ADVERSE REACTIONS
In the pre-marketing controlled clinical studies and their open extensions (2,423 patients with mean duration of follow-up of approximately 18 months), 1.4% of patients were discontinued due to adverse experiences attributable to ZOCOR. Adverse reactions have usually been mild and transient. ZOCOR has been evaluated for serious adverse reactions in more than 21,000 patients and is generally well tolerated.
Clinical Adverse Experiences
In Adults
Adverse experiences occurring in adults at an incidence of 1% or greater in patients treated with ZOCOR, regardless of causality, in controlled clinical studies are shown in Table 9.
TABLE 9: Adverse Experiences in Clinical Studies Incidence 1 Percent or Greater, Regardless of Causality | ZOCOR
(N = 1,583)
% | Placebo
(N = 157)
% | Cholestyramine
(N = 179)
% |
| Body as a Whole | | | |
| Abdominal pain | 3.2 | 3.2 | 8.9 |
| Asthenia | 1.6 | 2.5 | 1.1 |
| Gastrointestinal | | | |
| Constipation | 2.3 | 1.3 | 29.1 |
| Diarrhea | 1.9 | 2.5 | 7.8 |
| Dyspepsia | 1.1 | — | 4.5 |
| Flatulence | 1.9 | 1.3 | 14.5 |
| Nausea | 1.3 | 1.9 | 10.1 |
| Nervous System/ Psychiatric | | | |
| Headache | 3.5 | 5.1 | 4.5 |
| Respiratory | | | |
| Upper respiratory infection | 2.1 | 1.9 | 3.4 |
Scandinavian Simvastatin Survival Study
Clinical Adverse Experiences
In 4S (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 4,444 patients treated with 20-40 mg/day of ZOCOR (n=2,221) or placebo (n=2,223), the safety and tolerability profiles were comparable between groups over the median 5.4 years of the study. The clinical adverse experiences reported as possibly, probably, or definitely drug-related in ≥ 0.5% in either treatment group are shown in Table 10.
TABLE 10: Drug-Related Clinical Adverse Experiences in 4S - Incidence 0.5 Percent or Greater | ZOCOR
(N = 2,221)
% | Placebo
(N = 2,223)
% |
| Body as a Whole | | |
| Abdominal pain | 0.9 | 0.9 |
| Gastrointestinal | | |
| Diarrhea | 0.5 | 0.3 |
| Dyspepsia | 0.6 | 0.5 |
| Flatulence | 0.9 | 0.7 |
| Nausea | 0.4 | 0.6 |
| Musculoskeletal | | |
| Myalgia | 1.2 | 1.3 |
| Skin | | |
| Eczema | 0.8 | 0.8 |
| Pruritus | 0.5 | 0.4 |
| Rash | 0.6 | 0.6 |
| Special Senses | | |
| Cataract | 0.5 | 0.8 |
Heart Protection Study
Clinical Adverse Experiences
In HPS (see CLINICAL PHARMACOLOGY, Clinical Studies), involving 20,536 patients treated with ZOCOR 40 mg/day (n=10,269) or placebo (n=10,267), the safety profiles were comparable between patients treated with ZOCOR and patients treated with placebo over the mean 5 years of the study. In this large trial, only serious adverse events and discontinuations due to any adverse events were recorded. Discontinuation rates due to adverse experiences were comparable (4.8% in patients treated with ZOCOR compared with 5.1% in patients treated with placebo). The incidence of myopathy/rhabdomyolysis was <0.1% in patients treated with ZOCOR.
The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with simvastatin therapy.
Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.
Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, vertigo, memory loss, paresthesia, peripheral neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.
Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which 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.
Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver, and, rarely, cirrhosis, fulminant hepatic necrosis, hepatic failure, and hepatoma; anorexia, vomiting.
Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails) have been reported.
Reproductive: gynecomastia, loss of libido, erectile dysfunction.
Eye: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, γ-glutamyl transpeptidase, and bilirubin; thyroid function abnormalities.
Laboratory Tests
Marked persistent increases of serum transaminases have been noted (see WARNINGS, Liver Dysfunction). About 5% of patients 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. Muscle pain or dysfunction usually was not reported (see WARNINGS, Myopathy/Rhabdomyolysis).
Concomitant Lipid-Lowering Therapy
In controlled clinical studies in which simvastatin was administered concomitantly with cholestyramine, no adverse reactions peculiar to this concomitant treatment were observed. The adverse reactions that occurred were limited to those reported previously with simvastatin or cholestyramine. The combined use of simvastatin at doses exceeding 10 mg/day with gemfibrozil should be avoided (see WARNINGS, Myopathy/Rhabdomyolysis).
Adolescent Patients (ages 10-17 years)
In a 48-week, controlled study in adolescent boys and girls who were at least 1 year post-menarche, 10-17 years of age with heterozygous familial hypercholesterolemia (n=175), the safety and tolerability profile of the group treated with ZOCOR (10-40 mg daily) was generally similar to that of the group treated with placebo, with the most common adverse experiences observed in both groups being upper respiratory infection, headache, abdominal pain, and nausea (see CLINICAL PHARMACOLOGY, Clinical Studies in Adolescents, and PRECAUTIONS, Pediatric Use).
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