Simvastatin Side Effects
Brand Names: Zocor
Please note - some side effects for Simvastatin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).
Side Effects of Simvastatin - for the consumer
Simvastatin/Niacin
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 Simvastatin/Niacin:
Seek medical attention right away if any of these SEVERE side effects occur when using Simvastatin/Niacin:Back pain; constipation; diarrhea; flushing (eg, dizziness, itching, redness, tingling, warmth); headache; nausea; runny or stuffy nose; stomach upset.
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); change in amount of urine produced; dark urine; fast or irregular heartbeat; fainting; fever; joint pain; memory problems; muscle pain, tenderness, or weakness; numbness or persistent tingling of the hands or feet; pale stools; red, swollen, blistered, or peeling skin; severe or persistent dizziness or lightheadedness; severe or persistent nausea or stomach pain; swelling of the hands, legs, or feet; unusual bruising or bleeding; unusual tiredness, discomfort, or weakness; vision changes; yellowing of the eyes or skin.
Simvastatin
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 Simvastatin:
Seek medical attention right away if any of these SEVERE side effects occur when using Simvastatin:Constipation.
TopSevere allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain; dark urine; muscle pain, tenderness, or weakness (with or without fever and fatigue); pale stools; red, swollen, blistered, or peeling skin; severe or persistent stomach pain; yellowing of skin or eyes.
For the professional
Simvastatin
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 Simvastatin. Adverse reactions have usually been mild and transient. Simvastatin has been evaluated for serious adverse reactions in more than 21,000 patients and is generally well tolerated.
Clinical Adverse Experiences
In AdultsAdverse experiences occurring in adults at an incidence of 1% or greater in patients treated with Simvastatin, regardless of causality, in controlled clinical studies are shown in Table 9.
Simvastatin (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 ExperiencesIn 4S involving 4,444 patients treated with 20-40 mg/day of Simvastatin (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.
Simvastatin (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 ExperiencesIn HPS, involving 20,536 patients treated with Simvastatin 40 mg/day (n=10,269) or placebo (n=10,267), the safety profiles were comparable between patients treated with Simvastatin 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 Simvastatin compared with 5.1% in patients treated with placebo). The incidence of myopathy/rhabdomyolysis was <0.1% in patients treated with Simvastatin.
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. 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.
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.
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 Simvastatin (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. Top
By body system
Musculoskeletal side effects
Musculoskeletal side effects of simvastatin have included elevations in creatine kinase, myopathy, dermatomyositis, and rhabdomyolysis. Other musculoskeletal side effects reported with HMG-CoA reductase inhibitors have included arthralgia, myalgia, tendon rupture, and dermatomyositis.
In addition, some data have suggested that exposure to HMG-CoA reductase inhibitors is associated with a decreased risk of bone fractures in persons older than 50 years of age.
HMG-CoA reductase inhibitors (statins) have been associated with rare cases of severe myopathy and rhabdomyolysis, accompanied by increases in creatine kinase, myoglobinuria, proteinuria, and renal failure. Concomitant use with gemfibrozil (fibric acid derivatives), niacin, cyclosporine, erythromycin (macrolides) or azole antifungals may increase the incidence and severity of musculoskeletal side effects. Other variables associated with an increased risk of statin-induced myopathy include, advanced age, small body stature, female gender, renal and/or hepatic dysfunction, perioperative periods, hypothyroidism, diabetes mellitus, and alcoholism.
Milder forms of myotoxicity (i.e., myalgia) are commonly reported and occur in approximately 5% to 7% of patients taking a statin drug.
Patients should be instructed to report symptoms of muscle pain, weakness, or tenderness. If such symptoms develop, creatine kinase should be measured, and if elevated, simvastatin should be discontinued. The value of regular monitoring of creatine kinase is not known. In some studies, elevations in creatine kinase occurred in up to 5.2% of patients on simvastatin. In most cases, these elevations were mild, transient, and not associated with clinical symptoms.
At least six cases of simvastatin-induced rhabdomyolysis associated with concomitant use of a macrolide antibiotic (i.e., erythromycin, clarithromycin) have been reported. In all cases the patients had been receiving simvastatin routinely (40 to 80 mg/day) prior to short-term (7 to 10 days) macrolide therapy. The proposed mechanism of interaction is inhibition of CYP450 3A4 metabolism and/or P-glycoprotein transport of simvastatin. Symptoms included myalgia, muscle weakness, elevated serum creatine kinase levels, and in some patients elevated liver transaminase levels.
