Fluvastatin (Lescol XL) is the first synthetically derived HMG-CoA reductase inhibitor or a statin (in short). It is indicated in patients with hypercholesterolemia.

Fluvastatin (Lescol XL) Uses:

• Dyslipidemias:

  • Heterozygous familial and nonfamilial hypercholesterolemia and mixed dyslipidemia:
    • Adjunct to diet to reduce elevated total cholesterol (total-C), triglyceride, low-density lipoprotein-cholesterol (LDLC), and apolipoprotein B (apo-B) levels and to increase HDL-C in adults with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson types IIa and IIb).
  • Heterozygous familial hypercholesterolemia:
    • As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in children of 10 years or more than 10 years and adolescents of 16 years or less than 16 years of age (female patients must be at least 1-year post menarche) with heterozygous familial hypercholesterolemia and an LDL-C that remains ≥190 mg/dL or ≥160 mg/dL (with ≥2 cardiovascular risk factors or a positive family history of premature cardiovascular disease).

• Prevention of cardiovascular disease (CVD):

  • Secondary prevention of CVD:
    • To slow the progression of coronary atherosclerosis in patients with coronary heart disease;
    • reduce the risk of coronary revascularization procedures in patients with coronary heart disease
  • Limitations of use:
    • Has not been studied in conditions where the major abnormality is the elevation of chylomicrons, very-low-density lipoprotein (VLDL), or intermediate-density lipoprotein (IDL) (ie, hyperlipoproteinemia types I, III, IV, or V).

• Off Label Use of Fluvastatin in Adults:

  • Used in cardiac risk reduction for noncardiac surgery (perioperative therapy)
  • Used in non-cardioembolic stroke/TIA (secondary prevention)

Fluvastatin (Lescol XL) Dose in Adults

Fluvastatin (Lescol XL) Dose in the treatment of Heterozygous familial and nonfamilial hypercholesterolemia: Oral:

• Immediate-release:

  • 40 mg once in a day in the evening or 40 mg two times in a day.

• Extended-release:

  • 80 mg once in a day (anytime)

Fluvastatin (Lescol XL) Dose in the treatment of Mixed dyslipidemia: Oral:

• Immediate-release:

  • 40 mg once in a day in the evening or 40 mg two times a day.

• Extended-release:

  • 80 mg once in a day (anytime)

• Patients requiring ≥ 25% decrease in LDL-C: Oral:

  • Immediate-release:
    • Initial: 40 mg once in a day in the evening or 40 mg two times a day.
  • Extended-release:
    • Initial: 80 mg once in a day (anytime)

• Patients requiring <25% decrease in LDL-C:

  • Oral: Initial: Immediate release:
    • 20 mg once in a day in the evening;
    • may increase based on tolerability and response to a maximum recommended dose of 80 mg per day, given in 2 divided doses (immediate-release) or as a single daily dose (extended-release)

Fluvastatin (Lescol XL) Dose in the treatment of Prevention of cardiovascular disease/reduce the risk of atherosclerotic cardiovascular disease: Oral:

ACC/AHA Blood Cholesterol Guideline recommendations:

Note: When choosing to initiate therapy and selecting dose-intensity, consider atherosclerotic cardiovascular disease (ASCVD) risk, risk-enhancing factors, possibility for side effects, and drug interactions.

• Primary prevention:

  • LDL-C ≥190 mg/dL and age 20 to 75 years:
    • High-intensity therapy required;
      • use alternate statin therapy (eg, atorvastatin or rosuvastatin)
  • Diabetes, age 40 to 75 years, and an estimated 10-year ASCVD risk <7.5%:
    • Moderate-intensity therapy:
      • Immediate-release: 40 mg two times a day.
      • Extended-release: 80 mg once in a day.
  • Diabetes, age 40 to 75 years, and an estimated 10-year ASCVD risk ≥7.5%:
    • High-intensity therapy necessary;
    • use alternate statin therapy (eg, atorvastatin or rosuvastatin).
  • LDL-C 70 to 189 mg/dL, age 40 to 75 years, and an estimated 10-year ASCVD risk ≥7.5%:
  • Moderate- to high-intensity therapy:
    • Immediate-release:
      • 40 mg two times in a  day or consider using high-intensity statin therapy (eg, atorvastatin or rosuvastatin).
    • Extended-release:
      • 80 mg once daily or consider using high-intensity statin therapy (eg, atorvastatin or rosuvastatin).

