Vytorin Side Effects

Please note - some side effects for Vytorin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Vytorin - for the Consumer

Vytorin

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Vytorin:

Diarrhea; flu-like symptoms; headache; nausea; pain in the arms or legs; upper respiratory tract infection.

Seek medical attention right away if any of these SEVERE side effects occur when using Vytorin:

Severe allergic reactions (rash; hives; itching; difficulty breathing or swallowing; tightness in the chest; swelling of the mouth, face, lips, throat, or tongue; unusual hoarseness); breathing problems (eg, persistent cough, shortness of breath); burning, numbness, or tingling; change in the amount of urine produced; dark or red-colored urine; decreased sexual ability; depression; dizziness; fast or irregular heartbeat; fever, chills, or persistent sore throat; joint pain; loss of appetite; memory problems; muscle tenderness, pain, or weakness (with or without fever and fatigue); pale stools; red, swollen, blistered, or peeling skin; severe or persistent nausea or stomach or back pain; shortness of breath; trouble sleeping; unusual bruising or bleeding; unusual tiredness or weakness; vomiting; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Vytorin Side Effects - for the Professional

Vytorin

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Rhabdomyolysis and myopathy [see Warnings and Precautions (5.1)]
• Liver enzyme abnormalities [see Warnings and Precautions (5.2)]

Clinical Trials Experience

Vytorin

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

In the Vytorin (ezetimibe/simvastatin) placebo-controlled clinical trials database of 1420 patients (age range 20-83 years, 52% women, 87% Caucasians, 3% Blacks, 5% Hispanics, 3% Asians) with a median treatment duration of 27 weeks, 5% of patients on Vytorin and 2.2% of patients on placebo discontinued due to adverse reactions.

The most common adverse reactions in the group treated with Vytorin that led to treatment discontinuation and occurred at a rate greater than placebo were:

• Increased ALT (0.9%)
• Myalgia (0.6%)
• Increased AST (0.4%)
• Back pain (0.4%)

The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in controlled clinical trials were: headache (5.8%), increased ALT (3.7%), myalgia (3.6%), upper respiratory tract infection (3.6%), and diarrhea (2.8%).

Vytorin has been evaluated for safety in more than 10,189 patients in clinical trials.

Table 2 summarizes the frequency of clinical adverse reactions reported in ≥2% of patients treated with Vytorin (n=1420) and at an incidence greater than placebo, regardless of causality assessment, from four placebo-controlled trials.

Table 2*: Clinical Adverse Reactions Occurring in ≥2% of Patients Treated with Vytorin and at an Incidence Greater than Placebo, Regardless of Causality

Body System/Organ Class Adverse Reaction	Placebo (%) n=371	Ezetimibe 10 mg (%) n=302	Simvastatin† (%) n=1234	Vytorin† (%) n=1420
* Includes two placebo-controlled combination studies in which the active ingredients equivalent to Vytorin were coadministered and two placebo-controlled studies in which Vytorin was administered. † All doses.
Body as a whole – general disorders
Headache	5.4	6.0	5.9	5.8
Gastrointestinal system disorders
Diarrhea	2.2	5.0	3.7	2.8
Infections and infestations
Influenza	0.8	1.0	1.9	2.3
Upper respiratory tract infection	2.7	5.0	5.0	3.6
Musculoskeletal and connective tissue disorders
Myalgia	2.4	2.3	2.6	3.6
Pain in extremity	1.3	3.0	2.0	2.3

Ezetimibe

Other adverse reactions reported with ezetimibe in placebo-controlled studies, regardless of causality assessment: Musculoskeletal system disorders: arthralgia; Infections and infestations: sinusitis; Body as a whole – general disorders: fatigue.

Simvastatin

In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.

Other adverse reactions reported with simvastatin in placebo-controlled clinical studies, regardless of causality assessment: Cardiac disorders: atrial fibrillation; Ear and labyrinth disorders: vertigo; Gastrointestinal disorders: abdominal pain, constipation, dyspepsia, flatulence, gastritis; Skin and subcutaneous tissue disorders: eczema, rash; Endocrine disorders: diabetes mellitus; Infections and infestations: bronchitis, sinusitis, urinary tract infections; Body as a whole – general disorders: asthenia, edema/swelling; Psychiatric disorders: insomnia.

Laboratory Tests

Marked persistent increases of hepatic serum transaminases have been noted [see Warnings and Precautions (5.2)]. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have been reported. About 5% of patients taking simvastatin had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK [see Warnings and Precautions (5.1)].

Post-Marketing Experience

Because the below reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been reported in post-marketing experience for Vytorin or ezetimibe or simvastatin: pruritus; alopecia; erythema multiforme; a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails); dizziness; muscle cramps; myalgia; arthralgia; pancreatitis; paresthesia; peripheral neuropathy; vomiting; nausea; anemia; erectile dysfunction; interstitial lung disease; myopathy/rhabdomyolysis [see Warnings and Precautions (5.1)]; hepatitis/jaundice; fatal and non-fatal hepatic failure; depression; cholelithiasis; cholecystitis; thrombocytopenia; elevations in liver transaminases; elevated creatine phosphokinase.

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.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. 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).

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Side Effects by Body System - for Healthcare Professionals

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 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, and agitation 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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