Fluvastatin

Cases of myopathy, including rhabdomyolysis, have been reported with fluvastatin coadministered with colchicine, and caution should be exercised when prescribing fluvastatin with colchicine.

Bleeding and/or increased prothrombin times have been reported in patients taking coumarin anticoagulants concomitantly with other HMG-CoA reductase inhibitors. Therefore, patients receiving warfarin-type anticoagulants should have their prothrombin times closely monitored when fluvastatin sodium is initiated or the dosage of fluvastatin sodium is changed.

Concomitant administration of fluvastatin and phenytoin increased phenytoin exposures. Patients should continue to be monitored appropriately when fluvastatin therapy is initiated or when fluvastatin dose is changed.

Concomitant administration of fluvastatin and glyburide increased glyburide exposures. Patients on concomitant therapy of glyburide and fluvastatin should continue to be monitored appropriately.

For more Interactions (Complete) data for Fluvastatin (14 total), please visit the HSDB record page.

Fluvastatin therapy is associated with mild, asymptomatic and usually transient serum aminotransferase elevations in 1% to 5% of patients but in levels above 3 times ULN is approximately 1%. In summary analyses of large scale studies with prospective monitoring, ALT elevations above normal occurred in up to 5% of patients; ALT levels of above 3 times the upper limit of normal (ULN) occurred in 1.1% of fluvastatin treated versus 0.3% of placebo recipients. These elevations were more common with higher doses of fluvastatin. Most of these elevations were self-limited and did not require dose modification. Fluvastatin is the statin most commonly associated with serum aminotransferase elevations and the highest rates of symptomatic liver injury, yet frank, clinically apparent hepatic injury from fluvastatin is still quite rare estimated to occur in 1.7 per 10,000 person years of use. In the few cases that have been reported, the onset of clinical injury has been within 1 to 4 months, the pattern of injury is typically cholestatic or mixed. Rash, fever and eosinophilia are uncommon. At least one case with features of autoimmunity has been described. Most cases resolve within a few months of onset. Rare cases of acute liver failure and death have been attributed to fluvastatin.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 6000(SRC), determined from a structure estimation method(2), indicates that fluvastatin is expected to be immobile in soil(SRC). The estimated pKa of fluvastatin is 4.5(3), indicating that this compound will exist partially in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of fluvastatin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 5.6X10-17 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Fluvastatin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.9X10-16 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2016).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 6000(SRC), determined from a structure estimation method(2), indicates that fluvastatin is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 5.6X10-17 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from an estimated log Kow of 4.85(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2016).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), fluvastatin, which has an estimated vapor pressure of 1.9X10-16 mm Hg at 25 °C(SRC), determined from a fragment constant method(2) is expected to exist solely in the particulate phase. Particulate-phase fluvastatin may be removed from the air by wet and dry deposition(SRC). Fluvastatin contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Two major adverse drug reactions of statins (including fluvastatin) are hepatotoxicity and myopathy. Hepatotoxicity can range from an elevation of transaminase levels to clinically apparent hepatic injury. The idiosyncratic, clinically apparent liver injury is due to a hypersensitivity reaction. In most instances, the elevated serum transaminase levels during fluvastatin therapy are self-limited. Discontinuation is recommended for elevations above ten times and persistent elevations above five times the ULN(upper limit of normal).

IDENTIFICATION AND USE: Fluvastatin is anticholesteremic agent and hydroxymethylglutaryl-CoA reductase inhibitor. HUMAN EXPOSURE AND TOXICITY: Rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with fluvastatin capsules and other drugs in this class. There have been rare reports of fatal and non-fatal hepatic failure in patients taking statins, including fluvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with fluvastatin, promptly interrupt therapy. Fluvastatin capsules are contraindicated in women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Fluvastatin capsules may cause fetal harm when administered to pregnant women. Adverse drug reaction reports have demonstrated the occurrence of neuropsychiatric reactions associated with statin treatment. They include behavioral alterations; cognitive and memory impairments; sleep disturbance; and sexual dysfunction. ANIMAL STUDIES: The carcinogenicity study conducted in mice at dose levels of 0.3, 15 and 30 mg/kg/day revealed, as in rats, a statistically significant increase in forestomach squamous cell papillomas in males and females at 30 mg/kg/day and in females at 15 mg/kg/day. Fluvastatin produced delays in skeletal development in rats at doses of 12 mg/kg/day and in rabbits at doses of 10 mg/kg/day. No evidence of mutagenicity was observed in vitro, with or without metabolic activation, in the following studies: microbial mutagen tests using mutant strains of Salmonella typhimurium or Escherichia coli; malignant transformation assay in BALB/3T3 cells; unscheduled DNA synthesis in rat primary hepatocytes; chromosomal aberrations in V79 Chinese Hamster cells; HGPRT V79 Chinese Hamster cells. In addition, there was no evidence of mutagenicity in vivo in either a rat or mouse micronucleus test.