• Secondary prevention:

  • Patient has clinical ASCVD (eg, coronary heart disease, stroke/TIA, or peripheral arterial disease presumed to be of atherosclerotic origin) or is post-CABG and:
    • Age ≤75 years:
      • High-intensity therapy necessary; use alternate statin therapy (eg, atorvastatin or rosuvastatin).
    • Age >75 years: Moderate- to high-intensity therapy:
      • Immediate-release:
        • 40 mg two times in a day or consider using high-intensity statin therapy (eg, atorvastatin or rosuvastatin);
        • if moderate-intensity therapy is started and tolerated, increase to a high-intensity statin therapy within 3 months (Rosenson 2019).
      • Extended-release:
        • 80 mg once in a day or consider using high-intensity statin therapy (eg, atorvastatin or rosuvastatin);
        • if moderate-intensity therapy is started and tolerated, increase to a high-intensity statin therapy within 3 months.

• US Preventive Services Task Force Recommendations:

  • Age 40 to 75 years, no history of CVD, with ≥1 CVD risk factor (diabetes, hypertension, dyslipidemia, or smoking), and calculated 10-year CVD event risk of ≥10%:

  • Primary prevention:

    • Low-intensity therapy:
    • Immediate-release: 20 to 40 mg once in a day.

  • Moderate-intensity therapy:

    • Immediate-release: 40 mg two times in a day.
    • Extended-release: 80 mg once in a day.

Note:

• These recommendations do not pertain to patients with very high cholesterol levels (eg, LDL >190 mg/dL, familial hypercholesterolemia) (were excluded from primary prevention trials);
• use clinical judgment in the treatment of these patients.
• In patients with a calculated 10-year CVD event risk of 7.5 percent to 10 percent, statin use may be considered based on patient characteristics.

• Concomitant use with cyclosporine or fluconazole:

  • Immediate-release:
    • Do not exceed fluvastatin 20 mg two times a day.

Fluvastatin (Lescol XL) Dose in Childrens

Fluvastatin (Lescol XL) Dose in Children with Hyperlipidemia or heterozygous familial and nonfamilial hypercholesterolemia:

Note:

• Begin treatment if after an adequate trial of diet the following are present:
  • LDL-C ≥190 mg/dL or LDL-C remains ≥160 mg/dL and positive family history of premature cardiovascular disease or meets NCEP classification.
  • Therapy may be considered for children 8-9 years of age meeting the above criteria or for children with diabetes mellitus and LDL-C ≥130 mg/dL.

• Children ≥10 years and Adolescents ≤16 years (female patients should be ≥1-year post menarche): Oral:

  • Immediate-release capsule:
    • Initial: 20 mg once in a day; may titrate dose or frequency (two times daily dosing) at 6-week intervals;
    • maximum dose: 40 mg two times in a day.
  • Extended-release tablet:
    • Should not be used to initiate therapy;
    • may convert patient if the total daily dose is 80 mg per day

• Dosing adjustment for fluvastatin with concomitant medications:

  • Children and Adolescents:

    • Cyclosporine, fluconazole:
      • Do not exceed 20 mg two times a day.

• Fluvastatin (Lescol XL) Dosing adjustment for toxicity: Muscle symptoms (potential myopathy):

  • Children ≥10 years and Adolescents:

    • Discontinue use until symptoms can be evaluated;
    • check creatine phosphokinase (CPK) level;
    • based on experience in adult patients, also evaluate the patient for conditions that may increase the risk for muscle symptoms (eg, hypothyroidism, reduced renal or hepatic function, rheumatologic disorders such as steroid myopathy, polymyalgia rheumatica, vitamin D deficiency, or primary muscle diseases).
      • Upon resolution (symptoms and any associated CPK abnormalities), resume the original or consider a lower dose of retitrate and fluvastatin.
      • If muscle symptoms recur, discontinue fluvastatin use.
      • After muscle symptom resolution, may then reinitiate a different statin at an initial low dose; gradually increase if tolerated.
      • Based on experience in adult patients, if muscle symptoms or elevated CPK persists for 2 months in the absence of continued statin use, consider other causes of muscle symptoms.
      • If determined to be due to another condition aside from statin use, may resume statin therapy at the original dose (NHLBI 2011; Stone 2013).

