Source: Health Products Regulatory Authority (IE) Revision Year: 2023 Publisher: Organon Pharma (Ireland) Limited, 2 Dublin Landings, North Wall Quay North Dock, Dublin, D01 V4A3, Ireland
Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.
Pregnancy and lactation (see section 4.6).
Active liver disease or unexplained persistent elevations in serum transaminases.
Concomitant administration of potent CYP3A4 inhibitors (agents that increase AUC approximately 5‑fold or greater) (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, nefazodone, and drugs containing cobicistat) (see sections 4.4 and 4.5).
Concomitant administration of gemfibrozil, ciclosporin, or danazol (see sections 4.4 and 4.5).
In patients with HoFH, concomitant administration of lomitapide with doses >10/40mg INEGY (see sections 4.2, 4.4 and 4.5).
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.
INEGY 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 section 4.5).
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 sections 4.8 and 5.1.)
The risk of myopathy is greater in patients on INEGY 10/80 mg compared with other statin‑based therapies with similar LDL-C-lowering efficacy. Therefore, the 10/80‑mg dose of INEGY should only be used in patients with severe hypercholesterolaemia and at high risk for cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks. In patients taking INEGY 10/80 mg for whom an interacting agent is needed, a lower dose of INEGY or an alternative statin-based regimen with less potential for drug-drug interactions should be used (see below Measures to reduce the risk of myopathy caused by medicinal product interactions and sections 4.2, 4.3, and 4.5).
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 INEGY 10/40mg daily (n=9,067) or simvastatin 40mg daily (n=9,077). During a median follow-up of 6.0 years, the incidence of myopathy was 0.2% for INEGY and 0.1% for simvastatin, where myopathy was defined as unexplained muscle weakness or pain with a serum CK ≥10times ULN or two consecutive observations of CK ≥5 and <10times ULN. The incidence of rhabdomyolysis was 0.1% for INEGY 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 section 4.8.)
In a clinical trial in which over 9,000 patients with chronic kidney disease were randomised to receive INEGY 10/20 mg daily (n=4,650) or placebo (n=4,620) (median follow-up 4.9 years), the incidence of myopathy was 0.2% for INEGY and 0.1% for placebo. (See section 4.8.)
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 = 7,367) compared with 0.24% for Chinese patients (n = 5,468). While the only Asian population assessed in this clinical trial was Chinese, caution should be used when prescribing INEGY to Asian patients and the lowest dose necessary should be employed.
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 (80mg) 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 80mg 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 section 5.2). Where available, genotyping for the presence of the C allele should be considered as part of the benefit-risk assessment prior to prescribing 80mg 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 (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.
All patients starting therapy with INEGY, or whose dose of INEGY 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:
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 INEGY) should only be initiated with caution. If CK levels are significantly elevated at baseline (>5 X ULN), treatment should not be started.
If muscle pain, weakness or cramps occur whilst a patient is receiving treatment with INEGY, 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 section 4.8).
If symptoms resolve and CK levels return to normal, then re-introduction of INEGY 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 section 5.1). 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 INEGY should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.
The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of INEGY with potent inhibitors of CYP3A4 (such as itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, nefazodone, and medicinal products containing cobicistat), as well as ciclosporin, danazol, and gemfibrozil. Use of these medicinal products is contraindicated (see section 4.3).
Due to the simvastatin component of INEGY, 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 or diltiazem with certain doses of INEGY (see sections 4.2 and 4.5). The risk of myopathy including rhabdomyolysis may be increased by concomitant administration of fusidic acid with INEGY. For patients with HoFH, this risk may be increased by concomitant use of lomitapide with INEGY (see section 4.5).
Consequently, regarding CYP3A4 inhibitors, the use of INEGY 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 sections 4.3 and 4.5). If treatment with potent CYP3A4 inhibitors (agents that increase AUC approximately 5‑fold or greater) is unavoidable, therapy with INEGY must be suspended (and use of an alternative statin considered) during the course of treatment. Moreover, caution should be exercised when combining INEGY with certain other less potent CYP3A4 inhibitors: fluconazole, verapamil, diltiazem (see sections 4.2 and 4.5). Concomitant intake of grapefruit juice and INEGY 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 section 4.5). 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 INEGY and fusidic acid should only be considered on a case-by-case basis under close medical supervision.
The combined use of INEGY at doses higher than 10/20 mg daily with lipid-lowering doses (≥1 g/day) of niacin should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5).
