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Myopathy/Rhabdomyolysis: In post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin concomitantly with ezetimibe. However, rhabdomyolysis has been reported very rarely with ezetimibe monotherapy and very rarely with the addition of ezetimibe to other agents known to be associated with increased risk of rhabdomyolysis.
VYTORIN contains simvastatin. Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above 10 X the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and very rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma (i.e., elevated simvastatin and simvastatin acid plasma levels), which may be due, in part, to interacting drugs that interfere with simvastatin metabolism and/or transporter pathways (see Interactions).
As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related for simvastatin. In a clinical trial database in which 41,413 patients were treated with simvastatin, 24,747 (approximately 60 %) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03 %, 0.08 % and 0.61 % at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.
In a clinical trial in which patients with a history of myocardial infarction were treated with simvastatin 80 mg/day (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0% compared with 0.02% for patients on 20 mg/day. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%. (See Adverse Reactions and Pharmacology: Pharmacodynamics under Actions.)
The risk of myopathy is greater in patients on VYTORIN 10/80 mg compared with other statin-based therapies with similar LDL-C-lowering efficacy. Therefore, the 10/80 mg dose of ezetimibe/simvastatin should be used only in patients who have been taking this dose for 12 months or more without evidence of muscle toxicity. The 10/80 mg dose of ezetimibe/simvastatin should not be started in new patients, including patients already taking lower doses of the drug. In patients taking VYTORIN 10/80 mg for whom an interacting agent is needed, a lower dose of VYTORIN or an alternative statin-based regimen with less potential for drug-drug interactions should be used (see Measures to reduce the risk of myopathy caused by medicinal product interactions as follows and Dosage & Administration, Contraindications and Interactions).
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 VYTORIN 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 VYTORIN 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 VYTORIN 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. (See Adverse Reactions.)
In a clinical trial in which over 9000 patients with chronic kidney disease were randomised to receive VYTORIN 10/20 mg daily (n=4650) or placebo (n=4620) (median follow-up 4.9 years), the incidence of myopathy was 0.2 % for VYTORIN and 0.1 % for placebo. (See Adverse Reactions.)
In a clinical trial in which patients at high risk of cardiovascular disease were treated with simvastatin 40 mg/day (median follow-up 3.9 years), the incidence of myopathy was approximately 0.05 % for non-Chinese patients (n = 7367) compared with 0.24 % for Chinese patients (n = 5468). While the only Asian population assessed in this clinical trial was Chinese, caution should be used when prescribing VYTORIN to Asian patients and the lowest dose necessary should be employed.
Reduced function of transport proteins: Reduced function of hepatic OATP transport proteins can increase the systemic exposure of simvastatin acid and increase the risk of myopathy and rhabdomyolysis. Reduced function can occur as the result of inhibition by interacting medicines (e.g. ciclosporin) or in patients who are carriers of the SLCO1B1 c.521T>C genotype.
Patients carrying the SLCO1B1 gene allele (c.521T>C) coding for a less active OATP1B1 protein have an increased systemic exposure of simvastatin acid and increased risk of myopathy. The risk of high dose (80 mg) simvastatin related myopathy is about 1 % in general, without genetic testing. Based on the results of the SEARCH trial, homozygote C allele carriers (also called CC) treated with 80 mg have a 15% risk of myopathy within one year, while the risk in heterozygote C allele carriers (CT) is 1.5%. The corresponding risk is 0.3% in patients having the most common genotype (TT) (see Pharmacology: Pharmacokinetics under Actions). Where available, genotyping for the presence of the C allele should be considered as part of the benefit-risk assessment prior to prescribing 80 mg simvastatin for individual patients and high doses avoided in those found to carry the CC genotype. However, absence of this gene upon genotyping does not exclude that myopathy can still occur.
Creatine Kinase measurement: Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (>5 X ULN), levels should be re-measured within 5 to 7 days later to confirm the results.
Before the treatment: All patients starting therapy with VYTORIN, or whose dose of VYTORIN is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness.
Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis. In order to establish a reference baseline value, a CK level should be measured before starting treatment in the following situations: Elderly (age ≥65 years); Female gender; Renal impairment; Uncontrolled hypothyroidism; Personal or familial history of hereditary muscular disorders; Previous history of muscular toxicity with a statin or fibrate; Alcohol abuse.
In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended. If a patient has previously experienced a muscle disorder on a fibrate or a statin, treatment with any statin-containing product (such as VYTORIN) should only be initiated with caution. If CK levels are significantly elevated at baseline (>5 X ULN), treatment should not be started.
