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VYTORIN (or coadministration of ezetimibe and simvastatin equivalent to VYTORIN) has been evaluated for safety in approximately 12,000 patients in clinical trials. VYTORIN was generally well tolerated.
The following common (≥1/100, <1/10) or uncommon (≥1/1000, <1/100) drug-related adverse experiences were reported in patients taking VYTORIN (n=2404) and at a greater incidence than placebo (n=1340): 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.
Nervous system disorders: Uncommon: dizziness; headache.
Gastrointestinal disorders: Uncommon: abdominal pain; abdominal discomfort; abdominal pain upper; dyspepsia; flatulence; nausea; vomiting.
Skin and subcutaneous tissue disorders: Uncommon: pruritus; rash.
Musculoskeletal and connective tissue disorders: Uncommon: arthralgia; muscle spasms; muscular weakness; musculoskeletal discomfort; neck pain; pain in extremity.
General disorders and administration site conditions: Uncommon: asthenia; fatigue; malaise; edema peripheral.
Psychiatric disorders: Uncommon: sleep disorder.
The following common (≥ 1/100, <1/10) or uncommon (≥ 1/1000, <1/100); drug-related adverse experiences were reported in patients taking VYTORIN (n=9595) and at a greater incidence than statins administered alone (n=8883): Investigations: Common: ALT and/or AST increased.
Uncommon: blood bilirubin increased; blood CK increased; gamma-glutamyltransferase increased.
Nervous system disorders: Uncommon: headache; paresthesia.
Gastrointestinal disorders: Uncommon: abdominal distension; diarrhea; dry mouth; dyspepsia; flatulence; gastroesophageal reflux disease; vomiting.
Skin and subcutaneous tissue disorders: Uncommon: pruritus; rash; urticaria.
Musculoskeletal and connective tissue disorders: Common: myalgia.
Uncommon: arthralgia; back pain; muscle spasms; muscular weakness; musculoskeletal pain; pain in extremity.
General disorders and administration site conditions: Uncommon: asthenia; chest pain; fatigue; edema peripheral.
Psychiatric disorders: Uncommon: insomnia.
VYTORIN Coadministered with Fenofibrate: In a controlled clinical study, the adverse reaction profile reported for coadministered VYTORIN and fenofibrate was consistent with those reported for VYTORIN and/or fenofibrate alone.
Pediatric (10 to 17 Years of Age) Patients: In a study involving adolescent (10 to 17 years of age) patients with heterozygous familial hypercholesterolemia (n=248), the safety and tolerability profile of the group treated with VYTORIN was similar to that of adult patients treated with VYTORIN (see USE IN CHILDREN under PRECAUTIONS).
Patients with Coronary Heart Disease: In the IMPROVE-IT study, involving 18,144 patients treated with either VYTORIN 10/40 mg (n=9067; of whom 6% were uptitrated to VYTORIN 10/80 mg) or simvastatin 40 mg (n=9077; 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 VYTORIN and 10.1% for patients treated with simvastatin. The incidence of myopathy was 0.2% for VYTORIN 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 VYTORIN 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 X ULN and <10 X 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 VYTORIN and 2.3% for simvastatin. (See PRECAUTIONS.) Gallbladder-related adverse effects were reported in 3.1% vs 3.5% of patients allocated to VYTORIN and simvastatin, respectively. The incidence of cholecystectomy hospitalizations 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.
Patients with Chronic Kidney Disease: In SHARP, involving over 9000 patients treated with VYTORIN 10/20 mg daily (n=4650) or placebo (n=4620), 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 VYTORIN, 9.8% in patients treated with placebo). The incidence of myopathy/rhabdomyolysis was 0.2% in patients treated with VYTORIN and 0.1% in patients treated with placebo. Consecutive elevations of transaminases (>3 X ULN) occurred in 0.7% of patients treated with VYTORIN compared with 0.6% of patients treated with placebo (see PRECAUTIONS). In this trial, there were no statistically significant increases in the incidence of pre-specified adverse events, including cancer (9.4% for VYTORIN, 9.5% for placebo), hepatitis, cholecystectomy or complications of gallstones or pancreatitis.
Post-marketing Experience: The following additional adverse reactions have been reported in post-marketing use with VYTORIN or during clinical studies or post-marketing use with one of the individual components. The adverse reactions reported for VYTORIN are consistent with those previously reported with ezetimibe and/or simvastatin.
Investigations: liver function test abnormal.
Blood and lymphatic system disorders: thrombocytopenia; anemia.
Nervous system disorders: peripheral neuropathy; myasthenia gravis (see Myasthenia Gravis/Ocular Myasthenia under PRECAUTIONS).
Eye disorders: ocular myasthenia (see Myasthenia Gravis/Ocular Myasthenia under PRECAUTIONS).
Respiratory, thoracic and mediastinal disorders: cough; interstitial lung disease.
Gastrointestinal disorders: constipation; pancreatitis; gastritis.
Skin and subcutaneous tissue disorders: alopecia;
hypersensitivity reactions, including rash, lichen planus, urticaria,
anaphylaxis, angio-edema;
severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome
(SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilic and
systemic symptoms (DRESS) and erythema multiforme.
Musculoskeletal and connective tissue disorders: muscle cramps; myopathy/rhabdomyolysis (see Myopathy/Rhabdomyolysis under PRECAUTIONS).
There have been very rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents (see Myopathy/Rhabdomyolysis under PRECAUTIONS).
Metabolism and nutrition disorders: decreased appetite.
Vascular disorders: hot flush; hypertension.
General disorders and administration site conditions: pain.
Hepato-biliary disorders: hepatitis/jaundice; fatal and non-fatal hepatic failure; cholelithiasis; cholecystitis; drug-induced liver injury.
Reproductive system and breast disorders: erectile dysfunction.
Psychiatric disorders: depression.
An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, ESR increased, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnea and malaise.
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).
Ezetimibe Coadministered with Fenofibrate: In a multicenter, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidemia, 625 patients were treated for up to 12 weeks and 576 for up to 1 year. This study was not designed to compare treatment groups for infrequent events. Incidence rates (95% CI) for clinically important elevations (>3 X ULN, consecutive) in serum transaminases were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for fenofibrate monotherapy and ezetimibe coadministered with fenofibrate, respectively, adjusted for treatment exposure. Corresponding incidence rates for cholecystectomy were 0.6% (0.0, 3.1) and 1.7% (0.6, 4.0) for fenofibrate monotherapy and ezetimibe coadministered with fenofibrate, respectively (see PRECAUTIONS). There were no CPK elevations >10 X ULN in either treatment group in this study.
Laboratory Values: In controlled clinical coadministration 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 VYTORIN. These elevations were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. (See PRECAUTIONS.)
Clinically important elevations of CK (≥ 10 X ULN) were seen in 0.2% of the patients treated with VYTORIN.
Increases in HbA1c and fasting serum glucose levels have been reported with statins, including simvastatin.
