinese patients, co- administration of Ezetimibe/Simvastatin with have not been studied in paediatric patients 10 to 17 years of age.
disorder on a fibrate or a statin, treatment with any statin-containing lipid-modifying doses (≥1 g/day) of niacin (nicotinic acid) is not Ezetimibe has not been studied in patients younger than 10 years of age
product (such as Ezetimibe/Simvastatin) should only be initiated with recommended in Asian patients. Acipimox is structurally related to or in pre-menarchal girls. The long-term efficacy of therapy with
caution. If CK levels are significantly elevated at baseline (>5 X ULN), niacin, therefore, the risk for muscle related toxic effects may be similar. ezetimibe in patients below 17 years of age to reduce morbidity and
treatment should not be started. Whilst on treatment: If muscle pain, The combined use of Ezetimibe/Simvastatin at doses higher than 10/20 mortality in adulthood has not been studied. Fibrates: The safety and
weakness or cramps occur whilst a patient is receiving treatment with mg daily with amiodarone, amlodipine, verapamil, or diltiazem should efficacy of ezetimibe administered with fibrates have not been
Ezetimibe/Simvastatin, their CK levels should be measured. If these be avoided. In patients with HoFH, the combined use of Ezetimibe/ established. Anticoagulants: If Ezetimibe/ Simvastatin is added to
levels are found, in the absence of strenuous exercise, to be significantly Simvastatin at doses higher than 10/40 mg daily with lomitapide must warfarin, another coumarin anticoagulant, or fluindione, the
elevated (>5 X ULN), treatment should be stopped. If muscular be avoided. Patients taking other medicines labelled as having a International Normalised Ratio (INR) should be appropriately
symptoms are severe and cause daily discomfort, even if CK levels are moderate inhibitory effect on CYP3A4 at therapeutic doses monitored. Interstitial lung disease: Cases of interstitial lung disease
<5 X ULN, treatment discontinuation may be considered. If myopathy is concomitantly with Ezetimibe/Simvastatin, particularly higher have been reported with some statins, including simvastatin, especially
Product Presentation Ezetimibe / Simvastatin Tablets suspected for any other reason, treatment should be discontinued. Ezetimibe/Simvastatin doses, may have an increased risk of myopathy. with long term therapy. Presenting features can include dyspnoea, non-
Strength 10mg/20mg 10mg/40mg 10mg/80mg There have been very rare reports of an immune-mediated necrotizing When co-administering Ezetimibe/Simvastatin with a moderate productive cough and deterioration in general health (fatigue, weight
myopathy (IMNM) during or after treatment with some statins. IMNM is inhibitor of CYP3A4 (agents that increase AUC approximately 2-5 fold), loss and fever). If it is suspected a patient has developed interstitial lung
Pack Size 28 28 28 clinically characterised by persistent proximal muscle weakness and a dose adjustment may be necessary. For certain moderate CYP3A4 disease, Ezetimibe/Simvastatin therapy should be discontinued.
Product Format uncoated tablet uncoated tablet uncoated tablet elevated serum creatine kinase, which persist despite discontinuation of inhibitors e.g. diltiazem, a maximum dose of 10/20 mg Ezetimibe/ Lactose: Patients with rare hereditary problems of galactose intolerance,
statin treatment. If symptoms resolve and CK levels return to normal, Simvastatin is recommended. Simvastatin is a substrate of the Breast total lactase deficiency or glucose- galactose malabsorption should not
Legal Category POM POM POM then re-introduction of Ezetimibe/Simvastatin or introduction of Cancer Resistant Protein (BCRP) efflux transporter. Concomitant take this medicine. Effects on ability to drive and use machines: it should
Pack Dimensions (HxWxD) 178mmx24mmx75mm 115mmx25mmx86mm 178mmx24mmx72mm another statin-containing product may be considered at the lowest administration of products that are inhibitors of BCRP (e.g., elbasvir and be taken into account that dizziness has been reported.