Whilst on treatment: If muscle pain, weakness or cramps occur whilst a patient is receiving treatment with VYTORIN, their CK levels should be measured. If these levels are found, in the absence of strenuous exercise, to be significantly elevated (>5 X ULN), treatment should be stopped. If muscular symptoms are severe and cause daily discomfort, even if CK levels are <5 X ULN, treatment discontinuation may be considered. If myopathy is suspected for any other reason, treatment should be discontinued.
There have been very rare reports of an immune-mediated necrotising myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterised by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment (see Adverse Reactions).
If symptoms resolve and CK levels return to normal, then re-introduction of VYTORIN or introduction of another statin-containing product may be considered at the lowest dose and with close monitoring.
A higher rate of myopathy has been observed in patients titrated to the 80 mg dose of simvastatin (see Pharmacology: Pharmacodynamics under Actions). Periodic CK measurements are recommended as they may be useful to identify subclinical cases of myopathy. However, there is no assurance that such monitoring will prevent myopathy.
Therapy with VYTORIN should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.
Measures to reduce the risk of myopathy caused by medicinal product interactions (see also Interactions): The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of VYTORIN with potent inhibitors of CYP3A4 (such as itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, nefazodone, medicinal products containing cobicistat), as well as ciclosporin, danazol, and gemfibrozil. Use of these medicinal products is contraindicated (see Contraindications).
Due to the simvastatin component of VYTORIN, the risk of myopathy and rhabdomyolysis is also increased by concomitant use of other fibrates, lipid-lowering doses (≥1 g/day) of niacin or by concomitant use of amiodarone, amlodipine, verapamil, ranolazine or diltiazem with certain doses of VYTORIN (see Dosage & Administration and Interactions). The risk of myopathy including rhabdomyolysis may be increased by concomitant administration of fusidic acid with VYTORIN. For patients with HoFH, this risk may be increased by concomitant use of lomitapide with VYTORIN (see Interactions).
Consequently, regarding CYP3A4 inhibitors, the use of VYTORIN concomitantly with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and medicinal products containing cobicistat is contraindicated (see Contraindications and Interactions). If treatment with potent CYP3A4 inhibitors (agents that increase AUC approximately 5-fold or greater) is unavoidable, therapy with VYTORIN must be suspended (and use of an alternative statin considered) during the course of treatment. Moreover, caution should be exercised when combining VYTORIN with certain other less potent CYP3A4 inhibitors: fluconazole, verapamil, diltiazem (see Dosage & Administration and Interactions). Concomitant intake of grapefruit juice and VYTORIN should be avoided.
Simvastatin must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see Interactions). The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.
Statin therapy may be re-introduced seven days after the last dose of fusidic acid. In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g. for the treatment of severe infections, the need for co-administration of VYTORIN and fusidic acid should only be considered on a case-by-case basis under close medical supervision.
The combined use of VYTORIN at doses higher than 10/20 mg daily with lipid-lowering doses (≥ 1 g/day) of niacin should be avoided (see Dosage & Administration and Interactions).
Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid), either of which can cause myopathy when given alone.
In a clinical trial (median follow-up 3.9 years) involving patients at high risk of cardiovascular disease and with well-controlled LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses (≥1 g/day) of niacin (nicotinic acid). Therefore, physicians contemplating combined therapy with simvastatin and lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid) or products containing niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and when the dose of either medicinal product is increased.
In addition, in this trial, the incidence of myopathy was approximately 0.24 % for Chinese patients on simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg compared with 1.24 % for Chinese patients on simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg co-administered with modified-release nicotinic acid/laropiprant 2000 mg/40 mg. While the only Asian population assessed in this clinical trial was Chinese, because the incidence of myopathy is higher in Chinese than in non-Chinese patients, co-administration of VYTORIN with lipid-modifying doses (≥1 g/day) of niacin (nicotinic acid) is not recommended in Asian patients.
Acipimox is structurally related to niacin. Although acipimox was not studied, the risk for muscle related toxic effects may be similar to niacin.
The combined use of VYTORIN at doses higher than 10/10 mg daily with verapamil, or diltiazem should be avoided. The combined use of VYTORIN at doses higher than 10/20 mg daily with amiodarone, amlodipine, or ranolazine should be avoided. In patients with HoFH, the combined use of VYTORIN at doses higher than 10/40 mg daily with lomitapide must be avoided. (See Dosage & Administration, Contraindications and Interactions.)
