Side Effects and Contraindications of Ezetimibe

Ezetimibe is considered one of the best-tolerated drugs for lowering cholesterol: in controlled trials the frequency of side reactions on monotherapy was close to placebo. However, «well tolerated» does not mean «without risks». The editorial team examines which adverse effects have been described for ezetimibe, how the safety profile changes in combination with statins, and for whom the drug is contraindicated.

Safety profile: what the studies showed

Ezetimibe acts locally in the intestine and does not affect the cytochrome P450 systems, so it has a limited range of mechanisms through which systemic side effects could arise. This is reflected in the clinical data: in placebo-controlled trials the frequency of drug discontinuation due to adverse reactions was close to the placebo group.

According to the official prescribing information, among reactions that occurred somewhat more often than on placebo, monotherapy described upper respiratory tract infections, diarrhea, joint pain, sinusitis and pain in the extremities. In combination with a statin, nasopharyngitis and myalgia are added to the list. Most of these phenomena are mild and transient.

The most extensive information on long-term safety was provided by the IMPROVE-IT trial (Cannon et al., 2015), in which more than 18 thousand patients were followed for an average of several years. The frequency of muscle complications, gallbladder events, elevated liver enzymes and cancer did not differ significantly between the simvastatin + ezetimibe and simvastatin + placebo groups.

It is important to remember that the safety profile of the combination is determined mainly by the statin. That is, a patient taking atorvastatin together with ezetimibe must take into account all the precautions regarding the statin — from muscle symptoms to drug interactions.

The liver, muscles and gallbladder

According to the prescribing information, in controlled trials of the combination of ezetimibe with a statin, consecutive elevations of transaminases three or more times above the upper limit of normal occurred in approximately 1.3% of patients versus 0.4% on the statin alone. In most cases it was asymptomatic and disappeared after discontinuation or even while continuing treatment.

Therefore, when prescribing the combination, liver tests are monitored in accordance with the recommendations for the statin. In the post-marketing period, isolated cases of hepatitis were also reported, but the causal relationship in such reports is difficult to establish.

As for muscles: post-marketing data describe myalgia, elevated CK, myopathy and even rhabdomyolysis. Most such cases concerned patients who were simultaneously taking a statin or other drugs with myotoxic potential. However, every new pronounced muscle complaint requires evaluation by a doctor, even if the person is taking only ezetimibe.

Since ezetimibe changes cholesterol metabolism in bile, the question of gallstone disease has been considered. Particular attention is paid to the combination with fibrates, which themselves increase the lithogenicity of bile: cholelithiasis and cholecystitis were described in the post-marketing period, and the combination with gemfibrozil is not recommended.

Rare reactions and the question of cancer

Rare but potentially serious reactions include manifestations of hypersensitivity: rash, urticaria, angioedema, and in isolated cases anaphylaxis. Erythema multiforme, pancreatitis, thrombocytopenia, dizziness, headache and paresthesias were also reported.

• Swelling of the face, lips or tongue or difficulty breathing — emergency medical care.
• Severe pain in the upper abdomen radiating to the back — a reason to rule out pancreatitis.
• Jaundice, dark urine — assessment of liver function.
• Pronounced muscle weakness or darkening of the urine — analysis of CK and kidney function.

A separate question is oncological safety. In the SEAS trial, where patients with aortic stenosis received simvastatin with ezetimibe, a somewhat larger number of cancer cases was observed. An independent analysis of data from three large trials (Peto et al., 2008) did not confirm a reliable association, and later the large IMPROVE-IT trial found no increase in cancer frequency.

So as of today there are no grounds to consider ezetimibe carcinogenic. However, this story well illustrates why individual signals in small trials require verification in large samples before conclusions are drawn.

Contraindications and special groups

An absolute contraindication is hypersensitivity to ezetimibe or the components of the drug. In combination with a statin, the statin's contraindications also apply: active liver disease or persistent unexplained elevation of transaminases, pregnancy and breastfeeding.

Ezetimibe is not recommended for patients with moderate or severe hepatic impairment, since their systemic concentration of the drug increases significantly, and there is insufficient safety data. In mild hepatic impairment, adjustment is usually not needed.

As for the kidneys: in renal impairment, adjustment of the ezetimibe dose is generally not needed. The SHARP trial (Baigent et al., 2011) in patients with chronic kidney disease demonstrated that the combination of simvastatin with ezetimibe reduced the frequency of major atherosclerotic events without significant safety problems.

There is insufficient data on use during pregnancy, so ezetimibe monotherapy during this period is used only in cases of extreme need, and this is decided by a doctor; the combination with a statin is contraindicated. In children the drug is used according to indications, in particular for familial hypercholesterolemia and sitosterolemia, under the supervision of a specialist.

Interactions that affect safety

Ezetimibe is not metabolized by the CYP system, so its interaction profile is much simpler than that of statins. However, several combinations require attention (Kosoglou et al., 2005).

Cyclosporine significantly increases the concentration of ezetimibe, and ezetimibe in turn can slightly increase the level of cyclosporine. In patients after transplantation, this combination is prescribed with caution and monitoring of cyclosporine concentration.

Bile acid sequestrants (cholestyramine and others) bind ezetimibe and reduce its effectiveness, so the intake is separated in time according to the recommendation of the prescribing information. Fibrates, as already mentioned, increase the risk of gallstone disease; the combination with fenofibrate is possible under monitoring, with gemfibrozil — not recommended.

In patients taking warfarin, monitoring of INR is recommended at the start of ezetimibe. For athletes it is also important to consider that hepatotoxic substances, including oral anabolic steroids, complicate the assessment of liver tests and increase the overall load on the liver.

Editorial conclusions

Ezetimibe as monotherapy is tolerated almost like placebo; the most common complaints are mild gastrointestinal disorders, joint pain, upper respiratory tract infections.

In combination with a statin, transaminases rise somewhat more often, and the muscle safety profile is determined mainly by the statin. Rare reactions include hypersensitivity, pancreatitis and gallbladder complications.

Moderate and severe hepatic impairment, pregnancy in combination with a statin, and hypersensitivity are the key restrictions. The cancer signal in SEAS was not confirmed in subsequent analyses.

To complete the picture, read the articles «Ezetimibe: mechanism of action», «Why athletes might need Ezetimibe» and «Interaction of Atorvastatin with other drugs».

References

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