dose and with close monitoring. A higher rate of myopathy has been grazoprevir) may lead to increased plasma concentrations of simvastatin Fertility, Pregnancy & Lactation: Pregnancy: Atherosclerosis is
Shelf Life 24 months 24 months 24 months observed in patients titrated to the 80 mg dose of simvastatin. Periodic and an increased risk of myopathy; therefore, a dose adjustment of a chronic process, and ordinarily discontinuation of lipid-lowering
CK measurements are recommended as they may be useful to identify simvastatin should be considered depending on the prescribed dose. drugs during pregnancy should have little impact on the long-term
PIP Code 124-5406 124-5414 124-5422
subclinical cases of myopathy. Therapy with Ezetimibe/Simvastatin Co-administration of elbasvir and grazoprevir with simvastatin has not risk associated with primary hypercholesterolaemia. Ezetimibe with
EAN Code 5055565770054 5055565770061 5055565770078 should be temporarily stopped a few days prior to elective major been studied; however, the dose of Ezetimibe/ Simvastatin should not simvastatin: is contraindicated during pregnancy. No clinical data are
surgery and when any major medical or surgical condition supervenes. exceed 10/20 mg daily in patients receiving concomitant medication available on the use of Ezetimibe/ Simvastatin or Ezetimibe alone
Prescribing Information: Measures to reduce the risk of myopathy caused by medicinal product with products containing elbasvir or grazoprevir. The safety and efficacy during pregnancy. Simvastatin: The safety of simvastatin in pregnant
interactions: The risk of myopathy and rhabdomyolysis is significantly of ezetimibe with simvastatin administered with fibrates have not been women has not been established. Rare reports of congenital anomalies
Ezetimibe/Simvastatin 10mg/20mg, 10mg/40mg, 10mg/80mg Tablets increased by concomitant use of Ezetimibe/Simvastatin with potent studied. There is an increased risk of myopathy when simvastatin is used following intrauterine exposure to HMG-CoA reductase inhibitors
inhibitors of CYP3A4 (see list in ‘Contraindications’ section), as well as concomitantly with fibrates (especially gemfibrozil). Therefore, have been received. However, in an analysis of approximately 200
Please refer to the Summary of Product Characteristics (SmPC) before prescribing. ciclosporin, danazol, and gemfibrozil. Use of these medicinal products is concomitant use of Ezetimibe/Simvastatin with gemfibrozil is prospectively followed pregnancies exposed during the first trimester
contraindicated. Due to the simvastatin component of Ezetimibe/ contraindicated and concomitant use with other fibrates is not to simvastatin or another closely related HMG-CoA reductase inhibitor,
Presentation: Each tablet contains 10mg ezetimibe and 20mg, 40mg, exceed 10/40 mg/day. Co-administration with other medicines: Dosing developed rhabdomyolysis were taking a statin concomitantly with Simvastatin, the risk of myopathy and rhabdomyolysis is also increased recommended. Daptomycin: Cases of myopathy and/or rhabdomyolysis the incidence of congenital anomalies was comparable to that seen
or 80mg of simvastatin. of Ezetimibe/Simvastatin should occur either ≥2 hours before or ≥4 ezetimibe. However, rhabdomyolysis has been reported very rarely with by concomitant use of other fibrates, lipid-lowering doses (≥1 g/day) of have been reported with HMG-CoA reductase inhibitors (e.g. in the general population. Maternal treatment with simvastatin
Indications: Prevention of Cardiovascular Events: Indicated to hours after administration of a bile acid sequestrant. In patients taking ezetimibe monotherapy and very rarely with the addition of ezetimibe niacin or by concomitant use of amiodarone, amlodipine, verapamil or simvastatin and ezetimibe/simvastatin) co-administered with may reduce the foetal levels of mevalonate which is a precursor of
reduce the risk of cardiovascular events in patients with coronary amiodarone, amlodipine, verapamil, diltiazem, or products containing to other agents known to be associated with increased risk of diltiazem with certain doses of Ezetimibe/Simvastatin. The risk of daptomycin. Caution should be used when prescribing HMG-CoA cholesterol biosynthesis. For this reason, Ezetimibe/Simvastatin must
heart disease (CHD) and a history of acute coronary syndrome (ACS), elbasvir or grazoprevir concomitantly with Ezetimibe/Simvastatin, the rhabdomyolysis. Simvastatin, like other inhibitors of HMG-CoA myopathy including rhabdomyolysis may be increased by concomitant reductase inhibitors with daptomycin, as either agent can cause not be used in women who are pregnant, trying to become pregnant
either previously treated with a statin or not. Hypercholesterolaemia: dose of Ezetimibe/Simvastatin should not exceed 10/20 mg/day. In reductase, occasionally causes myopathy manifested as muscle pain, administration of fusidic acid with Ezetimibe/Simvastatin. For patients myopathy and/or rhabdomyolysis when given alone. Consideration or suspect they are pregnant. Treatment with Ezetimibe/Simvastatin