Patients taking other medicines labeled as having a moderate inhibitory effect on CYP3A4 at therapeutic doses concomitantly with VYTORIN, particularly higher VYTORIN doses, may have an increased risk of myopathy. When co-administering VYTORIN with a moderate inhibitor of CYP3A4 (agents that increase AUC approximately 2-5 fold), a dose adjustment may be necessary. For certain moderate CYP3A4 inhibitors e.g. diltiazem, a maximum dose of 10/10 mg VYTORIN is recommended (see Dosage & Administration).
Simvastatin is a substrate of the Breast Cancer Resistant Protein (BCRP) efflux transporter. Concomitant administration of products that are inhibitors of BCRP (e.g., elbasvir and grazoprevir) may lead to increased plasma concentrations of simvastatin and an increased risk of myopathy; therefore a dose adjustment of simvastatin should be considered depending on the prescribed dose. Co-administration of elbasvir and grazoprevir with simvastatin has not been studied; however, the dose of VYTORIN should not exceed 10/20 mg daily in patients receiving concomitant medication with products containing elbasvir or grazoprevir (see Interactions).
The safety and efficacy of VYTORIN administered with fibrates have not been studied. There is an increased risk of myopathy when simvastatin is used concomitantly with fibrates (especially gemfibrozil). Therefore, concomitant use of VYTORIN with gemfibrozil is contraindicated (see Contraindications) and concomitant use with other fibrates is not recommended (see Interactions).
Daptomycin: Cases of myopathy and/or rhabdomyolysis have been reported with HMG-CoA reductase inhibitors (e.g. simvastatin and ezetimibe/simvastatin) co-administered with daptomycin. Caution should be used when prescribing HMG-CoA reductase inhibitors with daptomycin, as either agent can cause myopathy and/or rhabdomyolysis when given alone. Consideration should be given to temporarily suspend VYTORIN in patients taking daptomycin unless the benefits of concomitant administration outweigh the risk. Consult the prescribing information of Daptomycin to obtain further information about this potential interaction with HMG-CoA reductase inhibitors (e.g. simvastatin and ezetimibe/simvastatin) and for further guidance related to monitoring. (See Interactions.)
Liver Enzymes: In controlled co-administration trials in patients receiving ezetimibe with simvastatin, consecutive transaminase elevations (≥3 X ULN) have been observed (see Adverse Reactions).
In IMPROVE-IT, 18,144 patients with coronary heart disease and ACS event history were randomised to receive VYTORIN 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 VYTORIN and 2.3% for simvastatin. (See Adverse Reactions.)
In a controlled clinical study in which over 9000 patients with chronic kidney disease were randomised to receive VYTORIN 10/20 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 VYTORIN and 0.6 % for placebo (see Adverse Reactions).
It is recommended that liver function tests should be performed before initiation of VYTORIN, and thereafter when clinically indicated. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3 X ULN and are persistent, the drug should be discontinued. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy (see Myopathy/Rhabdomyolysis as previously mentioned).
There have been rare post-marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinaemia or jaundice occurs during treatment with VYTORIN promptly interrupt therapy. If an alternate etiology is not found, do not restart VYTORIN.
VYTORIN should be used with caution in patients who consume substantial quantities of alcohol.
Hepatic impairment: Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, VYTORIN is not recommended (see Pharmacology: Pharmacokinetics under Actions).
Diabetes mellitus: Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI > 30 kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.
Fibrates: The safety and efficacy of ezetimibe administered with fibrates have not been established (see as previously mentioned and Contraindications and Interactions).
Anticoagulants: If VYTORIN is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored (see Interactions).
Interstitial lung disease: Cases of interstitial lung disease have been reported with some statins, including simvastatin, especially with long term therapy (see Adverse Reactions). Presenting features can include dyspnoea, non productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, VYTORIN therapy should be discontinued.
Excipient: 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.
Use in Children: Efficacy and safety of ezetimibe co-administered with simvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolaemia 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 ezetimibe for a treatment period > 33 weeks on growth and sexual maturation have not been studied (see Dosage & Administration and Adverse Reactions).
The safety and efficacy of ezetimibe co-administered with doses of simvastatin above 40mg daily have not been studied in paediatric patients 10 to 17 years of age.
Ezetimibe has not been studied in patients younger than 10 years of age or in pre-menarchal girls. (See Dosage & Administration and Adverse Reactions.)
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.
