A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Lescol-XL Warnings, Precautions, Pregnancy, Nursing, Abuse - Fluvastatin
Lescol-XL Warnings, Precautions, Pregnancy, Nursing, Abuse - Fluvastatin
WARNINGS
Liver Enzymes
Biochemical abnormalities of liver function have been associated
with HMG-CoA reductase inhibitors and other lipid-lowering agents. Approximately
1.1% of patients treated with Lescol® (fluvastatin sodium) capsules
in worldwide trials developed dose-related, persistent elevations of transaminase
levels to more than 3 times the upper limit of normal. Fourteen of these patients
(0.6%) were discontinued from therapy. In all clinical trials, a total of 33/2969
patients (1.1%) had persistent transaminase elevations with an average fluvastatin
exposure of approximately 71.2 weeks; 19 of these patients (0.6%) were discontinued.
The majority of patients with these abnormal biochemical findings were asymptomatic.
In a pooled analysis of all placebo-controlled studies in which
Lescol capsules were used, persistent transaminase elevations (>3 times the
upper limit of normal [ULN] on two consecutive weekly measurements) occurred
in 0.2%, 1.5%, and 2.7% of patients treated with 20, 40, and 80 mg (titrated
to 40 mg twice daily) Lescol capsules, respectively. Ninety-one percent of the
cases of persistent liver function test abnormalities (20 of 22 patients) occurred
within 12 weeks of therapy and in all patients with persistent liver function
test abnormalities there was an abnormal liver function test present at baseline
or by week 8.
In the pooled analysis of the 24-week controlled trials, persistent
transaminase elevation occurred in 1.9%, 1.8% and 4.9% of patients treated with
Lescol® XL (fluvastatin sodium) 80 mg, Lescol 40 mg and Lescol
40 mg twice daily, respectively. In 13 of 16 patients treated with Lescol XL
the abnormality occurred within 12 weeks of initiation of treatment with Lescol
XL 80 mg.
It is recommended that liver function tests be performed
before the initiation of therapy and at 12 weeks following initiation of treatment
or elevation in dose. Patients who develop transaminase elevations or signs
and symptoms of liver disease should be monitored to confirm the finding and
should be followed thereafter with frequent liver function tests until the levels
return to normal. Should an increase in AST or ALT of three times the upper
limit of normal or greater persist (found on two consecutive occasions) withdrawal
of fluvastatin sodium therapy is recommended.
Active liver disease or unexplained transaminase elevations
are contraindications to the use of Lescol and Lescol XL (see CONTRAINDICATIONS).
Caution should be exercised when fluvastatin sodium is administered to
patients with a history of liver disease or heavy alcohol ingestion (see
CLINICAL PHARMACOLOGY:
Pharmacokinetics/Metabolism). Such patients should be closely monitored.
Skeletal Muscle
Rhabdomyolysis with renal dysfunction secondary to myoglobinuria
has been reported with fluvastatin and with other drugs in this class. Myopathy,
defined as muscle aching or muscle weakness in conjunction with increases in
creatine phosphokinase (CPK) values to greater than 10 times the upper limit
of normal, has been reported.
Myopathy should be considered in any patients with diffuse
myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients
should be advised to report promptly unexplained muscle pain, tenderness or
weakness, particularly if accompanied by malaise or fever. Fluvastatin sodium
therapy should be discontinued if markedly elevated CPK levels occur or myopathy
is diagnosed or suspected. Fluvastatin sodium therapy should also be temporarily
withheld in any patient experiencing an acute or serious condition predisposing
to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis;
hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte
disorders; or uncontrolled epilepsy.
The risk of myopathy and or rhabdomyolysis during treatment
with HMG-CoA reductase inhibitors has been reported to be increased if therapy
with either cyclosporine, gemfibrozil, erythromycin, or niacin is administered
concurrently. Myopathy was not observed in a clinical trial in 74 patients involving
patients who were treated with fluvastatin sodium together with niacin.
Uncomplicated myalgia has been observed infrequently in patients
treated with Lescol at rates indistinguishable from placebo.
The use of fibrates alone may occasionally be associated with
myopathy. The combined use of HMG-CoA reductase inhibitors and fibrates should
generally be avoided.
PRECAUTIONS
General
Before instituting therapy with Lescol® (fluvastatin
sodium) or Lescol® XL (fluvastatin sodium), an attempt should
be made to control hypercholesterolemia with appropriate diet, exercise, and
weight reduction in obese patients, and to treat other underlying medical problems
(see INDICATIONS AND
USAGE).
The HMG-CoA reductase inhibitors may cause elevation of creatine
phosphokinase and transaminase levels (see WARNINGS
and ADVERSE REACTIONS). This
should be considered in the differential diagnosis of chest pain in a
patient on therapy with fluvastatin sodium.
Homozygous Familial Hypercholesterolemia
HMG-CoA reductase inhibitors are reported to be less effective
in patients with rare homozygous familial hypercholesterolemia, possibly because
these patients have few functional LDL receptors.
Information for patients
Patients should be advised to report promptly unexplained muscle
pain, tenderness or weakness, particularly if accompanied by malaise or fever.