Indicated as adjunctive therapy to diet for use in patients with primary patients taking lipid-lowering doses (≥1 g/day) of niacin concomitantly tenderness or weakness with creatine kinase (CK) above 10 X the upper with HoFH, this risk may be increased by concomitant use of lomitapide should be given to temporarily suspend Ezetimibe/Simvastatin in must be suspended for the duration of pregnancy or until it has been
(heterozygous familial and non-familial) hypercholesterolaemia with Ezetimibe/ Simvastatin, the dose of Ezetimibe/Simvastatin should limit of normal (ULN). Myopathy sometimes takes the form of with Ezetimibe/Simvastatin. Therefore, the use of Ezetimibe/ patients taking daptomycin unless the benefits of concomitant determined that the woman is not pregnant. Ezetimibe: No clinical data
or mixed hyperlipidaemia where use of combination product is not exceed 10/20 mg/day. Elderly: No dosage adjustment is required. rhabdomyolysis with or without acute renal failure secondary to Simvastatin concomitantly with potent CYP3A4 inhibitors is administration outweigh the risk. Consult the prescribing information are available on the use of ezetimibe during pregnancy. Breast-feeding:
appropriate; patients not appropriately controlled with a statin alone, Paediatric population: Initiation of treatment must be performed under myoglobinuria, and very rare fatalities have occurred. The risk of contraindicated. If treatment with potent CYP3A4 inhibitors (agents of Daptomycin to obtain further information about this potential Ezetimibe/Simvastatin is contraindicated during lactation. It is not
or patients already treated with a statin and ezetimibe. Homozygous review of a specialist. Adolescents ≥10 years (pubertal status: boys myopathy is increased by high levels of HMG-CoA reductase inhibitory that increase AUC approximately 5 fold or greater) is unavoidable, interaction with HMG-CoA reductase inhibitors (e.g. simvastatin and known if the active components of Ezetimibe/Simvastatin are secreted
Familial Hypercholesterolaemia (HoFH): Indicated as adjunctive Tanner Stage II and above and girls who are at least one year post- activity in plasma, which may be due, in part, to interacting drugs that therapy with Ezetimibe/Simvastatin must be suspended (and use of an ezetimibe/simvastatin) and for further guidance related to monitoring. into human breast milk.
therapy to diet for use in patients with HoFH. Patients may also receive menarche): clinical experience in paediatric and adolescent patients interfere with simvastatin metabolism and/or transporter pathways. As alternative statin considered) during the course of treatment. Moreover, Liver Enzymes: In controlled co-administration trials in patients Adverse Events include: Adverse events which could be considered
adjunctive treatments (e.g. low-density lipoprotein [LDL] apheresis). (aged 10-17 years old) is limited. The recommended usual starting with other HMG-CoA reductase inhibitors, the risk of myopathy/ caution should be exercised when combining Ezetimibe/Simvastatin receiving ezetimibe with simvastatin, consecutive transaminase serious: Thrombocytopaenia, anaemia, gastritis, anaphylaxis,
rhabdomyolysis is dose related for simvastatin. The risk of myopathy is
with certain other less potent CYP3A4 inhibitors: fluconazole, elevations (≥3 X ULN) have been observed. It is recommended that liver hypersensitivity, peripheral neuropathy, hypertension, dyspnoea,
Dosage and Administration: Ezetimibe/Simvastatin can be dose is 10/10 mg once a day in the evening. The recommended dosing greater in patients on Ezetimibe/Simvastatin 10/80 mg compared with verapamil, diltiazem. Concomitant intake of grapefruit juice and function tests be performed before treatment with Ezetimibe/
interstitial lung disease, pancreatitis, hepatitis/jaundice, fatal and non-
administered as a single dose in the evening with or without food. The range is 10/10 mg/day to a maximum of 10/40 mg/day. Children <10 other statin- based therapies with similar LDL-C-lowering efficacy. Ezetimibe/Simvastatin should be avoided. Simvastatin must not be co- Simvastatin begins and thereafter when clinically indicated. Patients fatal hepatic failure, cholelithiasis, cholecystitis, erythema multiforme,
tablet should not be split. Hypercholesterolaemia: The patient should years: Ezetimibe/ Simvastatin is not recommended due to insufficient Therefore, the 10/80-mg dose of Ezetimibe/Simvastatin should only be administered with systemic formulations of fusidic acid or within 7 days titrated to the 10/80 mg dose should receive an additional test prior to angioedema, muscle rupture, rhabdomyolysis with or without acute
be on an appropriate lipid-lowering diet and should continue on this data on safety and efficacy. Hepatic Impairment: No dosage adjustment used in patients with severe hypercholesterolemia and at high risk for of stopping fusidic acid treatment. In patients where the use of systemic titration, 3 months after titration to the 10/80 mg dose, and periodically renal failure, diabetes mellitus.