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 2,000 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 INEGY 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 INEGY at doses higher than 10/20 mg daily with amiodarone, amlodipine, verapamil, or diltiazem should be avoided. In patients with HoFH, the combined use of INEGY at doses higher than 10/40 mg daily with lomitapide must be avoided. (See sections 4.2, 4.3 and 4.5).
Patients taking other medicines labeled as having a moderate inhibitory effect on CYP3A4 at therapeutic doses concomitantly with INEGY, particularly higher INEGY doses, may have an increased risk of myopathy. When co-administering INEGY 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 10/20mg INEGY is recommended (see section 4.2).
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 INEGY should not exceed 10/20 mg daily in patients receiving concomitant medication with products containing elbasvir or grazoprevir (see section 4.5).
The safety and efficacy of INEGY 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 INEGY with gemfibrozil is contraindicated (see section 4.3) and concomitant use with other fibrates is not recommended (see section 4.5).
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 INEGY in patients taking daptomycin unless the benefits of concomitant administration outweigh the risk. Consult the prescribing information of Ddaptomycin 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 section 4.5).
In controlled co-administration trials in patients receiving ezetimibe with simvastatin, consecutivetransaminase elevations (³3 X ULN) have been observed (see section 4.8).
In IMPROVE-IT, 18,144 patients with coronary heart disease and ACS event history were randomised to receive INEGY 10/40 mg daily (n=9,067) or simvastatin 40 mg daily (n=9,077). During a median follow-up of 6.0 years, the incidence of consecutive elevations of transaminases (≥3 X ULN) was 2.5% for INEGY and 2.3% for simvastatin (See section 4.8).
In a controlled clinical study in which over 9,000 patients with chronic kidney disease were randomised to receive INEGY 10/20 mg daily (n=4,650), or placebo (n=4,620) (median follow-up period of 4.9 years), the incidence of consecutive elevations of transaminases (>3 X ULN) was 0.7% for INEGY and 0.6% for placebo (see section 4.8).
It is recommended that liver function tests be performed before treatment with INEGY begins and thereafter when clinically indicated. Patients titrated to the 10/80‑mg dose should receive an additional test prior to titration, 3 months after titration to the 10/80‑mg dose, and periodically thereafter (e.g. , semiannually) for the first year of treatment. 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 above Myopathy/Rhabdomyolysis).
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 INEGY promptly interrupt therapy. If an alternate aetiology is not found, do not restart INEGY.
INEGY should be used with caution in patients who consume substantial quantities of alcohol.
Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, INEGY is not recommended (see section 5.2).
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.
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 sStage 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 sections 4.2 and 4.8).
The safety and efficacy of ezetimibe co-administered with doses of simvastatin above 40mg daily have not been studied in paediatric patients 10 to 17years of age.
Ezetimibe has not been studied in patients younger than 10 years of age or in pre-menarchal girls. (See sections 4.2 and 4.8.)
The long-term efficacy of therapy with ezetimibe in patients below 17years of age to reduce morbidity and mortality in adulthood has not been studied.
The safety and efficacy of ezetimibe administered with fibrates have not been established (see above and sections 4.3 and 4.5).
If INEGY is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored (see section 4.5).
Cases of interstitial lung disease have been reported with some statins, including simvastatin, especially with long term therapy (see section 4.8). 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, INEGY therapy should be discontinued.
Patients with rare hereditary problems of galactose intolerance, the Lapp total lactase deficiency or glucose‑galactose malabsorption should not take this medicine.
INEGY contains less than 1 mmol (23 mg) sodium per tablet, that is to say essentially sodium-free.
Multiple mechanisms may contribute to potential interactions with HMG Co-A reductase inhibitors. Drugs or herbal products that inhibit certain enzymes (e.g. CYP3A4) and/or transporter (e.g. OATP1B) pathways may increase simvastatin and simvastatin acid plasma concentrations and may lead to an increased risk of myopathy/rhabdomyolysis.
Consult the prescribing information of all concomitantly used drugs to obtain further information about their potential interactions with simvastatin and/or the potential for enzyme or transporter alterations and possible adjustments to dose and regimens.
