Ezetimibe / simvastatin Side Effects

Some side effects of ezetimibe / simvastatin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

For the Consumer

Applies to ezetimibe / simvastatin: oral tablet

Get emergency medical help if you have any of these signs of an allergic reaction while taking ezetimibe / simvastatin: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop taking ezetimibe and simvastatin and call your doctor at once if you have any of these serious side effects:

• unexplained muscle pain, tenderness, or weakness;

• fever, unusual tiredness, and dark colored urine;

• swelling, weight gain, urinating less than usual or not at all;

• chest pain, dry cough, wheezing, feeling short of breath;

• severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate;

• nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

• high blood sugar (increased thirst, increased urination, hunger, dry mouth, fruity breath odor, drowsiness, dry skin, blurred vision, weight loss).

Less serious side effects of ezetimibe / simvastatin may include:

• headache, dizziness, depressed mood;

• memory problems, confusion;

• back pain, joint pain, mild muscle pain;

• numbness or tingly feeling;

• trouble having an erection;

• diarrhea;

• sleep problems (insomnia); or

• cold symptoms such as stuffy nose, sneezing, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

For Healthcare Professionals

Applies to ezetimibe / simvastatin: oral tablet

Gastrointestinal

Gastrointestinal side effects associated with ezetimibe have included diarrhea (3.7%), abdominal pain (3.0%), and nausea. Pancreatitis has been reported in postmarketing experience.

Gastrointestinal side effects associated with simvastatin have been reported the most frequently. These have included constipation (2.3% to 5.7%), nausea (1.3% to 4.4%), flatulence (1.9% to 3.4%), diarrhea (1.9% to 2.9%), dyspepsia (1.1% to 2.9%), and abdominal pain. A case of protein-losing enteropathy has been reported. Pancreatitis, anorexia, and vomiting have been reported with HMG-CoA reductase inhibitors therapy.

Musculoskeletal

Simvastatin has been associated with rare cases of severe myopathy and rhabdomyolysis. This is accompanied by elevations in creatine kinase, myoglobinuria, and proteinuria, as well as renal failure. Experience with HMG-CoA reductase inhibitors indicates that concomitant use with gemfibrozil, niacin, cyclosporine, or erythromycin may increase the incidence and the severity of musculoskeletal side effects.

A case of spontaneous biceps tendon rupture developed in a patient after 4 months of treatment with ezetimibe-simvastatin. Upon rechallenge 2 months later, the patient developed pain in the contralateral arm overlying the biceps tendon. Following discontinuation of ezetimibe-simvastatin, pain resolved 2 weeks later. Inhibition of matrix metalloproteinases has been suggested as the contributing factor in the development of tendon rupture.

Musculoskeletal side effects associated with ezetimibe including back pain (4.1%) and arthralgia (3.8%) have been reported. Myalgia, elevated creatine phosphokinase, and rare reports of myopathy/rhabdomyolysis have been reported in postmarketing experience.

Musculoskeletal side effects associated with simvastatin including elevations in creatine kinase, myopathy, dermatomyositis, and rhabdomyolysis have been reported. Arthralgia and myalgia associated with HMG-CoA reductase inhibitors have been reported.

Musculoskeletal side effects associated with the combination of ezetimibe-simvastatin include at least one case of tendon rupture.

Renal

Renal side effects associated with simvastatin including myoglobinuria and acute renal failure secondary to rhabdomyolysis have been reported.

Hepatic

Persistent elevations in liver function tests three times normal values are reported in up to 1.5% of patients on simvastatin in clinical trials. In one study, this led to the discontinuation of simvastatin in 0.6% of patients. In other patients, elevations in liver function tests were transient and returned to normal with continued simvastatin therapy.

Hepatic side effects associated with ezetimibe including elevations in liver transaminases, hepatitis, cholelithiasis, and cholecystitis have been reported in postmarketing experience.

Hepatic side effects associated with simvastatin including elevations in liver function tests (1.5%) have been reported. Hepatitis (including chronic active hepatitis), cholestatic jaundice, fatty changes in the liver, cirrhosis, and fulminant hepatic necrosis have been reported with HMG-CoA reductase inhibitors therapy. Hepatic failure has been reported in postmarketing experience.

Dermatologic

Dermatologic side effects reported with HMG-CoA reductase inhibitors have included eczematous, pruritic rash, toxic epidermal necrolysis, erythema multiforme, photosensitivity, purpura, and alopecia.