diet during treatment with Ezetimibe/Simvastatin. The dosage range of is required in patients with mild hepatic impairment (Child-Pugh score cardiovascular complications who have not achieved their treatment fusidic acid is considered essential, statin treatment should be thereafter (e.g., semi-annually) for the first year of treatment. Special
Ezetimibe/Simvastatin is 10/10 mg/day through 10/80 mg/day, with a 5 to 6). Treatment with Ezetimibe/ Simvastatin is not recommended goals on lower doses and when the benefits are expected to outweigh discontinued throughout the duration of fusidic acid treatment. There attention should be paid to patients who develop elevated serum Other Very Common adverse events: None.
typical dose of 10/20 mg/day or 10/40 mg/day given as a single dose in patients with moderate (Child-Pugh score 7 to 9) or severe (Child- the potential risks. In patients taking Ezetimibe/Simvastatin 10/80 mg have been reports of rhabdomyolysis (including some fatalities) in transaminase levels, and in these patients, measurements should be Other Common adverse events: Myalgia, alanine transaminase (ALT)
in the evening. The 10/80-mg dose is only recommended in patients Pugh score >9) liver dysfunction. Renal Impairment: No modification for whom an interacting agent is needed, a lower dose of Ezetimibe/ patients receiving fusidic acid and statins in combination. The patient repeated promptly and then performed more frequently. If the and/or aspartate aminotransferase (AST) increased, blood creatine
with severe hypercholesterolaemia and at high risk for cardiovascular of dosage should be necessary in patients with mild renal impairment Simvastatin or an alternative statin- based regimen with less potential should be advised to seek medical advice immediately if they experience transaminase levels show evidence of progression, particularly if they kinase (CK) increased.
complications who have not achieved their treatment goals on lower (estimated glomerular filtration rate ≥60 ml/min/1.73 m2). In patients for drug-drug interactions should be used. In a clinical trial in which any symptoms of muscle weakness, pain or tenderness. Statin therapy rise to 3 X ULN and are persistent, the drug should be discontinued. Note See SmPC for details of other adverse events.
doses and when the benefits are expected to outweigh the potential with chronic kidney disease and estimated glomerular filtration patients at high risk of cardiovascular disease were treated with may be re-introduced seven days after the last dose of fusidic acid. In that ALT may emanate from muscle, therefore ALT rising with CK may Presentation and Price:
risks. The patient’s low-density lipoprotein cholesterol (LDL-C) level, rate <60 ml/min/1.73 m2, the recommended dose of Ezetimibe/ simvastatin 40 mg/day (median follow-up 3.9 years), the incidence of exceptional circumstances, where prolonged systemic fusidic acid is indicate myopathy. There have been rare post-marketing reports of fatal 10mg/20mg x 28 £33.42, 10mg/40mg x 28 £38.98, 10mg/80mg x
coronary heart disease risk status, and response to current cholesterol- Simvastatin is 10/20 mg once a day in the evening. Higher doses should myopathy was approximately 0.05 % for non-Chinese patients needed, e.g. for the treatment of severe infections, the need for co- and non-fatal hepatic failure in patients taking statins, including 28 £41.21
lowering therapy should be considered when starting therapy or be implemented cautiously. (n=7367) compared with 0.24 % for Chinese patients (n=5468). While administration of Ezetimibe/Simvastatin and fusidic acid should only be simvastatin. If serious liver injury with clinical symptoms and/or Legal Category: POM
adjusting the dose. Adjustments of dosage, if required, should be Contraindications: Hypersensitivity to the active substances or to the only Asian population assessed in this clinical trial was Chinese, considered on a case-by-case basis under close medical supervision. The hyperbilirubinaemia or jaundice occurs during treatment with Further information is available from:
made at intervals of not less than 4 weeks. Patients with Coronary Heart any of the excipients. Pregnancy and lactation. Active liver disease or caution should be used when prescribing Ezetimibe/Simvastatin to combined use of Ezetimibe/Simvastatin at doses higher than 10/20 mg Ezetimibe/Simvastatin promptly interrupt therapy. If an alternate Accord-UK Ltd, Whiddon Valley, Barnstaple, Devon, EX32 8NS.