Interactions with lipid-lowering medicinal products that can cause myopathy when given alone The risk of myopathy, including rhabdomyolysis, is increased during concomitant administration of simvastatin with fibrates. Additionally, there is a pharmacokinetic interaction of simvastatin with gemfibrozil resulting in increased simvastatin plasma levels (see below Pharmacokinetic interactions and sections 4.3 and 4.4). Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co‑administered with lipid‑modifying doses (≥1 g/day) of niacin (see section 4.4).
Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile (see section 5.3). Although the relevance of this preclinical finding to humans is unknown, co-administration of INEGY with fibrates is not recommended (see section 4.4).
Prescribing recommendations for interacting agents are summarised in the table below (further details are provided in the text; see also sections 4.2, 4.3, and 4.4).
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis:
| Interacting agents | Prescribing recommendations |
|---|---|
| Potent CYP3A4 inhibitors, e.g., Itraconazole Ketoconazole Posaconazole Voriconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors (e.g., nelfinavir) Boceprevir Telaprevir Nefazodone Cobicistat Ciclosporin Danazol Gemfibrozil | Contraindicated with INEGY |
| Other Fibrates Fusidic acid | Not recommended with INEGY |
| Niacin (nicotinic acid) (≥1 g/day) | For Asian patients, not recommended with INEGY |
| Amiodarone Amlodipine Verapamil Diltiazem Niacin (≥1 g/day) Elbasvir Grazoprevir | Do not exceed 10/20 mg INEGY daily |
| Lomitapide | For patients with HoFH, do not exceed 10/40 mg INEGY daily |
| Daptomycin | It should be considered to temporarily suspend INEGY in patients taking daptomycin unless the benefits of concomitant administration outweigh the risk (see section 4.4) |
| Ticagrelor | Doses greater than 10/40 mg INEGY daily are not recommended |
| Grapefruit juice | Avoid grapefruit juice when taking INEGY |
Niacin: In a study of 15 healthy adults, concomitant INEGY (10/20 mg daily for 7 days) caused a small increase in the mean AUCs of niacin (22%) and nicotinuric acid (19%) administered as NIASPAN extended-release tablets (1,000 mg for 2 days and 2,000 mg for 5 days following a low-fat breakfast). In the same study, concomitant NIASPAN slightly increased the mean AUCs of ezetimibe (9%), total ezetimibe (26%), simvastatin (20%) and simvastatin acid (35%). (See sections 4.2 and 4.4).
Drug interaction studies with higher doses of simvastatin have not been investigated.
Antacids: Concomitant antacid administration decreased the rate of absorption of ezetimibe but had no effect on the bioavailability of ezetimibe. This decreased rate of absorption is not considered clinically significant.
Cholestyramine: Concomitant cholestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55%. The incremental LDL‑C reduction due to adding INEGY to cholestyramine may be lessened by this interaction (see section 4.2).
Ciclosporin: In a study of eight post-renal transplant patients with creatinine clearance of >50 mLl/minon a stable dose of ciclosporin, a single 10‑mg dose of ezetimibe resulted in a 3.4‑fold (range 2.3‑ to 7.9‑fold) increase in the mean AUC for total ezetimibe compared to a healthy control population, receiving ezetimibe alone, from another study (n=17). In a different study, a renal transplant patient with severe renal impairment who was receiving ciclosporin and multiple other medications demonstrated a 12‑fold greater exposure to total ezetimibe compared to concurrent controls receiving ezetimibe alone. In a two-period crossover study in twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days with a single 100‑mg dose of ciclosporin on Day 7 resulted in a mean 15% increase in ciclosporin AUC (range 10% decrease to 51% increase) compared to a single 100‑mg dose of ciclosporin alone. A controlled study on the effect of co-administered ezetimibe on ciclosporin exposure in renal transplant patients has not been conducted. Concomitant administration of INEGY with ciclosporin is contraindicated (see section 4.3).
Fibrates: Concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations approximately 1.5- and 1.7‑fold, respectively. Although these increases are not considered clinically significant, co-administration of INEGY with gemfibrozil is contraindicated and with other fibrates is not recommended (see sections 4.3 and 4.4).
Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the concentration of HMG‑CoA reductase inhibitory activity in plasma during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, nefazodone, and medicinal products containing cobicistat. Concomitant administration of itraconazole resulted in a more than 10‑fold increase in exposure to simvastatin acid (the active beta‑hydroxyacid metabolite). Telithromycin caused an 11‑fold increase in exposure to simvastatin acid.
