Simvastatin Side Effects

Some side effects of simvastatin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

For the Consumer

Applies to simvastatin: oral tablet

Get emergency medical help if you have any of these signs of an allergic reaction while taking simvastatin: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using simvastatin and call your doctor at once if you have:

• unexplained muscle pain, tenderness, or weakness;

• confusion, memory problems;

• fever, unusual tiredness, and dark colored urine;

• pain or burning when you urinate;

• swelling, weight gain, little or no urinating;

• increased thirst, increased urination, hunger, dry mouth, fruity breath odor, drowsiness, dry skin, blurred vision, weight loss; or

• nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Less serious side effects of simvastatin may include:

• headache;

• joint pain, mild muscle pain;

• constipation, stomach pain or indigestion, mild nausea;

• mild skin rash;

• sleep problems (insomnia); or

• cold symptoms such as stuffy nose, sneezing, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

For Healthcare Professionals

Applies to simvastatin: oral tablet

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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