A rare case of simvastatin-induced bilateral leg compartment syndrome and myonecrosis developed in a patient with hypothyroidism after one month of therapy with simvastatin. Following withdrawal of simvastatin and emergency fasciotomies the patient recovered.
Hepatic side effects
Hepatic side effects have included elevations in liver function tests (1.5%). Other hepatic side effects reported with HMG-CoA reductase inhibitors have included hepatitis (including chronic active hepatitis), cholestatic jaundice, fatty changes in the liver, cirrhosis, hepatic failure, and fulminant hepatic necrosis.
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. Liver function tests should be closely monitored. Simvastatin should be discontinued in patients with persistent, significant elevations (three times normal) in liver function parameters.
Gastrointestinal side effects
Gastrointestinal side effects have been among the most common complaints in patients on simvastatin. These tended to be mild and transient in nature and often dissipated with continued therapy.
Gastrointestinal side effects 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. Simvastatin has been implicated in a case of protein-losing enteropathy. Other gastrointestinal side effects of HMG-CoA reductase inhibitors have included pancreatitis, anorexia, and vomiting.
Hematologic side effects
Hematologic side effects including hemolytic anemia, thrombocytopenia, and leukopenia have occurred with HMG-CoA reductase inhibitors. These effects may be manifestations of a hypersensitivity reaction. Thrombotic thrombocytopenic purpura (TTP) has also been associated with simvastatin use.
Nervous system side effects
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.
Nervous system side effects have included headache (6.5%) and cognitive impairment. Other nervous system side effects reported with HMG-CoA reductase inhibitors have included cranial nerve dysfunction, tremor, vertigo, memory loss, paresthesias, peripheral neuropathy, and peripheral nerve palsy.
Renal side effects
Renal side effects have included myoglobinuria and acute renal failure secondary to rhabdomyolysis.
Cardiovascular side effects
The Scandinavian Simvastatin Survival Study (4S) demonstrated a 30% reduction in total mortality in patients followed for a median of 5.4 years and a 42% decrease in death from coronary heart disease compared to placebo. Simvastatin reduced the risk of major coronary events by 34%, hospital verified nonfatal myocardial infarction by 37%, and the need for coronary artery bypass graft or angioplasty by 37%, all significant compared to placebo.
Cardiovascular side effects including angina have been reported in as many as 3.1% of treated patients. In addition, study data indicates that total mortality is decreased in patients with hyperlipidemia and coronary heart disease using simvastatin.
Dermatologic side effects
Dermatologic side effects reported with HMG-CoA reductase inhibitors have included eczematous, pruritic rash, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity, purpura, and alopecia. These effects may be manifestations of a hypersensitivity.
Endocrine side effects
Endocrine side effects of HMG-CoA reductase inhibitors have included hypospermia, gynecomastia, and thyroid function abnormalities. In addition, acid maltase deficiency (the genetic disorder also referred to as Pompe's Disease) has been revealed following simvastatin therapy in at least one presymptomatic patient.
Hypersensitivity side effects
Hypersensitivity reactions are reported rarely with HMG-CoA reductase inhibitors and include anaphylaxis, angioedema, urticaria, fever, chills, flushing, malaise, and dyspnea.
Immunologic side effects
Immunologic side effects of simvastatin have included a case of lupus-like syndrome which has been reported with other HMG-CoA reductase inhibitors. Other immunologic side effects reported with HMG-CoA reductase inhibitors have included positive ANA, ESR increase, polymyalgia rheumatica, and vasculitis.
Ocular side effects
Ocular side effects of HMG-CoA reductase inhibitors have included progression of cataracts and ophthalmoplegia. There is no clear indication that simvastatin causes lens opacities in humans.
Psychiatric side effects
Psychiatric side effects have included depression, suicidal thoughts, delusions, paranoia, and agitation; causality is unknown. In one uncontrolled study of simvastatin, psychiatric side effects were the second most frequent complaint. Other psychiatric side effects of HMG-CoA reductase inhibitors have included decreased libido, anxiety, insomnia, and nightmares.
Genitourinary side effects
Halkin, et al report a case in which use of both lovastatin and pravastatin on different occasions in the same patient led to reversible impotence. The impotence resolved within 2 weeks after discontinuation of the HMG-CoA reductase inhibitor.
Genitourinary side effects of HMG-CoA reductase inhibitors have included erectile dysfunction, impotence, and testicular pain.
Oncologic side effects
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.
TopMore resources:
Simvastatin - Includes detailed dosage instructions.
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