Fluvastatin

Article Author:
William Gossman
Article Editor:
Charles Preuss
Updated:
11/13/2018 4:26:44 PM
PubMed Link:
Fluvastatin

Indications

According to the 2013 American College of Cardiology/American Heart Association guidelines, the focus of primary prevention is on atherosclerotic cardiovascular disease (ASCVD), including coronary heart disease, stroke, and peripheral arterial disease.  Comparison guidelines are provided in the organization's 2016 United States cholesterol treatment update. Treatment recommendations for primary prevention of ASCVD are provided for those with LDL cholesterol greater than or equal to 190 mg/dL and those with and without diabetes mellitus. Recommendations also are provided for secondary prevention for those with established ASCVD and for those who are greater than 75 years of age. For each category, treatment with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) is recommended.

In adults, fluvastatin is indicated for hypercholesterolemia and mixed dyslipidemia. It is used to decrease the amount of total blood cholesterol. The primary purpose of the therapy is to reduce low-density lipoprotein cholesterol and triglycerides and to increase levels of high-density lipoproteins. When used together with a low-fat diet, a weight-loss program, and exercise, fluvastatin may reduce the risk of heart attack and stroke in people who have heart disease or who are at risk of developing heart disease.

In children and adolescents between 10 and 16 years of age, fluvastatin is indicated for heterozygous familial hypercholesterolemia. The indication is for those who are unresponsive to dietary restriction, and their LDL cholesterol remains greater than 190 mg/dL. It also is indicated when dietary restriction has failed, and the individual's LDL cholesterol is greater than 160 mg/dL plus the individual has a positive family history of premature cardiovascular disease or has two or more cardiovascular risk factors. Females must be post-menarche for at least 1 year to meet criteria for fluvastatin use. In those less than 10 years of age, the safety and efficacy of fluvastatin have not been established.

Mechanism of Action

Fluvastatin is classified as an HMG-CoA reductase inhibitor. HMG-CoA reductase, the first committed enzyme of the mevalonate pathway, plays a role in the rate-limiting step of cholesterol synthesis in the liver. Statins competitively inhibit HMG-CoA reductase. Because they are molecularly similar in structure to HMG-CoA, they fit into the enzyme's active site. This creates competition with the native substrate, HMG-CoA. In turn, there is a reduction of the rate by which HMG-CoA reductase can produce mevalonate. Mevalonate is the next molecule in the cascade that eventually produces cholesterol. Moreover, the lowering of blood cholesterol levels by fluvastatin causes an increase in the expression of LDL receptors on the liver hepatocytes and enhanced stimulation of LDL breakdown.

The bioavailability of the fluvastatin capsule is 24%, and the extended-release tablet is 29%. Fluvastatin is metabolized by the hepatic P450 enzyme CYP2C9. Ninety-five percent of the drug is excreted in feces. The remaining 5% is excreted in urine.

Administration

Fluvastatin's ability to block cholesterol synthesis in the liver is significant because circulating cholesterol primarily is derived from internal production rather than from diet. The fluvastatin capsule is considered a low-intensity statin because it lowers LDL cholesterol by less than 30%. The fluvastatin extended-release tablet is considered a moderate-intensity statin because it lowers LDL cholesterol between 30% and 50%. High-intensity statins lower LDL cholesterol by greater than or equal to 50%.

Fluvastatin typically is taken orally once daily, with or without food, at around the same time every day. It also may be taken twice a day. Fluvastatin immediate-release capsules have a relatively short half-life of 3 hours. Because cholesterol synthesis takes place primarily at night, fluvastatin capsules are considered to be most effective when taken at night. The extended-release tablets have a half-life of 9 hours and can be taken any time of the day.

For adults with hypercholesterolemia and mixed dyslipidemia, the starting dose of fluvastatin immediate-release capsules is 20 mg in the evening if the LDL cholesterol lowering goal is less than 25%. The starting dose is 40 mg in the evening or twice a day if the LDL cholesterol lowering goal is more than 25%. The maintenance dose is 20 to 80 mg per day. Of note, two 40 mg immediate release capsules should not be taken at one time. The fluvastatin 80 mg extended-release tablets are taken once a day, at any time of day.

For children and adolescents with heterozygous familial hypercholesterolemia who are between 10 and 16 years of age, the starting dose of fluvastatin immediate-release capsules is 20 mg orally once a day. The maintenance dose is 20 to 80 mg per day. The maximum dose is 40 mg twice a day (immediate release) and 80 mg once a day (extended release).

Adverse Effects

Fluvastatin adverse effects

  • General: Fatigue
  • Musculoskeletal: Arthralgia, myalgia, myositis, and rhabdomyolysis\
  • Skin: Rash, dermatitis, pruritis, and eczema
  • Neurologic: Headache, dizziness, forgetfulness, confusion, and neuropathy
  • Psychiatric: Insomnia
  • Endocrine: Increased risk of diabetes mellitus
  • Eyes: Ophthalmoplegia
  • Ear, nose, and throat: Sinusitis, rhinitis, and pharyngitis
  • Pulmonary: Interstitial lung disease and bronchitis
  • Gastrointestinal: Nausea, vomiting, constipation, diarrhea, dyspepsia, pancreatitis, hepatitis, cholestatic jaundice, cirrhosis, anorexia, and  fatal and nonfatal hepatic failure
  • Genitourinary: Urinary tract infection
  • Reproductive: Erectile dysfunction and gynecomastia
  • Laboratory abnormalities: Increased liver transaminases and increased creatine phosphokinase

Contraindications

The use of fluvastatin is contraindicated in patients who have a hypersensitivity to the drug. Other contraindications are active liver disease or unexplained, persistent elevations of serum transaminases. Its use also is contraindicated during pregnancy or while breastfeeding. Potentially serious drug interactions may exist with fluvastatin, requiring that the dose or frequency of administration be adjusted. Drug interactions include combining fluvastatin with a fibrate, niacin, or a protease inhibitor. Combining fluvastatin with these drugs increases the risk of rhabdomyolysis. A complete medication list should be obtained from the patient before prescribing fluvastatin.

There are numerous cautions for the use of fluvastatin that should be considered when a patient is taking the medication as prescribed. Adverse cognitive effects are reversible upon cessation of the drug. Caution should be used in patients with heavy alcohol use, renal failure, or history of liver disease. Because there is an increase in the risk of developing diabetes mellitus, caution should be exercised if a patient has increased blood glucose levels or increased hemoglobin A1c levels.

Monitoring

Because fluvastatin can cause elevations in liver enzymes, patients must be regularly followed and have their liver enzymes monitored. Patients should be educated on refraining from drinking or eating grapefruit, as these can lead to inhibition of the liver enzymes and consequently high levels of the drug in the circulation. At any time the patient develops muscle pain, one must rule of rhabdomyolysis.

Toxicity

Although rare with the use of statins, rhabdomyolysis is a serious and potentially fatal complication. Rhabdomyolysis is the most severe form of myotoxicity and can occur with the use of any statin. The exact mechanism is unknown. Although rhabdomyolysis can occur with monotherapy, it is more likely to occur when combined with other drugs. Available data primarily comes from individual case studies and show that statins, including fluvastatin, combined with fibrates is the most common cause of statin-related rhabdomyolysis. Individual case studies also show that statins combined with antifungals, macrolides, fusidic acid, cyclosporine, protease inhibitors, and calcium channel blockers increase the risk for rhabdomyolysis. Patient risk factors that may predispose an individual to develop statin-induced rhabdomyolysis include low body mass index, advanced age, female sex, hypothyroidism, hypertension, polypharmacy, and alcohol or drug use disorder.