fluvastatin (Lescol, Lescol XL)

Dosing and uses of Lescol, Lescol XL (fluvastatin)

• Adult
• Pediatric

 

Adult dosage forms and strengths

capsules

• 20mg
• 40mg

tablets, extended release

• 80mg

 

Hypercholesterolemia & Mixed Dyslipidemia

Start 20-40 mg PO qHs

Dose range 20-80 mg PO qDay

If 80 mg/day needed, divide into 40 mg PO q12hr

Sustained-release (Lescol XL): 80 mg PO qDay

 

Patients Requiring <25% Decrease in LDL-C

20 mg PO qDay; may adjust dose based on response and tolerability not to exceed 40 mg PO q12hr (immediate release capsule) or 80 mg PO q24hr extended release tablet

 

Renal Impairment

CrCl <30 mL/min: Adjust dose amount; not to exceed 40 mg/day

 

Hepatic Impairment

Contraindicated in active liver disease or unexplained transaminase elevations

 

Overdose Management

Adverse drug reactions from overdose may include peripheral neuropathy, diarrhea, increased K+, myopathy, rhabdomyolysis, acute renal failure, elevated LFT's, eye lens opacities

Treatment is supportive

 

Pediatric dosage forms and strengths

capsules

• 20mg
• 40mg

tablets, extended release

• 80mg

 

Heterozygous Familial Hypercholesterolemia

Indicated for adolescents unresponsive to dietary restriction and LDL-C remains >190 mg/dL, OR LDL-C >160 mg/dL AND positive family history exists or 2 or more cardivascular risk factors; girls must be at least 1 year postmenarche

<10 years: Safety and efficacy not established

10-16 years: 20 mg PO qHS initially; may increase dose at 6 week intervals up to 40 mg PO q12hr immediate release or 80 mg (Lescol XL) PO qDay

 

Lescol, Lescol XL (fluvastatin) adverse (side) effects

1-10%

Headache (9%)

Dyspepsia (8%)

Abdominal pain (5%)

Diarrhea (5%)

Myalgia (5%)

Fatigue (3%)

Insomnia (3%)

Nausea (3%)

Sinusitis (3%)

Bronchitis (2%)

UTI (2%)

Transaminases increased (1.1%)

 

<1%

Rash

Back pain

Arthralgia

Myopathy

Rhabdomyolysis

Rupture of tendon

CPK increased

Pharyngitis

Rhinitis

Cough

Constipation

Pancreatitis

Dizziness

 

Postmarketing Reports

Musculoskeletal: Muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias, muscle spasms, muscle weakness, myositis

Neurological: Dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, vertigo, paresthesia, hypoesthesia, dysesthesia, peripheral neuropathy, peripheral nerve palsy; also rare reports of cognitive impairment (eg, memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use

Psychiatric: Anxiety, insomnia, depression, psychic disturbances

Hypersensitivity reactions: Hypersensitivity syndrome including anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, increased ESR, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity reaction, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, and erythema multiforme including Stevens-Johnson syndrome

Gastrointestinal: Pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, anorexia, vomiting, fatal and nonfatal hepatic failure

Skin: Rash, dermatitis, including bullous dermatitis, eczema, alopecia, pruritus, a variety of skin changes (eg, nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails)

Reproductive: Gynecomastia, loss of libido, erectile dysfunction

Eye: Progression of cataracts (lens opacities), ophthalmoplegia

Laboratory abnormalities: Elevated transaminases, alkaline phosphatase, gamma-glutamyl transpeptidase and bilirubin; thyroid function abnormalities

 

Warnings

Contraindications

Hypersensitivity to fluvastatin

Active liver disease, or unexplained elevated transminases

Pregnancy, lactation

 

Cautions

Non-serious and reversible cognitive side effects may occur

Increased blood sugar and glycosylated hemoglobin (HbA1c) levels reported with statin intake

Heavy alcohol use, history of liver disease, renal failure

Myopathy, risk of myopathy - incr by co-administration w/ fibrates, niacin, cyclosporine, macrolides, azole antifungals.

Withhold or discontinue treatment if myopathy develops, renal failure, or transaminase levels >3 times the upper limit of normaL

Rare reports of immune-mediated necrotizing myopathy (IMNM), characterized by increased serum creatine kinase that persist despite discontinuing statin

Lipid-lowering effects additive with bile-acid binding resin or niacin

Take 2 hr after bile acid sequestrant

 

Pregnancy and lactation

Pregnancy category: X

Lactation: enters breast milk; contraindicated

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Lescol, Lescol XL (fluvastatin)

Mechanism of action

HMG-CoA reductase inhibitor, inhibits the rate-limiting step in cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase

 

Absorption

Bioavailability: 24% (capsule); 29% (extended release tablet)

Onset: 3-4 wk (Lescol)

Peak Plasma Time: 0.5-1 hr (capsule); 3hr (extended release tablet)

 

Distribution

Protein Bound: 98% (Lescol)

Vd: 0.35 L/kg (Lescol)

 

Metabolism

Metabolite: No active metabolite

Metabolism: hepatic P450 enzyme CYP2C9 (75%); CYP2C8 (5%); CYP3A4 (20%)

 

Elimination

Half-Life: <3 hr (capsule); 9hr (extended release tablet)

Total Body Clearance: 0.97 L/hr/kg (Lescol)

Excretion: feces (95%), urine (5%) (Lescol)

 

Pharmacogenomics

SLCO1B1 (OATP1B1) CC genotype significantly increases AUCs of parent drug and metabolites compared with the CT or TT genotypes

This polymorphism is proposed to reduced transport into the liver, the main site of statin metabolism and elimination, resulting in elevated plasma concentrations

SLCO1B1 polymorphism is thought to have a lesser effect on the more hydrophilic statins (eg, rosuvastatin, fluvastatin) compared with more those that are more lipophilic (eg, atorvastatin, pravastatin, simvastatin)

Other genetic polymorphisms of elimination (eg, CYP450, P-glycoprotein) for each individual drug must also be considered to explain variability for statin clearance among patients that exhibit SCLO1B1 polymorphism

SLCO1B1 CC genotype is most common in Caucasians and Asians (15%)

Risk of myopathy is 2.6- to 4.3-fold higher if the C allele is present and 16.9-fold higher in CC homozygotes compared with TT homozygotes

Genetic testing laboratories

• Optivia Biotechnology, Inc (https://optiviabio.com/index.html)