Women should be informed that if they become pregnant while
receiving Lescol or Lescol XL the drug should be discontinued immediately
to avoid possible harmful effects on a developing fetus from a relative
deficit of cholesterol and biological products derived from cholesterol.
In addition, Lescol or Lescol XL should not be taken during nursing. (See
CONTRAINDICATIONS.)
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 2-year study was performed in rats at dose levels of 6, 9,
and 18-24 (escalated after 1 year) mg/kg/day. These treatment levels represented
plasma drug levels of approximately 9, 13, and 26-35 times the mean human plasma
drug concentration after a 40 mg oral dose. A low incidence of forestomach squamous
papillomas and 1 carcinoma of the forestomach at the 24 mg/kg/day dose level
was considered to reflect the prolonged hyperplasia induced by direct contact
exposure to fluvastatin sodium rather than to a systemic effect of the drug.
In addition, an increased incidence of thyroid follicular cell adeno-mas and
carcinomas was recorded for males treated with 18-24 mg/kg/day. The increased
incidence of thyroid follicular cell neoplasm in male rats with fluvastatin
sodium appears to be consistent with findings from other HMG-CoA reductase inhibitors.
In contrast to other HMG-CoA reductase inhibitors, no hepatic adenomas or carcinomas
were observed.
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. These treatment levels represented
plasma drug levels of approximately 0.05, 2, and 7 times the mean human plasma
drug concentration after a 40 mg oral dose.
No evidence of mutagenicity was observed in vitro, with or
without rat-liver 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.
In a study in rats at dose levels for females of 0.6, 2 and
6 mg/kg/day and at dose levels for males of 2, 10 and 20 mg/kg/day, fluvastatin
sodium had no adverse effects on the fertility or reproductive performance.
Seminal vesicles and testes were small in hamsters treated for 3 months at 20
mg/kg/day (approximately three times the 40 milligram human daily dose based
on surface area, mg/m2). There was tubular degeneration and aspermatogenesis
in testes as well as vesiculitis of seminal vesicles. Vesiculitis of seminal
vesicles and edema of the testes were also seen in rats treated for 2 years
at 18 mg/kg/day (approximately 4 times the human Cmax achieved with
a 40 milligram daily dose).
Pregnancy
Pregnancy Category X
See CONTRAINDICATIONS.
Fluvastatin sodium produced delays in skeletal development
in rats at doses of 12 mg/kg/day and in rabbits at doses of 10 mg/kg/day. Malaligned
thoracic vertebrae were seen in rats at 36 mg/kg, a dose that produced maternal
toxicity. These doses resulted in 2 times (rat at 12 mg/kg) or 5 times (rabbit
at 10 mg/kg) the 40 mg human exposure based on mg/m2 surface area.
A study in which female rats were dosed during the third trimester at 12 and
24 mg/kg/day resulted in maternal mortality at or near term and postpartum.
In addition, fetal and neonatal lethality were apparent. No effects on the dam
or fetus occurred at 2 mg/kg/day. A second study at levels of 2, 6, 12 and 24
mg/kg/day confirmed the findings in the first study with neonatal mortality
beginning at 6 mg/kg. A modified Segment III study was performed at dose levels
of 12 or 24 mg/kg/day with or without the presence of concurrent supplementation
with mevalonic acid, a product of HMG-CoA reductase which is essential for cholesterol
biosynthesis. The concurrent administration of mevalonic acid completely prevented
the maternal and neonatal mortality but did not prevent low body weights in
pups at 24 mg/kg on days 0 and 7 postpartum. Therefore, the maternal and neonatal
lethality observed with fluvastatin sodium reflect its exaggerated pharmacologic
effect during pregnancy. There are no data with fluvastatin sodium in pregnant
women. However, rare reports of congenital anomalies have been received following
intrauterine exposure to other HMG-CoA reductase inhibitors. There has been
one report of severe congenital bony deformity, tracheo-esophageal fistula,
and anal atresia (VATER association) in a baby born to a woman who took another
HMG-CoA reductase inhibitor with dextroamphetamine sulfate during the first
trimester of pregnancy. Lescol or Lescol XL should be administered to women
of child-bearing potential only when such patients are highly unlikely to conceive
and have been informed of the potential hazards.
If a woman becomes pregnant while taking Lescol or Lescol XL,
the drug should be discontinued and the patient advised again as to the potential
hazards to the fetus.
Nursing Mothers
Based on preclinical data, drug is present in breast milk in
a 2:1 ratio (milk:plasma). Because of the potential for serious adverse
reactions in nursing infants, nursing women should not take Lescol or
Lescol XL (see CONTRAINDICATIONS).
Pediatric Use
Safety and effectiveness in individuals less than 18 years
old have not been established. Treatment in patients less than 18 years of age
is not recommended at this time.
Geriatric Use
The effect of age on the pharmacokinetics of immediate release
fluvastatin sodium was evaluated. Results indicate that for the general patient
population plasma concentrations of fluvastatin sodium do not vary as a function
of age. (See also CLINICAL PHARMACOLOGY:
Pharmacokinetics/Metabolism.)
Elderly patients (³65 years of age)
demonstrated a greater treatment response in respect to LDL-C, Total-C and LDL/HDL
ratio than patients <65 years of age.
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