Fluvastatin (Lescol XL) Pregnancy Risk Factor X

• Fluvastatin contraindicated for pregnant women or people who are at risk of becoming pregnant
• The role of cholesterol biosynthesis in fetal development may be significant; serum cholesterol and total triglycerides rise normally during pregnancy.
• It is unlikely that the temporary discontinuation of lipid-lowering medication during pregnancy will have an impact on long-term outcomes of primary hypercholesterolemia treatment.
• Research in pregnant women has shown evidence of fetal abnormalities. It is not recommended that pregnant women use contraindicated drugs.
• If an HMG-CoA reductase inhibitor for females with reproductive potential is needed, it is important to use appropriate contraception
• The HMG-CoA reductase inhibit should be stopped by pregnant women at least two months before they attempt to conceive.
• Congenital anomalies have been reported in cases of maternal HMG-CoA reductase inhibitions during pregnancy.
• However, the limited data available are difficult to interpret due to maternal disease, differences between agents and low exposure rates.
• If unplanned pregnancy occurs while on Fluvastatin, it should be stopped immediately.

Fluvastatin use during breastfeeding:

• It is unknown if fluvastatin can be found in breast milk.
• Manufacturers have advised against breastfeeding because of the risk of serious adverse reactions.

Fluvastatin (Lescol XL) Dose in Kidney Disease:

• Mild to moderate renal impairment:

  • No dosage adjustment required.

• Severe renal impairment:

  • Manufacturer's labeling doesn't provide any dosage adjustments; use with caution, particularly at doses >40 mg per day (has not been studied).

Fluvastatin (Lescol XL) Dose in Liver disease:

Use is contraindicated in active liver disease or unexplained transaminase elevations.

Side Effects of Fluvastatin (Lescol):

• Central Nervous System:

  • Headache
  • Fatigue
  • Insomnia

• Gastrointestinal:

  • Abdominal Pain
  • Diarrhea
  • Dyspepsia
  • Nausea

• Genitourinary:

  • Urinary Tract Infection

• Neuromuscular & Skeletal:

  • Myalgia

• Respiratory:

  • Sinusitis
  • Bronchitis

Contraindications to Fluvastatin (Lescol):

• Hypersensitivity to fluvastatin and any component of the formulation
• Active liver disease
• Unexplained persistent increases in serum transaminases
• Pregnancy or women who are planning to get pregnant
• Breastfeeding

Warnings and precautions

• Diabetes mellitus:.

  • Fluvastatin should be continued if a patient develops diabetes during treatment. Encourage the patient to maintain a healthy lifestyle, such as a heart-healthy diet, regular exercise, and healthy weight.

  • HMG-CoA reductase inhibits have been linked to an increase in HbA levels and fasting glucose. However, statin therapy's benefits (e.g., a lower risk of MI or stroke) outweigh the risks of dysglycemia.

• Hepatotoxicity:

  • AST and ALT elevations have been reported. In most cases, these elevations were temporary and resolved with continued therapy or after a short interruption to therapy.
  • At baseline, and as indicated by the physician, liver enzyme tests should be performed. If symptoms or signs of liver injury are present, they should also be taken.
  • The potential for adverse hepatic effects from ethanol may be increased. Patients should be instructed to limit their ethanol intake.
  • It has been shown to be safe for those suffering from active hepatitis C.
  • Reports of postmarketing fatalities and non-fatal liver failure have been made and are very rare.
  • Stop treatment immediately if you experience severe hepatotoxicity, including clinical symptoms and/or hyperbilirubinemia, jaundice or other signs.
  • Do not take fluvastatin if an alternative cause is not found.
  • It was rare to observe drug-related liver disease.

• Myopathy/rhabdomyolysis:

  • Patients with hypothyroidism that has not been properly treated and patients who are taking colchicine (eg, for myopathy) should be cautious. These patients are more likely to develop myopathy.
  • It has been reported that immuno-mediated necrotizing myopathy (IMNM), associated with HMG–CoA reductase inhibitors, is also possible.

  • Patients should be closely monitored for rhabdomyolysis and acute renal failure due to myoglobinuria or myopathy.

  • This is a dose-dependent risk and increases if you use erythromycin, cyclosporine, or other lipid-lowering medication (eg fibrates, niacin at dosages >=1g/day).
  • Patients should be taught to report any unexplained pain, tenderness, weakness or brown urine, especially if it is accompanied by malaise, fever, or other symptoms.
  • If CPK levels are elevated or myopathy is suspected/diagnosed, discontinue therapy.

