Fluvastatin

Article Author:
Harry Ramsamooj
Article Editor:
Charles Preuss
Updated:
4/21/2020 9:09:41 AM
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 available in the organization's 2016 United States cholesterol treatment update. It also provides treatment recommendations for primary prevention of ASCVD for those with LDL cholesterol greater than or equal to 190 mg/dL and those with or without diabetes mellitus. Recommendations also are provided for secondary prevention for those with established ASCVD and for those who are older than 75 years of age. For each category, treatment with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) is the recommendation.[1]

In adults, indications for fluvastatin include hypercholesterolemia and mixed dyslipidemia. It helps 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 restrictions have 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 one year to meet the criteria for fluvastatin use. In those less than ten years of age, the safety and efficacy of fluvastatin have not been established.

Mechanism of Action

Fluvastatin is a member of the HMG-CoA reductase inhibitor drug class. 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 binding creates competition with the native substrate, HMG-CoA. In turn, there is a reduction in 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 concentrations by fluvastatin causes an increase in the expression of LDL receptors on the liver hepatocytes and enhanced stimulation of LDL breakdown.[2]

The bioavailability of the fluvastatin capsule is 24%, and the extended-release tablet is 29%. Fluvastatin metabolism is via the hepatic P450 enzyme CYP2C9.[3] Ninety-five percent of the drug is excreted in feces, with the remaining 5% excreted in the urine.[4]

Administration

Fluvastatin's ability to block cholesterol synthesis in the liver is significant because circulating cholesterol primarily derives from internal production rather than from diet. The fluvastatin capsule is a low-intensity statin because it lowers LDL cholesterol by less than 30%. The fluvastatin extended-release tablet is a moderate-intensity statin because it lowers LDL cholesterol between 30% and 50%.[5] High-intensity statins reduce LDL cholesterol by greater than or equal to 50%, e.g., atorvastatin.

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, the thinking is that fluvastatin capsules are most effective when taken at night. The extended-release tablets have a half-life of 9 hours, and dosing can be at 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, patients should not take two 40 mg immediate-release capsules 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[6][7]:

  • 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. The prescriber should obtain a complete medication list from the patient before prescribing fluvastatin.

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

Monitoring

Because fluvastatin can cause elevations in liver enzymes, patients must be regularly followed and have their liver enzymes monitored. Patients require education regarding refraining from drinking or eating grapefruit as this can lead to inhibition of the liver enzymes and, consequently, high concentrations of the drug in the circulation. If 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. Data about this toxicity primarily comes from individual case studies and shows that statins, including fluvastatin, when combined with fibrates, are the most common cause of statin-related rhabdomyolysis. Individual case studies also show that statins combined with antifungals, macrolides, fusidic acid, cyclosporin, 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. 

Enhancing Healthcare Team Outcomes

The healthcare team, i.e., clinicians, nurses, and pharmacists, must work together to make sure that patients with dyslipidemia correctly take their medications, e.g., fluvastatin and importantly, to discuss any serious drug side effects which they encounter, e.g., muscle pain, jaundice, etc. A complete medication list for the patient is necessary before prescribing fluvastatin to prevent clinically significant drug interactions, and a pharmacist can perform medication reconciliation to answer any questions or address concerns other healthcare team members may have.


References

[1] Lim TH,Orija IB,Pearlman BL, The new cholesterol treatment guidelines from the American College of Cardiology/American Heart Association, 2013: what clinicians need to know. Postgraduate medicine. 2014 Nov;     [PubMed PMID: 25387212]
[2] Yuan JN,Tsai MY,Hegland J,Hunninghake DB, Effects of fluvastatin (XU 62-320), an HMG-CoA reductase inhibitor, on the distribution and composition of low density lipoprotein subspecies in humans. Atherosclerosis. 1991 Apr;     [PubMed PMID: 1854361]
[3] Drug-drug interactions that interfere with statin metabolism., Hirota T,Ieiri I,, Expert opinion on drug metabolism & toxicology, 2015 Sep     [PubMed PMID: 26058399]
[4] Tse FL,Jaffe JM,Troendle A, Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers. Journal of clinical pharmacology. 1992 Jul;     [PubMed PMID: 1640002]
[5] Peters TK,Mehra M,Muratti EN, Efficacy and safety of fluvastatin in hypertensive patients. An analysis of a clinical trial database. American journal of hypertension. 1993 Nov;     [PubMed PMID: 8297542]
[6] Jokubaitis LA, Updated clinical safety experience with fluvastatin. The American journal of cardiology. 1994 May 26;     [PubMed PMID: 8198019]
[7] Hagen E,Istad H,Ose L,Bodd E,Eriksen HM,Selvig V,Bard JM,Fruchart JC,Borge M,Wolf MC, Fluvastatin efficacy and tolerability in comparison and in combination with cholestyramine. European journal of clinical pharmacology. 1994;     [PubMed PMID: 7957541]