Approved Drug Label (PDF)
4
Contraindications
Additions and/or
revisions underlined:
LESCOL XL is contraindicated in patients with:
Acute liver failure or decompensated cirrhosis
[see Warnings and Precautions (5.3)].
Hypersensitivity to fluvastatin or any of the excipients in LESCOL XL. Hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson syndrome have been reported
[see Adverse
Reactions (6.2)].
5
Warnings and Precautions
5.1 Myopathy and
Rhabdomyolysis
Subsection title revised
Additions and/or
revisions underlined:
LESCOL XL may cause myopathy (muscle
pain, tenderness, or weakness associated with elevated creatine
kinase [CK]) and rhabdomyolysis.
Acute kidney injury secondary to
myoglobinuria and rare fatalities have occurred as a result of
rhabdomyolysis with statins, including LESCOL XL.
Myopathy, defined
as muscle aching or muscle weakness in conjunction with increases in CK, values to greater
than 10 times the upper limit
of normal (ULN) was < 0.1% in fluvastatin clinical trials [see Adverse Reactions (6.1)].
Risk Factors
for Myopathy
Risk
factors for myopathy include age 65 years or greater, uncontrolled
hypothyroidism, renal impairment, and concomitant use
with certain other drugs (including other lipid-lowering therapies) [see Drug Interactions (7.1)].
Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis
Avoid
concomitant use of LESCOL XL with gemfibrozil, cyclosporin, and fluconazole. When used concomitantly with
LESCOL XL, lipid modifying doses (? 1 g/day) of niacin, fibrates,
and colchicine may also increase
the risk of myopathy
and rhabdomyolysis [see Drug Interactions
(7.1)].
Discontinue LESCOL
XL if markedly elevated CK
levels occur or if myopathy
is either diagnosed
or suspected. Muscle symptoms and CK increases
may resolve if LESCOL XL is discontinued. Temporarily discontinue LESCOL XL in
patients experiencing an acute or serious condition at high risk of
developing renal failure
secondary to rhabdomyolysis, e.g., sepsis, shock,
severe hypovolemia, major surgery, trauma, severe metabolic, endocrine, or
electrolyte disorders, or uncontrolled epilepsy.
Inform patients
of the risk of myopathy
and rhabdomyolysis when starting LESCOL
XL. Instruct patients
to promptly report any
unexplained muscle pain, tenderness, or weakness, particularly if accompanied
by malaise or fever.
5.2 Immune-Mediated
Necrotizing Myopathy
Additions and/or
revisions underlined:
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence
when the same or a different statin was administered. IMNM is characterized
by proximal muscle weakness and elevated serum CK, which persist despite
discontinuation of statin treatment; positive anti-HMG CoA reductase antibody, muscle
biopsy showing necrotizing myopathy,
and improvement with immunosuppressive
agents. Additional neuromuscular and serologic testing may be necessary.
Treatment with immunosuppressive agents may be
required. Discontinue LESCOL XL if IMNM is suspected.
5.3 Hepatic
Dysfunction
Subsection title revised
Additions and/or
revisions underlined:
Increases
in serum transaminases have been reported with use of LESCOL XL [see Adverse Reactions (6.1)]. In
most cases, these changes
appeared soon after
initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after
a brief interruption in therapy. Persistent increases to more than three
times the ULN in serum transaminases have occurred in approximately 1.1% of
patients receiving fluvastatin in clinical trials.
Marked persistent increases of hepatic
transaminases have also occurred with fluvastatin. There have been rare post- marketing reports of fatal and
non-fatal hepatic failure in patients taking statins, including LESCOL XL.
Patients who consume substantial quantities of alcohol
and/or have a history of liver disease
may be at increased risk for
hepatic injury.
Consider
liver enzyme testing before LESCOL XL initiation and thereafter, when
clinically indicated. LESCOL XL is contraindicated in patients with acute liver
failure or decompensated cirrhosis [see
Contraindications (4)]. If serious hepatic
injury with clinical
symptoms and/or hyperbilirubinemia or jaundice occurs,
promptly discontinue LESCOL
XL.
5.4
Increases in HbA1c and Fasting Serum Glucose Levels
Subsection title revised
Additions and/or revisions underlined:
Increases in HbA1c and fasting serum glucose levels have been reported with statins, including
LESCOL XL. Optimize lifestyle measures, including
regular exercise, maintaining a healthy body weight, and making healthy food
choices.
6
Adverse Reactions
Additions and/or
revisions underlined:
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Myopathy and Rhabdomyolysis [see Warnings
and Precautions (5.1)]
Immune-Mediated Necrotizing Myopathy
[see Warnings and Precautions (5.2)]
Hepatic Dysfunction [see Warnings
and Precautions (5.3)]
Increases in HbA1c and Fasting
Serum Glucose Levels [see Warnings and Precautions (5.4)]
6.1 Clinical
Trials Experience
Extensive changes; please refer to label for complete information
6.2 Postmarketing
Experience
Additions and/or
revisions underlined:
The following
adverse reactions have
been identified during
postapproval use of fluvastatin. Because
these reactions are
reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
Musculoskeletal: Muscle cramps, myopathy,
rhabdomyolysis, arthralgias, muscle spasms, muscle
weakness, myositis. There
have been rare reports of IMNM associated with statin use [see Warnings and Precautions (5.2)].
Neurological: Dysfunction of certain
cranial nerves (including alteration of taste,
impairment of extra-ocular movement, facial paresis), tremor, vertigo, paresthesia,
hypoesthesia, dysesthesia, peripheral neuropathy, peripheral nerve palsy.
