Simvastatin

CAS No: 79902-63-9

Appearance: White powder

Application Notes:

A competitive inhibitor of HMG-CoA reductase. A synthetic analog of lovastatin.

Reference:

Hoffman, W.F., et al.: J. Med. Chem., 29, 849 (1986), Mol, M.J., et al.: Lancet, 2, 936 (1986),

When Simvastatin should not be used
Some people should not take Simvastatin. Discuss this with your doctor.

Simvastatin should not be used by patients who are allergic to any of its ingredients. In addition to the active ingredient simvastatin, each tablet contains the following inactive ingredients: cellulose, lactose, magnesium stearate, iron oxides, talc, titanium dioxide, and starch. Butylated hydroxyanisole is added as a preservative.

Patients with liver problems: Simvastatin should not be used by patients with active liver disease or repeated blood test results indicating possible liver problems. (See WARNINGS.)

Women who are or may become pregnant: Pregnant women should not take Simvastatin because it may harm the fetus. Women of childbearing age should not take Simvastatin unless it is highly unlikely that they will become pregnant. If a woman does become pregnant while on Simvastatin, she should stop taking the drug and talk to her doctor at once.

Women who are breast-feeding should not take Simvastatin.

Patients who are also taking the prescription drug Posicor (mibefradil) should not take Simvastatin.

Warnings
Liver: About 1% of patients who took simvastatin in clinical trials developed elevated levels of some liver enzymes. Patients who had these increases usually had no symptoms. Elevated liver enzymes usually returned to normal levels when therapy with simvastatin was stopped.

In the simvastatin Survival Study, the number of patients with more than one liver enzyme level elevation to greater than 3 times the normal upper limit was no different between the simvastatin and placebo groups. Only 8 patients on simvastatin and 5 on placebo discontinued therapy due to elevated liver enzyme levels. Patients were started on 20 mg of simvastatin, and one third had their dose raised to 40 mg.

Your doctor should perform routine blood tests to check these enzymes before you start treatment with simvastatin and periodically thereafter (for example, semiannually) for your first year of treatment or until one year after your last elevation in dose. If your enzyme levels increase, your doctor should order more frequent tests. If your liver enzyme levels remain unusually high, your doctor should discontinue your medication.

Tell your doctor about any liver disease you may have had in the past and about how much alcohol you consume. simvastatin should be used with caution in patients who consume large amounts of alcohol.

Muscle: Tell your doctor right away if you experience any muscle pain, tenderness, or weakness at any time during treatment with simvastatin, particularly if you have a fever or if you are generally not feeling well, so your doctor can decide if simvastatin should be stopped. Some patients may have muscle pain or weakness while taking simvastatin. Rarely, this can include muscle breakdown resulting in kidney damage. The risk of muscle breakdown is greater in patients taking certain other drugs along with simvastatin, such as the lipid-lowering drug Lopid (gemfibrozil), a fibrate; lipid-lowering doses of nicotinic acid (niacin); the antibiotics erythromycin and clarithromycin; nefazodone; antifungal drugs that are azole derivatives, such as itraconazole and ketoconazole; the calcium channel blocker Posicor; or drugs that suppress the immune system (called immunosuppressive drugs, such as Sandimmune [cyclosporine]). Therapy with simvastatin should be temporarily interrupted if you are going to take an azole derivative antifungal medication, such as itraconazole. Patients using simvastatin along with any of these other drugs should be carefully monitored by their physician. The risk of muscle breakdown is greater in patients with kidney problems or diabetes.

If you have conditions that can increase your risk of muscle breakdown, which in turn can cause kidney damage, your doctor should temporarily withhold or stop simvastatin. Such conditions include severe infection, low blood pressure, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures. Also, since there are no known adverse consequences of briefly stopping therapy with simvastatin, treatment should be stopped a few days before elective major surgery. Discuss this with your doctor, who can explain these conditions to you.

Because there are risks in combining therapy with simvastatin with lipid-lowering doses of nicotinic acid (niacin) or with drugs that suppress the immune system, your doctor should carefully weigh the potential benefits and risks. He or she should also carefully monitor patients for any muscle pain, tenderness, or weakness, particularly during the initial months of therapy and if the dose of either drug is increased. Your doctor may also monitor the level of certain muscle enzymes in your body, but there is no assurance that such monitoring will prevent the occurrence of severe muscle disease.

Precautions
Before starting treatment with simvastatin, try to lower your cholesterol by other methods such as diet, exercise, and weight loss. Ask your doctor about how best to do this. Any other medical problems that can cause high cholesterol should also be treated.

Simvastatin is less effective in patients with the rare disorder known as homozygous familial hypercholesterolemia.

Drug Interactions: Because of possible serious drug interactions, it is important to tell your doctor what other drugs you are taking, including those obtained without a prescription.