• Steroidogenesis-reducing diseases:

  • Patients with certain conditions or who are taking medications that decrease steroidogenesis should be cautious.

• Hepatic impairment, ethanol and/or ethanol abuse:

  • Patients with a history or high intake of ethanol should be cautious. Patients with undiagnosed or active liver disease and transaminase elevations are not recommended.

• Renal impairment

  • Patients with kidney impairment should be cautious; they are more likely to develop myopathy.

Fluvastatin: Drug Interaction

Monitoring parameters:

ACC/AHA Blood Cholesterol Guideline recommendations (ACC/AHA [Grundy 2018]; ACC/AHA [Stone 2013]):

• Lipid panel (total cholesterol, HDL, LDL, triglycerides):
  • Lipid profile (fasting or nonfasting) before initiating treatment.
  • Fasting lipid profile should be rechecked 4 to 12 weeks after starting therapy and every 3 to 12 months thereafter.
  • If 2 consecutive LDL levels are less than 40 mg/dL, consider decreasing the dose.
• Hepatic transaminase levels:
  • Baseline measurement of hepatic transaminase levels (AST and ALT);
  • measure AST, ALT, total bilirubin, and alkaline phosphatase if symptoms suggest hepatotoxicity (eg, unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine or yellowing of skin or sclera) during therapy.
• CPK:
  • CPK should not be routinely measured.
  • Baseline CPK measurement is reasonable for some individuals (eg, family history of statin intolerance or muscle disease, clinical presentation, concomitant drug therapy that may increase risk of myopathy).
  • May measure CPK in any patient with symptoms suggestive of myopathy (stiffness, cramping, weakness, pain, tenderness, or generalized fatigue).
  • Evaluate for new-onset diabetes mellitus during therapy; if diabetes develops, continue statin therapy, and encourage adherence to a heart-healthy diet, physical activity, a healthy body weight, and tobacco cessation.
  • If the patient develops a confusional state or memory impairment, may evaluate the patient for nonstatin causes (eg, exposure to other drugs), systemic and neuropsychiatric causes, and the possibility of adverse effects associated with statin therapy.

How to administer Fluvastatin (Lescol)?

Oral:

• Patient should be placed on a standard cholesterol-lowering diet before and during treatment.
• Administer without regard to meals.
• Do not break, chew, or crush extended-release tablets; do not open immediate-release capsules.
• Do not administer two 40 mg immediate-release capsules at once.

Mechanism of action of Fluvastatin (Lescol):

• Acts by competitively inhibiting 3-hydroxyl-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the reduction of HMG-CoA to mevalonate; this is an early rate-limiting step in cholesterol biosynthesis.
• HDL levels are higher than total, LDL and VLDL cholesterols, apolipoproteinB, and plasma triglycerides.
• They are able to reduce high-sensitivity CRP (hsCRP) levels.
• However, they also have pleiotropic effects such as improved endothelial function and reduced inflammation at the site.

The onset of action:

• Peak effect: Maximal LDL-C reductions achieved within 4 weeks

Protein binding:

• 98 percent

Metabolism:

• Hepatic to inactive and active metabolites (oxidative metabolism via CYP2C9 [~75%], CYP2C8 [~5%], and CYP3A4 [~20%] isoenzymes); active forms do not circulate systemically; extensive (saturable) first-pass hepatic extraction

Bioavailability:

• Absolute: Immediate-release: 24 percent;
• Extended-release: ~29 percent  (increased by ~50 percent  when administered with a high-fat meal)

Half-life elimination:

• Immediate-release: ~3 hours;
• Extended-release: 7.3 to 10.5 hours (due to prolonged absorption time).

Time to peak:

• Immediate-release:
  • less than 1 hour (delayed more than 2-fold when administered with food as compared to administering 4 hours after the evening meal)
• Extended-release:
  • ~3 hours (minimally affected by low-fat meals; however, with a high-fat meal, delayed by 2-fold)

Excretion:

• Feces (~90%; <2 percent  unchanged); urine (~5%)

International Brand Names of Fluvastatin:

• Lescol XL
• Digaril
• Fluvas
• Fractal
• Fractal LP
• Lescol
• Lescol LP
• Lescol XL
• Lesterol
• Lochol
• Locol
• Luvinsta
• Lescol
• SANDOZ Fluvastatin
• TEVA-Fluvastatin
• Cranoc
• Luvinsta SR
• Vaditon
• Xilep
• Xilep XL

Fluvastatin Brand Names in Pakistan: