Simvastatin and Ezetimibe interacts in the following cases:
Treatment with ezetimibe/simvastatin combination is not recommended in patients with moderate (Child-Pugh score 7 to 9) or severe (Child-Pugh score >9) liver dysfunction.
Dosing of ezetimibe/simvastatin should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant.
In patients taking amiodarone, amlodipine, verapamil, diltiazem, or products containing elbasvir or grazoprevir concomitantly with ezetimibe/simvastatin, the dose of ezetimibe/simvastatin combination should not exceed 10/20 mg/day.
It should be considered to temporarily suspend ezetimibe/simvastatin in patients taking daptomycin unless the benefits of concomitant administration outweigh the risk.
Doses greater than 10/40 mg of ezetimibe/simvastatin daily are not recommended.
In patients taking lipid-lowering doses (≥1 g/day) of niacin concomitantly with ezetimibe/simvastatin, the dose of ezetimibe/simvastatin combination should not exceed 10/20 mg/day.
In patients with chronic kidney disease and estimated glomerular filtration rate <60 mL/min/1.73 m², the recommended dose of INEGY is 10/20 mg once a day in the evening. Higher doses should be implemented cautiously.
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.
Ezetimibe/simvastatin combination is contraindicated during pregnancy. No clinical data are available on the use of ezetimibe/simvastatin during pregnancy. Animal studies on combination therapy have demonstrated reproduction toxicity.
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, ezetimibe/simvastatin must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with ezetimibe/simvastatin must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant.
No clinical data are available on the use of ezetimibe during pregnancy.
Ezetimibe/simvastatin combination 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 ezetimibe/simvastatin are secreted into human breast milk.
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.
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.
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.
Ezetimibe/simvastatin combination has been evaluated for safety in approximately 12,000 patients in clinical trials.
The following adverse reactions were observed in clinical studies of ezetimibe/simvastatin in patients treated with ezetimibe/simvastatin (n=2,404) and at a greater incidence than placebo (n=1,340), in patients treated with ezetimibe/simvastatin (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 ezetimibe/simvastatin fixed-dose combination or ezetimibe or simvastatin. These reactions are presented in the table below 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).
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 |
| 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; 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).
** 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.
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, involving 18,144 patients treated with either ezetimibe/simvastatin 10/40 mg (n=9,067; of whom 6% were uptitrated to ezetimibe/simvastatin 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 ezetimibe/simvastatin and 10.1% for patients treated with simvastatin. The incidence of myopathy was 0.2% for ezetimibe/simvastatin and 0.1% for simvastatin, where myopathy was defined as unexplained muscle weakness or pain with a serum CK ≥10 times ULN or two consecutive observations of CK ≥5 and <10 times ULN. The incidence of rhabdomyolysis was 0.1% for ezetimibe/simvastatin and 0.2% for simvastatin, where rhabdomyolysis was defined as unexplained muscle weakness or pain with a serum CK ≥10 times ULN with evidence of renal injury, ≥5 times ULN and <10 times ULN on two consecutive occasions with evidence of renal injury or CK ≥10,000 IU/L without evidence of renal injury. The incidence of consecutive elevations of transaminases (≥3 X ULN) was 2.5% for ezetimibe/simvastatin and 2.3% for simvastatin. Gallbladder-related adverse effects were reported in 3.1% vs 3.5% of patients allocated to ezetimibe/simvastatin and simvastatin, respectively. The incidence of cholecystectomy hospitalisations was 1.5% in both treatment groups. Cancer (defined as any new malignancy) was diagnosed during the trial in 9.4% vs 9.5%, respectively.
In the Study of Heart and Renal Protection (SHARP), involving over 9,000 patients treated with ezetimibe/simvastatin 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 ezetimibe/simvastatin, 9.8% in patients treated with placebo). The incidence of myopathy/rhabdomyolysis was 0.2% in patients treated with ezetimibe/simvastatin and 0.1% in patients treated with placebo. Consecutive elevations of transaminases (>3 X ULN) occurred in 0.7% of patients treated with ezetimibe/simvastatin compared with 0.6% of patients treated with placebo. In this trial, there were no statistically significant increases in the incidence of pre-specified adverse events, including cancer (9.4% for ezetimibe/simvastatin, 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 ezetimibe/simvastatin. These elevations were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment.
Clinically important elevations of CK (≥10 X ULN) were seen in 0.2% of the patients treated with ezetimibe/simvastatin.
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:
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