Zocor Side Effects

Generic Name: simvastatin

Please note - some side effects for Zocor 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 Zocor - for the Consumer

Zocor

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 Zocor:

Constipation; headache; mild stomach pain; nausea.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); 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 pain, tenderness, 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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Zocor Side Effects - for the Professional

Zocor

Clinical Trials Experience

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 pre-marketing controlled clinical studies and their open extensions (2,423 patients with median duration of follow-up of approximately 18 months), 1.4% of patients were discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: gastrointestinal disorders (0.5%), myalgia (0.1%), and arthralgia (0.1%). The most commonly reported adverse reactions (incidence ≥5%) in simvastatin controlled clinical trials were: upper respiratory infections (9.0%), headache (7.4%), abdominal pain (7.3%), constipation (6.6%), and nausea (5.4%).

Scandinavian Simvastatin Survival Study

In 4S involving 4,444 (age range 35-71 years, 19% women, 100% Caucasians) treated with 20-40 mg/day of Zocor (n=2,221) or placebo (n=2,223) over a median of 5.4 years, adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 2.

TABLE 2: Adverse Reactions Reported Regardless of Causality by ≥2% of Patients Treated with Zocor and Greater than Placebo in 4S

	Zocor (N = 2,221) %	Placebo (N = 2,223) %
Body as a Whole     Edema/swelling     Abdominal pain	2.7 5.9	2.3 5.8
Cardiovascular System Disorders     Atrial fibrillation	5.7	5.1
Digestive System Disorders     Constipation     Gastritis	2.2 4.9	1.6 3.9
Endocrine Disorders     Diabetes mellitus	4.2	3.6
Musculoskeletal Disorders     Myalgia	3.7	3.2
Nervous System / Psychiatric Disorders     Headache     Insomnia     Vertigo	2.5 4.0 4.5	2.1 3.8 4.2
Respiratory System Disorders     Bronchitis     Sinusitis	6.6 2.3	6.3 1.8
Skin / Skin Appendage Disorders     Eczema	4.5	3.0
Urogenital System Disorders     Infection, urinary tract	3.2	3.1

Heart Protection Study

In the Heart Protection Study (HPS), involving 20,536 patients (age range 40-80 years, 25% women, 97% Caucasians, 3% other races) treated with Zocor 40 mg/day (n=10,269) or placebo (n=10,267) over a mean of 5 years, only serious adverse reactions and discontinuations due to any adverse reactions were recorded. Discontinuation rates due to adverse reactions were 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.

Other Clinical Studies

In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with Zocor (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 in clinical trials were: diarrhea, rash, dyspepsia, flatulence, and asthenia.

Laboratory Tests

Marked persistent increases of hepatic transaminases have been noted [see Warnings and Precautions (5.2)]. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have also been reported. 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. [See Warnings and Precautions (5.1).]

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 (43.4% female, 97.7% Caucasians, 1.7% Hispanics, 0.6% Multiracial) with heterozygous familial hypercholesterolemia (n=175), treated with placebo or Zocor (10-40 mg daily), the most common adverse reactions observed in both groups were upper respiratory infection, headache, abdominal pain, and nausea [see Use in Specific Populations (8.4) and Clinical Studies (14.2)].

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 additional adverse reactions have been identified during postapproval use of simvastatin: pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), dizziness, muscle cramps, myalgia, pancreatitis, paresthesia, peripheral neuropathy, vomiting, anemia, erectile dysfunction, interstitial lung disease, rhabdomyolysis, hepatitis/jaundice, fatal and non-fatal hepatic failure, and depression.

An apparent hypersensitivity syndrome has been reported rarely which has included some 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

Musculoskeletal

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

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.

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.

Gastrointestinal

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

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

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

Renal side effects have included myoglobinuria and acute renal failure secondary to rhabdomyolysis.

Cardiovascular

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

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

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.

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including simvastatin.

Hypersensitivity

Hypersensitivity reactions are reported rarely with HMG-CoA reductase inhibitors and include anaphylaxis, angioedema, urticaria, fever, chills, flushing, malaise, and dyspnea.

Immunologic

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

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

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

Genitourinary side effects of HMG-CoA reductase inhibitors have included erectile dysfunction, impotence, and testicular pain.

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.

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.

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