Applies to ezetimibe / simvastatin: oral tablet.

Serious side effects

Along with its needed effects, ezetimibe/simvastatin may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking ezetimibe / simvastatin:

Incidence not known

• Bloating
• chills
• constipation
• darkened urine
• fast heartbeat
• fever
• hives, itching, skin rash
• hoarseness
• indigestion
• joint pain
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• loss of appetite
• nausea
• pains in the stomach, side, or abdomen, possibly radiating to the back
• redness of the skin
• stiffness
• stomach fullness
• swelling of the eyelids, face, lips, hands, or feet
• tightness in the chest
• trouble breathing or swallowing
• vomiting
• yellow eyes or skin

Other side effects

Some side effects of ezetimibe / simvastatin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

• Body aches or pain
• cough
• diarrhea
• difficulty with moving
• ear congestion
• general feeling of discomfort or illness
• headache
• loss of voice
• muscle aches and pains or cramping
• muscle stiffness
• pain in the arms or legs
• runny or stuffy nose
• shivering
• sneezing
• sore throat
• sweating
• swollen joints
• trouble sleeping
• unusual tiredness or weakness

For Healthcare Professionals

Applies to ezetimibe / simvastatin: oral tablet.

General

The more commonly reported adverse effects have included headache, increased ALT, myalgia, upper respiratory tract infection, and diarrhea.

Gastrointestinal

Ezetimibe-simvastatin:

Common (1% to 10%): Diarrhea

Ezetimibe:

Common (1% to 10%): Diarrhea, abdominal pain, nausea

Postmarketing reports: Pancreatitis

Simvastatin:

Common (1% to 10%): Constipation, nausea, flatulence, diarrhea, dyspepsia, abdominal pain, pancreatitis, anorexia, vomiting, gastritis

Very rare (less than 0.01%): Protein losing enteropathy^[Ref]

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.^[Ref]

Ezetimibe-simvastatin:

Common (1% to 10%): Myalgia, extremity pain

Very rare (less than 0.01%): Tendon rupture (one case)

Frequency not reported: Back pain

Postmarketing reports: Muscle cramps

Ezetimibe:

Common (1% to 10%): Back pain, arthralgia

Postmarketing reports: Myalgia, elevated creatine phosphokinase, rare reports of myopathy/rhabdomyolysis

Simvastatin:

Uncommon (0.1% to 1%): Myopathy, rhabdomyolysis

Frequency not reported: Elevations in creatine kinase, dermatomyositis, arthralgia, myalgia^[Ref]

Renal

Simvastatin:

Frequency not reported: Myoglobinuria, acute renal failure secondary to rhabdomyolysis^[Ref]

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.^[Ref]

Ezetimibe-simvastatin:

Common (1% to 10%): Increased ALT

Frequency not reported: Increased AST

Ezetimibe:

Postmarketing reports: Elevations in liver transaminases, hepatitis, cholelithiasis, cholecystitis

Simvastatin:

Common (1% to 10%): Elevations in liver function tests

Frequency not reported: Hepatitis (including chronic active hepatitis), cholestatic jaundice, fatty changes in the liver, cirrhosis, fulminant hepatic necrosis

Postmarketing reports: Hepatic failure, jaundice^[Ref]

Dermatologic

Simvastatin:

Frequency not reported: Eczematous, pruritic rash, toxic epidermal necrolysis, photosensitivity, purpura, erythema multiforme, photosensitivity, purpura, alopecia

Postmarketing reports: A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails)^[Ref]

Immunologic

Ezetimibe-simvastatin:

Frequency not reported: Influenza

Ezetimibe:

Common (1% to 10%): Viral infection

Simvastatin:

Very rare (less than 0.01%): Lupus-like syndrome

Frequency not reported: Positive ANA, ESR increase, polymyalgia rheumatica, vasculitis

Statin use:

Rare (0.01% to 0.1%): Immune-mediated necrotizing myopathy (IMNM)^[Ref]

Respiratory

Ezetimibe-simvastatin:

Common (1% to 10%): Upper respiratory tract infection

Frequency not reported: Interstitial lung disease causing breathing problems including persistent cough and/or shortness of breath or fever

Ezetimibe:

Common (1% to 10%): Coughing

Frequency not reported: Sinusitis

Simvastatin:

Frequency not reported: Sinusitis, pharyngitis^[Ref]

Cardiovascular

Simvastatin:

Common (1% to 10%): Angina

Frequency not reported: Atrial fibrillation, edema^[Ref]

Endocrine

Simvastatin:

Frequency not reported: Gynecomastia, thyroid function abnormalities^[Ref]

Genitourinary

Simvastatin:

Frequency not reported: Erectile dysfunction, impotence, urinary tract infections^[Ref]

Hematologic

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.^[Ref]

Ezetimibe-simvastatin:

Postmarketing reports: Epistaxis (one report), anemia

Ezetimibe:

Postmarketing reports: Thrombocytopenia

Simvastatin:

Frequency not reported: Hemolytic anemia, thrombocytopenia, leukopenia (possibly manifestations of a hypersensitivity reaction)^[Ref]

Hypersensitivity

Hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria have been reported. In addition, an apparent hypersensitivity syndrome has been reported rarely that has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.^[Ref]

Ezetimibe:

Postmarketing reports: Angioedema, anaphylaxis, rash, urticaria

Simvastatin:

Rare (less than 0.1%): Erythema multiforme, Stevens-Johnson syndrome, anaphylaxis, angioedema, urticaria, fever, chills, flushing, malaise, dyspnea

Postmarketing reports: Hypersensitivity reactions^[Ref]

Nervous system

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.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These reports have been generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).^[Ref]

Ezetimibe-simvastatin:

Common (1% to 10%): Headache

Frequency not reported: Confusion, fatigue

Ezetimibe:

Postmarketing reports: Dizziness, paraesthesia

Simvastatin:

Frequency not reported: Cranial nerve dysfunction, tremor, vertigo, memory loss, paraesthesias, peripheral neuropathy, peripheral nerve palsy

Statins:

Postmarketing reports: Cognitive impairment^[Ref]

Ocular

Simvastatin:

Frequency not reported: Progression of cataracts, ophthalmoplegia^[Ref]

Oncologic

Simvastatin:

Frequency not reported: Liver, thyroid, and lung adenomas and carcinomas^[Ref]

Psychiatric

Simvastatin:

Frequency not reported: Depression, suicidal thoughts, delusions, paranoia, agitation, decreased libido, anxiety, insomnia^[Ref]

Metabolic

Simvastatin:

Frequency not reported: Increases in HbA1c and fasting serum glucose levels

Other

Ezetimibe:

Frequency not reported: Fatigue, asthenia^[Ref]