Disease and ACS Event History: In the cardiovascular events risk reduction unexplained persistent elevations in serum transaminases. Concomitant Asian patients and the lowest dose necessary should be employed. daily with lipid-lowering doses (≥1 g/day) of niacin should be avoided etiology is not found, do not restart Ezetimibe/Simvastatin. Ezetimibe/ Marketing Authorisation Numbers: PL 20075/1370, 1371, 1372
study (IMPROVE-IT), the starting dose was 10/40 mg once a day in the administration of potent CYP3A4 inhibitors (agents that increase AUC Reduced function of transport proteins: Reduced function of hepatic unless the clinical benefit is likely to outweigh the increased risk of Simvastatin should be used with caution in patients who consume Date of PI Preparation: November 2022
evening. The 10/80mg dose is only recommended when the benefits approximately 5 fold or greater) (e.g., itraconazole, ketoconazole, OATP transport proteins can increase the systemic exposure of myopathy. Rare cases of myopathy/rhabdomyolysis have been substantial quantities of alcohol. Hepatic impairment: Due to the Document Number: UK-04633
are expected to outweigh the potential risks. Homozygous Familial posaconazole, voriconazole, erythromycin, clarithromycin, simvastatin acid and increase the risk of myopathy and rhabdomyolysis. associated with concomitant administration of HMG-CoA reductase unknown effects of the increased exposure to ezetimibe in patients with
Hypercholesterolaemia: The recommended starting dosage is 10/40 mg/ telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, Reduced function can occur as the result of inhibition by interacting inhibitors and lipid-modifying doses (≥1 g/day) of niacin (nicotinic moderate or severe hepatic impairment, Ezetimibe/ Simvastatin is not Adverse events should be reported.
day in the evening. The 10/80-mg dose is only recommended when telaprevir, nefazodone, and drugs containing cobicistat). Concomitant medicines (eg ciclosporin) or in patients who are carriers of the SLCO1B1 acid), either of which can cause myopathy when given alone. In a recommended. Diabetes mellitus: Some evidence suggests that statins Reporting forms and information can be found at
the benefits are expected to outweigh the potential risks. Ezetimibe/ administration of gemfibrozil, ciclosporin, or danazol. In patients with c.521T>C genotype. Creatine Kinase measurement: CK should not be clinical trial (median follow-up 3.9 years) involving patients at high risk as a class raise blood glucose, and in some patients, at high risk of future www.mhra.gov.uk/yellowcard
Simvastatin may be used as an adjunct to other lipid-lowering HoFH, concomitant administration of lomitapide with doses > 10/40 measured following strenuous exercise or in the presence of any of cardiovascular disease and with well-controlled LDL-C levels on diabetes, may produce a level of hyperglycaemia where formal diabetes Adverse events should also be reported to
treatments (e.g., LDL apheresis) in these patients or if such treatments mg Ezetimibe/Simvastatin. plausible alternative cause of CK increase as this makes value simvastatin 40 mg/day with or without ezetimibe 10 mg, there was no care is appropriate. This risk, however, is outweighed by the reduction in Accord-UK LTD on 01271 385257 or
are unavailable. In patients taking lomitapide concomitantly with Warnings and Precautions: Myopathy/Rhabdomyolysis: Cases of interpretation difficult. If CK levels are significantly elevated at baseline incremental benefit on cardiovascular outcomes with the addition of vascular risk with statins and therefore should not be a reason for email medinfo@accord-healthcare.com
Ezetimibe/Simvastatin, the dose of Ezetimibe/Simvastatin must not myopathy and rhabdomyolysis have been reported. Most patients who (>5 X ULN), levels should be re-measured within 5 to 7 days later to lipid-modifying doses (≥1 g/day) of niacin (nicotinic acid). Therefore, stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9

UK-04982 | Date of Preparation: April 2023 UK-04982 | Date of Preparation: April 2023

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