Although rare with statins, rhabdomyolysis is a serious and potentially fatal complication. Rhabdomyolysis is the most severe form of myotoxicity and can occur with the administration of any statin. 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. 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, are the most common cause of statin-related rhabdomyolysis when combined with fibrates. 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. In addition, cases of myopathy have been reported during postmarketing experience with concomitant administration of fluvastatin and colchicine. In patients presenting with rhabdomyolysis, clinicians should discontinue fluvastatin.

Based on an annual consumption of 4278.99 kg/yr, the estimated fluvastatin elimination from primary and secondary treatment processes was 44.35 and 72.39%, respectively, from wastewater facilities in Spain in 2009, giving a predicted environmental occurrence of 7.06 ng/L(1).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of fluvastatin can be estimated to be 6000(SRC). According to a classification scheme(2), this estimated Koc value suggests that fluvastatin is expected to be immobile in soil. The estimated pKa of fluvastatin is 4.5(3), indicating that this compound will exist partially in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/SIGNS AND SYMPTOMS/ There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including fluvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with fluvastatin sodium, promptly interrupt therapy. If an alternate etiology is not found do not restart fluvastatin sodium.

/SIGNS AND SYMPTOMS/ Rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with fluvastatin capsules and other drugs in this class.

/CASE REPORTS/ A 62-year-old woman treated with fluvastatin experienced three separate thrombocytopenic illnesses, severe on two occasions associated with nadir platelet count of 57,000/uL and 75,000/uL. The hospital pharmacist replaced fluvastatin by pravastatin during three stays. Platelet count increased some days after this substitution. These results suggest that fluvastatin could be involved in these thrombocytopenic episodes.

/CASE REPORTS/ HMG-CoA reductase inhibitors (statins) are widely used to treat hypercholesterolemia. Among the adverse effects associated with these drugs are statin-associated myopathies, ranging from asymptomatic elevation of serum creatine kinase to fatal rhabdomyolysis. ... We describe here a patient with liver cirrhosis who experienced fluvastatin-induced fatal rhabdomyolysis. This patient had been treated with simvastatin (20 mg/day) for coronary artery disease and was switched to fluvastatin (20 mg/day) 10 days before admission. He was also taking aspirin, betaxolol, candesartan, lactulose, and entecavir. Rhabdomyolysis was complicated and continued to progress. He was treated with massive hydration, urine alkalization, intravenous furosemide, and continuous renal replacement therapy for acute renal failure, but eventually died due to rhabdomyolysis complicated by hepatic failure. In conclusion, fluvastatin should be used with caution in patients with liver cirrhosis, especially with other medications metabolized with CYP2C9.

For more Human Toxicity Excerpts (Complete) data for Fluvastatin (11 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

fluvastatin

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

An estimated BCF of 3 was calculated in fish for fluvastatin(SRC), using an estimated log Kow of 4.85(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for fluvastatin is estimated as 5.6X10-17 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that fluvastatin is expected to be essentially nonvolatile from water and moist surfaces(2). Fluvastatin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.9X10-16 mm Hg(SRC), determined from a fragment constant method(3).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including fluvastatin sodium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Fluvastatin sodium/

MEDICATION

Anticholesteremic Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors

Use (kg; approx.) in Germany (2009): >2500

The synthesis starts with a Friedel-Crafts acylation of fluorobenzene with chloroacetyl chloride, followed by reaction with N-isopropylaniline and a ZnCl2 catalyzed indole ring closure in ethanol at 100 °C. Reaction of the 1,3-disubstituted indole with N-methyl-N-phenyl-3-aminoacrolein under Vilsmeier conditions affords the vinylogous aldehyde. For the preparation of N-methyl-N-phenyl-3-aminoacrolein a mixture of N-methyl-formanilide and butyl vinyl ether was added to oxalyl chloride, precipitation from isopropanol-hexane gave the reagent in 82% yield and 99% purity. In the next step the unsaturated aldehyde undergoes condensation with tert-butyl acetoacetate to tert-butyl 5-hydroxy-3-keto-6-heptenoate, which is diastereoselectively reduced to the syn-3,5-diol by means of methoxydiethylborane (generated in situ from triethylborane and methanol) and sodium borohydride at -78 °C (stereoselectivity 98-99%). Addition of aqueous hydrogen peroxide after the reduction step converts residual boronates into easily removable borates. The last step consists of hydrolysis of the tert-butyl ester. /Fluvastatin sodium/

Preparation: F.G. Kathawala, World Intellectual Property Organization patent 8402131; idem, United States of America patent 4739073 (1984, 1988 both to Sandoz).