Combination with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone,and medicinal products containing cobicistat is contraindicated, as well as gemfibrozil, ciclosporin, and danazol (see section 4.3). If treatment with potent CYP3A4 inhibitors (agents that increase AUC approximately 5‑fold or greater) is unavoidable, therapy with INEGY must be suspended (and use of an alternative statin considered) during the course of treatment. Caution should be exercised when combining INEGY with certain other less potent CYP3A4 inhibitors: fluconazole, verapamil, or diltiazem (see sections 4.2 and 4.4).
Ticagrelor: Co-administration of ticagrelor with simvastatin increased simvastatin Cmax by 81% and AUC by 56% and increased simvastatin acid Cmax by 64% and AUC by 52% with some individual increases equal to 2‑ to 3‑fold. Co-administration of ticagrelor with doses of simvastatin exceeding 40mg daily could cause adverse reactions of simvastatin and should be weighed against potential benefits. There was no effect of simvastatin on ticagrelor plasma levels. The concomitant use of ticagrelor with doses of simvastatin greater than 40mg is not recommended.
Fluconazole: Rare cases of rhabdomyolysis associated with concomitant administration of simvastatin and fluconazole have been reported. (see section 4.4).
Ciclosporin: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of ciclosporin with INEGY; therefore, use with ciclosporin is contraindicated (see sections 4.3 and 4.4). Although the mechanism is not fully understood, ciclosporin has been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1.
Danazol: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with INEGY; therefore, use with danazol is contraindicated (see sections 4.3 and 4.4).
Gemfibrozil: Gemfibrozil increases the AUC of simvastatin acid by 1.9‑fold, possibly due to inhibition of the glucuronidation pathway and/or OATP1B1 (see sections 4.3 and 4.4). Concomitant administration with gemfibrozil is contraindicated.
Fusidic acid: The risk of myopathy, including rhabdomyolysis, may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamics or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. Co-administration of this combination may cause increased plasma concentrations of both agents.
If treatment with systemic fusidic acid is necessary, INEGY treatment should be discontinued throughout the duration of the fusidic acid treatment. Also see section 4.4 Special warnings and precautions for use.
Amiodarone: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of amiodarone with simvastatin (see section 4.4). In a clinical trial, myopathy was reported in 6% of patients receiving simvastatin 80 mg and amiodarone. Therefore, the dose of INEGY should not exceed 10/20 mg daily in patients receiving concomitant medication with amiodarone.
Lomitapide: The risk of myopathy and rhabdomyolysis may be increased by concomitant administration of lomitapide with simvastatin (see sections 4.3 and 4.4). Therefore, in patients with HoFH, the dose of INEGY must not exceed 10/40 mg daily in patients receiving concomitant medication with lomitapide.
Moderate Inhibitors of CYP3A4: Patients taking other medicines labeled as having a moderate inhibitory effect on CYP3A4 concomitantly with INEGY, particularly higher INEGY doses, may have an increased risk of myopathy (see section 4.4).
Inhibitors of the Transport Protein OATP1B1: Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of medicinal products that are inhibitors of the transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid and an increased risk of myopathy (see sections 4.3 and 4.4).
Inhibitors of Breast Cancer Resistant Protein (BCRP): Concomitant administration of medicinal products that are inhibitors of BCRP, including products containing elbasvir or grazoprevir, may lead to increased plasma concentrations of simvastatin and an increased risk of myopathy (see sections 4.2 and 4.4).
Grapefruit juice: Grapefruit juice inhibits cytochrome P450 3A4. Concomitant intake of large quantities (over 1 litre daily) of grapefruit juice and simvastatin resulted in a 7‑fold increase in exposure to simvastatin acid. Intake of 240 mL of grapefruit juice in the morning and administration of simvastatin in the evening also resulted in a 1.9‑fold increase. Intake of grapefruit juice during treatment with INEGY should therefore be avoided.
Colchicine: There have been reports of myopathy and rhabdomyolysis with the concomitant administration of colchicine and simvastatin, in patients with renal impairment. Close clinical monitoring of such patients taking this combination is advised.
Rifampicin: Because rifampicin is a potent CYP3A4 inducer, patients undertaking long-term rifampicin therapy (e.g. treatment of tuberculosis) may experience loss of efficacy of simvastatin. In a pharmacokinetic study in normal volunteers, the area under the plasma concentration curve (AUC) for simvastatin acid was decreased by 93% with concomitant administration of rifampicin.