Simvastatin can interact with Posicor, Lopid, niacin, erythromycin, clarithromycin, nefazodone, certain antifungal drugs, and drugs that suppress the immune system (called immunosuppressive drugs, such as Sandimmune). (See WARNINGS, Muscle.)

Some patients taking lipid-lowering agents similar to ZOCOR and coumarin anticoagulants (a type of blood thinner) have experienced bleeding and/or increased blood clotting time. Patients taking these medicines should have their blood tested before starting therapy with simvastatin and should continue to be monitored.

Endocrine (Hormone) Function: simvastatin and other drugs in this class may affect the production of certain hormones. Caution should be exercised if a drug used to lower cholesterol levels is administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may decrease the levels or activity of hormones. If you are taking any such drugs, tell your doctor.

Central Nervous System Toxicity; Cancer, Mutations, Impairment of Fertility: Like most prescription drugs, simvastatin was required to be tested on animals before it was marketed for human use. Often these tests were designed to achieve higher drug concentrations than humans achieve at recommended dosing. In some tests, the animals had damage to the nerves in the central nervous system. In studies of mice with high doses of simvastatin, the likelihood of certain types of cancerous tumors increased. No evidence of mutations of or damage to genetic material has been seen. In one study with simvastatin, there was decreased fertility in male rats.

Pregnancy: Pregnant women should not take simvastatin because it may harm the fetus.

Safety in pregnancy has not been established. In studies with lipid-lowering agents similar to simvastatin, there have been rare reports of birth defects of the skeleton and digestive system. Therefore, women of childbearing age should not take simvastatin unless it is highly unlikely they will become pregnant. If a woman does become pregnant while taking simvastatin, she should stop taking the drug and talk to her doctor at once. The active ingredient of simvastatin did not cause birth defects in rats at 6 times the human dose or in rabbits at 4 times the human dose.

Nursing Mothers: Drugs taken by nursing mothers may be present in their breast milk. Because of the potential for serious adverse reactions in nursing infants, a woman taking simvastatin should not breast-feed. (See WHEN simvastatin SHOULD NOT BE USED.)

Pediatric Use: simvastatin is not recommended for children or patients under 20 years of age.

Side Effects
Most patients tolerate treatment with simvastatin well; however, like all prescription drugs, simvastatin can cause side effects, and some of them can be serious. Side effects that do occur are usually mild and short-lived. Only your doctor can weigh the risks versus the benefits of any prescription drug. In clinical studies with simvastatin, less than 1.5% of patients dropped out of the studies because of side effects. In a large, long-term study, patients taking simvastatin experienced similar side effects to those patients taking placebo (sugar pills). Some of the side effects that have been reported with simvastatin or related drugs are listed below. This list is not complete. Be sure to ask your doctor about side effects before taking simvastatin and to discuss any side effects that occur.

Digestive System: Constipation, diarrhea, upset stomach, gas, heartburn, stomach pain/cramps, anorexia, loss of appetite, nausea, inflammation of the pancreas, hepatitis, jaundice, fatty changes in the liver, and, rarely, severe liver damage and failure, cirrhosis, and liver cancer.

Muscle, Skeletal: Muscle cramps, aches, pain, and weakness; joint pain; muscle breakdown.

Nervous System: Dizziness, headache, insomnia, tingling, memory loss, damage to nerves causing weakness and/or loss of sensation and/or abnormal sensations, anxiety, depression, tremor, loss of balance, psychic disturbances.

Skin: Rash, itching, hair loss, dryness, nodules, discoloration.

Eye/Senses: Blurred vision, altered taste sensation, progression of cataracts, eye muscle weakness.

Hypersensitivity (Allergic) Reactions: On rare occasions, a wide variety of symptoms have been reported to occur either alone or together in groups (referred to as a syndrome) that appeared to be based on allergic-type reactions, which may rarely be fatal. These have included one or more of the following: a severe generalized reaction that may include shortness of breath, wheezing, digestive symptoms, and low blood pressure and even shock; an allergic reaction with swelling of the face, lips, tongue and/or throat with difficulty swallowing or breathing; symptoms mimicking lupus (a disorder in which a person's immune system may attack parts of his or her own body); severe muscle and blood vessel inflammation; bruises; various disorders of blood cells (that could result in anemia, infection, or blood clotting problems) or abnormal blood tests; inflamed or painful joints; hives; fatigue and weakness; sensitivity to sunlight; fever, chills; flushing; difficulty breathing; and severe skin disorders that vary from rash to a serious burn-like shedding of skin all over the body, including mucous membranes such as the lining of the mouth.

Other: Loss of sexual desire, breast enlargement, impotence.

Laboratory Tests: Liver function test abnormalities including elevated alkaline phosphatase and bilirubin; thyroid function abnormalities.

NOTE: This summary provides important information about simvastatin. If you would like more information, ask your doctor or pharmacist to let you read the professional labeling and then discuss it with them.