There
have been rare postmarketing reports of cognitive impairment (e.g., memory
loss, forgetfulness, amnesia, memory impairment, confusion) associated with the
use of all statins. The reports are generally nonserious, and reversible
upon statin discontinuation, with variable times to symptom onset (1 day to
years) and symptom resolution (median of 3 weeks). There
have been rare reports of new-onset or exacerbation of myasthenia gravis,
including ocular myasthenia, and reports of recurrence when the same or a different statin
was administered.
Psychiatric: Anxiety,
depression, psychic disturbances
Respiratory: Interstitial lung disease
Hypersensitivity reactions: An apparent hypersensitivity syndrome has been
reported rarely which has included one or more
of the following features: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, vasculitis, purpura,
thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR (erythrocyte
sedimentation rate) increase, eosinophilia, arthritis, arthralgia, urticaria,
asthenia, photosensitivity reaction, fever, chills, flushing, malaise, dyspnea,
toxic epidermal necrolysis, 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 non-fatal hepatic failure.
Skin: Rash, dermatitis, including
bullous dermatitis, eczema,
alopecia, pruritus, lichen
planus, a variety
of skin changes (e.g., 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.
7
Drug Interactions
Subsection title revised
Extensive changes;
please refer to label for complete information
8
Use in Specific Populations
8.1 Pregnancy
Pregnancy
and Lactation Labeling Rule (PLLR) conversion; please refer to label for
complete information
8.2 Lactation
Newly added
subsection:
Risk Summary
There is no information about the presence
of fluvastatin in human milk, the effects
of the drug on the breastfed infant or
the effects of the drug on milk
production. However, it has been shown that another drug in this class passes into human milk. Studies in rats have shown
that fluvastatin and/or its metabolites are present in the milk of lactating
rats. When a drug is present in animal milk, it is likely that the drug will be
present in human milk (see Data).
Statins, including LESCOL XL, decrease cholesterol synthesis and possibly the
synthesis of other biologically active substances derived from cholesterol and
may cause harm to the breastfed infant.
Because of the potential for serious
adverse reactions in a breastfed infant, based on the mechanism of action,
advise patients that breastfeeding is not recommended during treatment with LESCOL XL [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1)].
Data
Following a single oral administration of 1 mg/kg of radioactive fluvastatin to lactating rats, the concentration of total radioactivity was determined. Fluvastatin and/or its
metabolites were measured in the breast milk at a 2:1 ratio (milk:plasma).
8.4 Pediatric Use
Additions and/or
revisions underlined:
The
safety and effectiveness of LESCOL XL as an adjunct to diet to reduce
LDL-C have been established in pediatric patients 10 years of age and
older with HeFH.
Use of LESCOL XL for this indication is based on open-label, uncontrolled clinical trials
in 114 pediatric
patients 9 years of age and older
with HeFH. In these limited
uncontrolled studies, there
was no significant effect on growth or sexual maturation in the males
or females, or on menstrual cycle length in females.
The safety and effectiveness of LESCOL XL have not been established in pediatric patients
younger than 10 years of age
with HeFH or in pediatric patients with other types of hyperlipidemia (other
than HeFH).
8.5
Geriatric Use
Additions and/or
revisions underlined:
Fluvastatin exposures
were not significantly different between the nonelderly and elderly populations (age ? 65 years)[see Clinical
Pharmacology (12.3)].
Advanced age (? 65 years) is a risk factor for LESCOL XL-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be
cautious, recognizing the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug therapy and the
higher risk of myopathy. Monitor geriatric patients receiving LESCOL XL for the
increased risk of myopathy [see Warnings
and Precautions (5.1)].
8.6
Renal Impairment
Additions and/or revisions underlined:
Renal
impairment is a risk factor for myopathy and rhabdomyolysis. Dose adjustments
for mild to moderate renal impairment are not necessary. Fluvastatin has not
been studied at doses greater than 40 mg in patients with severe renal
impairment; therefore, use LESCOL XL with caution
in patients with severe renal
impairment. Monitor all patients with renal impairment for development
of myopathy [see Warnings and Precautions
(5.1), Clinical Pharmacology
(12.3)].
8.7
Hepatic Impairment
Additions and/or
revisions underlined:
LESCOL XL is contraindicated in patients with acute liver failure or decompensated cirrhosis
[see Contraindications (4),
Warnings and Precautions (5.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions
and/or revisions underlined:
Advise the patient to read the FDA-approved patient
labeling (Patient Information).
Myopathy and Rhabdomyolysis
Advise patients that LESCOL XL may
cause myopathy and rhabdomyolysis. Instruct patients to promptly report
any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever [see Warnings
and Precautions (5.1), Drug Interactions (7.1)].
Hepatic Dysfunction
nform patients that LESCOL XL may cause
liver enzyme elevations and possibly liver failure. Advise patients to promptly
report fatigue, anorexia, right upper abdominal discomfort, dark urine, or
jaundice [see Warnings and Precautions
(5.3)].
Increases in HbA1c and Fasting Serum Glucose Levels
Inform
patients that increases in HbA1c and fasting serum glucose levels may occur
with LESCOL XL. Encourage patients to optimize
lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions (5.4)].
Pregnancy
Advise
pregnant patients and patients who can become pregnant of the potential risk to
a fetus. Advise patients to inform their healthcare provider
of a known or suspected pregnancy to discuss
if LESCOL XL should be discontinued [see Use in
Specific Populations (8.1)].
Lactation
Advise patients that breastfeeding is
not recommended during
treatment with LESCOL
XL [see Use in Specific
Populations (8.2)].
PATIENT INFORMATION
Extensive changes;
please refer to label for complete information