Niacin: Cases of myopathy/rhabdomyolysis have been observed with simvastatin co-administered with lipid‑modifying doses (≥1 g/day) of niacin (see section 4.4).
Daptomycin: The risk of myopathy and/or rhabdomyolysis may be increased by concomitant administration of HMG-CoA reductase inhibitors (e.g. simvastatin and ezetimibe/simvastatin) and daptomycin (see section 4.4).
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.
Anticoagulants: Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. However, there have been post-marketing reports of increased International Normalised Ratio (INR) in patients who had ezetimibe added to warfarin or fluindione. If INEGY is added to warfarin, another coumarin anticoagulant, or fluindione, INR should be appropriately monitored (see section4.4).
Simvastatin: Simvastatin does not have an inhibitory effect on cytochrome P450 3A4. Therefore, simvastatin is not expected to affect plasma concentrations of substances metabolised via cytochrome P450 3A4.
Oral anticoagulants: In two clinical studies, one in normal volunteers and the other in hypercholesterolaemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. Very rare cases of elevated INR have been reported. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting INEGY and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of INEGY is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Interaction studies have only been performed in adults.
Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering drugs during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia.
INEGY is contraindicated during pregnancy. No clinical data are available on the use of INEGY during pregnancy. Animal studies on combination therapy have demonstrated reproduction toxicity (See section 5.3.)
The safety of simvastatin in pregnant women has not been established. No controlled clinical trials with simvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the first trimester to simvastatin or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to exclude a 2.5‑fold or greater increase in congenital anomalies over the background incidence.
Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking simvastatin or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with simvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. For this reason, INEGY must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with INEGY must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant (See section 4.3).
No clinical data are available on the use of ezetimibe during pregnancy.
INEGY is contraindicated during lactation. Studies on rats have shown that ezetimibe is excreted into breast milk. It is not known if the active components of INEGY are secreted into human breast milk (See section 4.3).
No clinical trial data are available on the effects of ezetimibe on human fertility. Ezetimibe had no effect on the fertility of male or female rats (see section 5.3).
No clinical trial data are available on the effects of simvastatin on human fertility. Simvastatin had no effect on the fertility of rats male and female (see section 5.3).
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.
INEGY (or co-administration of ezetimibe and simvastatin equivalent to INEGY) has been evaluated for safety in approximately 12,000 patients in clinical trials.
The following adverse reactions were observed in clinical studies of INEGY in patients treated with INEGY (n=2,404) and at a greater incidence than placebo (n=1,340), in patients treated with INEGY (n=9,595) and at a greater incidence than statins administered alone (n=8,883) in clinical studies of ezetimibe or simvastatin, and/or reported from post-marketing use with INEGY or ezetimibe or simvastatin. These reactions are presented in Table 1 by system organ class and by frequency.
The frequencies of adverse events are ranked according to the following: Very common (≥1/10), Common (≥1/100, <1/10), Uncommon (≥1/1000, <1/100), Rare (≥1/10,000, <1/1000), Very Rare (<1/10,000) including isolated reports, and Not Known (cannot be estimated from the available data).