Immunologic

Immunologic side effects associated with ezetimibe including sinusitis (3.6%), pharyngitis (2.3%), and viral infection (2.2%) have been reported.

Immunologic side effects associated with simvastatin (and other HMG-CoA reductase inhibitors) have included a case of lupus-like syndrome. Positive ANA, ESR increase, polymyalgia rheumatica, and vasculitis associated with HMG-CoA reductase inhibitors have been reported.

Respiratory

Respiratory side effects have included interstitial lung disease causing breathing problems including persistent cough and/or shortness of breath or fever.

Cardiovascular

Cardiovascular side effects associated with simvastatin including angina have been reported 3.1% of patients.

Endocrine

Endocrine side effects of HMG-CoA reductase inhibitors have included gynecomastia and thyroid function abnormalities.

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including simvastatin.

Genitourinary

Genitourinary side effects of HMG-CoA reductase inhibitors have included erectile dysfunction and impotence.

A patient who had taken lovastatin and pravastatin on different occasions developed reversible impotence. The impotence resolved within 2 weeks after the HMG-CoA reductase inhibitor was discontinued.

Hematologic

Hematologic side effects associated with ezetimibe including thrombocytopenia have been reported in postmarketing experience. Hematologic side effects associated with the combination therapy have included increased epistaxis in a 65-year-old male in a postmarketing experience.

Hematologic side effects associated with HMG-CoA reductase inhibitors therapy including hemolytic anemia, thrombocytopenia, and leukopenia have been reported. These effects may be manifestations of a hypersensitivity reaction.

A 65-year-old male with hereditary hemorrhagic telangiectasia (HHT) who had a history of minimal epistaxis began to experience profuse epistaxis 8 to 10 weeks after starting ezetimibe-simvastatin, The patient had been treated with simvastatin 20 mg alone for 9 years without any adverse effects. Two months after starting combination therapy with ezetimibe-simvastatin he noticed epistaxis that increased from a few drops every other day to profuse bleeding for 20 to 30 minutes daily. The patient reported initiation of ezetimibe-simvastatin as the only change in his treatment regimen in the past year. When he stopped ezetimibe-simvastatin, his epistaxis decreased. After six weeks without ezetimibe-simvastatin, he had only one moderate nose bleed. Four months later, the patient's hemoglobin was stable. He then started simvastatin 40 mg monotherapy. The profound epistaxis returned and the patient discontinued the medication. It remains unclear whether the patient's accelerated epistaxis was due to the combination therapy or the double dosage of simvastatin.

Hypersensitivity

Hypersensitivity side effects associated with ezetimibe including angioedema, anaphylaxis, rash, and urticaria have been reported in postmarketing experience.

Hypersensitivity side effects associated with HMG-CoA reductase inhibitors including (transferred from dermatologic) erythema multiforme and Stevens-Johnson syndrome have been reported. Anaphylaxis, angioedema, urticaria, fever, chills, flushing, malaise, and dyspnea have been reported rarely.

Nervous system

Nervous system side effects associated with ezetimibe-simvastatin including headache and confusion have been reported. Dizziness and paresthesia have been associated with ezetimibe in postmarketing experience.

Nervous system side effects associated with HMG-CoA reductase inhibitors including cranial nerve dysfunction, tremor, vertigo, memory loss, paresthesias, peripheral neuropathy, and peripheral nerve palsy have been reported.

A case of memory loss possibly related to simvastatin use has been reported. The patient developed gradual memory loss following 12 months of simvastatin therapy. He was switched to pravastatin, and within a month his memory was intact. Rechallenge with simvastatin was not performed.

Ocular

Ocular side effects associated with HMG-CoA reductase inhibitors including progression of cataracts and ophthalmoplegia have been reported.

Oncologic

Oncologic side effects including tumor growth have been associated with many lipid-lowering drugs in rodent studies. Simvastatin has been specifically associated with liver, thyroid, and lung adenomas and carcinomas. Long-term clinical trials will define the risk of cancer in humans.

Psychiatric

Psychiatric side effects associated with simvastatin including depression, suicidal thoughts, delusions, paranoia, agitation, memory loss, and confusion have been reported. In one uncontrolled study of simvastatin, psychiatric side effects were the second most frequent complaint. Decreased libido, anxiety, and insomnia associated with HMG-CoA reductase inhibitors have been reported.

Other

Other side effects associated with ezetimibe-simvastatin including fatigue, influenza, and upper respiratory tract infection have been reported.

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