Table 1. Adverse Reactions:
| System organ class Frequency | Adverse reaction |
|---|---|
| Blood and lymphatic system disorders | |
| Not Known | thrombocytopaenia; anaemia |
| Immune system disorders | |
| Very Rare | anaphylaxis |
| Not Known | hypersensitivity |
| Metabolism and nutrition disorders | |
| Not Known | decreased appetite |
| Psychiatric disorders | |
| Uncommon | sleep disorder; insomnia |
| Not Known | depression |
| Nervous system disorders | |
| Uncommon | dizziness; headache; paraesthesia |
| Not Known | peripheral neuropathy; memory impairment |
| Eye disorders | |
| Rare | vision blurred; visual impairment |
| Vascular disorders | |
| Not Known | hot flush; hypertension |
| Respiratory, thoracic and mediastinal disorders | |
| Not Known | cough; dyspnoea; interstitial lung disease (see section 4.4) |
| Gastrointestinal disorders | |
| Uncommon | abdominal pain; abdominal discomfort; abdominal pain upper; dyspepsia; flatulence; nausea; vomiting; abdominal distension; diarrhoea; dry mouth; gastroesophageal reflux disease |
| Not Known | constipation; pancreatitis; gastritis |
| Hepatobiliary disorders | |
| Not Known | hepatitis/jaundice; fatal and non-fatal hepatic failure; cholelithiasis; cholecystitis |
| Skin and subcutaneous tissue disorders | |
| Uncommon | pruritus; rash; urticaria |
| Very Rare | lichenoid drug eruptions |
| Not Known | alopecia; erythema multiforme; angioedema |
| Musculoskeletal and connective tissue disorders | |
| Common | myalgia |
| Uncommon | arthralgia; muscle spasms; muscular weakness; musculoskeletal discomfort; neck pain; pain in extremity; back pain; musculoskeletal pain |
| Very Rare | muscle rupture |
| Not Known | muscle cramps; myopathy* (including myositis); rhabdomyolysis with or without acute renal failure (see section 4.4); tendinopathy, sometimes complicated by rupture; immune-mediated necrotising myopathy (IMNM)** |
| Reproductive system and breast disorders | |
| Very Rare | gynaecomastia |
| Not Known | erectile dysfunction |
| General disorders and administration site conditions | |
| Uncommon | asthenia; chest pain; fatigue; malaise; oedema peripheral |
| Not Known | pain |
| Investigations | |
| Common | ALT and/or AST increased; blood CK increased |
| Uncommon | blood bilirubin increased; blood uric acid increased; gamma-glutamyltransferase increased; international normalised ratio increased; protein urine present; weight decreased |
| Not Known | elevated alkaline phosphatase; liver function test abnormal |
* In a clinical trial, myopathy occurred commonly in patients treated with simvastatin 80 mg/day compared to patients treated with 20 mg/day (1.0% vs 0.02%, respectively) (see sections 4.4 and 4.5).
** There have been very rare reports of immune-mediated necrotising myopathy (IMNM), an autoimmune myopathy, 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; muscle biopsy showing necrotising myopathy without significant inflammation; improvement with immunosuppressive agents (see section 4.4).
In a study involving adolescent (10 to 17 years of age) patients with heterozygous familial hypercholesterolaemia (n=248), elevations of ALT and/or AST (≥3 X ULN, consecutive) were observed in 3% (4 patients) of the ezetimibe/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 (≥10 X ULN). No cases of myopathy were reported.
This trial was not suited for comparison of rare adverse drug reactions.
In the IMPROVE-IT study (see section 5.1), involving 18,144 patients treated with either INEGY 10/40 mg (n=9,067; of whom 6% were uptitrated to INEGY 10/80 mg) or simvastatin 40 mg (n=9,077; 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 INEGY and 10.1% for patients treated with simvastatin. The incidence of myopathy was 0.2% for INEGY 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 INEGY 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 INEGY and 2.3% for simvastatin (See section 4.4). Gallbladder-related adverse effects were reported in 3.1% vs 3.5% of patients allocated to INEGY 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.
In the Study of Heart and Renal Protection (SHARP) (see section 5.1), involving over 9,000 patients treated with INEGY 10/20 mg daily (n=4,650) or placebo (n=4,620), 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 INEGY, 9.8% in patients treated with placebo). The incidence of myopathy/rhabdomyolysis was 0.2% in patients treated with INEGY and 0.1% in patients treated with placebo. Consecutive elevations of transaminases (>3 X ULN) occurred in 0.7% of patients treated with INEGY compared with 0.6% of patients treated with placebo (See section 4.4). In this trial, there were no statistically significant increases in the incidence of pre-specified adverse events, including cancer (9.4% for INEGY, 9.5% for placebo), hepatitis, cholecystectomy or complications of gallstones or pancreatitis.
In co-administration trials, the incidence of clinically important elevations in serum transaminases (ALT and/or AST ≥3 X ULN, consecutive) was 1.7% for patients treated with INEGY. These elevations were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment (See section 4.4).
Clinically important elevations of CK (≥10 X ULN) were seen in 0.2% of the patients treated with INEGY.
An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopaenia, eosinophilia, red blood cell sedimentation rate increased, arthritis and arthralgia, urticaria, photosensitivity reaction, pyrexia, flushing, dyspnoea and malaise.
Increases in HbA1c and fasting serum glucose levels have been reported with statins, including simvastatin.
There have been rare post-marketing reports of cognitive impairment (e.g. memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use, including simvastatin. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
The following additional adverse events have been reported with some statins:
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 HPRA Pharmacovigilance Website: www.hpra.ie.
Not applicable.
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