Approved Drug Label (PDF)
4
Contraindications
Additions and/or
revisions underlined:
EZALLOR SPRINKLE is
contraindicated in patients with:
- Acute
liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3)].
- Hypersensitivity
to rosuvastatin or any excipients in EZALLOR SPRINKLE. Hypersensitivity
reactions, including rash, pruritus, urticaria, and angioedema, have been
reported with EZALLOR SPRINKLE [see
Adverse Reactions (6.1)].
7
Drug Interactions
7.1 Drug Interactions
that Increase the Risk of Myopathy and Rhabdomyolysis with EZALLOR SPRINKLE
. . .
Table 5: Drug
Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with EZALLOR
SPRINKLE
Addition of Ticagrelor to
Table 5; see underlined text:
. . .
Ticagrelor
Clinical
Impact: Concomitant use of EZALLOR SPRINKLE and ticagrelor has been
shown to increase rosuvastatin concentrations, which may result in increased
risk of myopathy. Cases of myopathy and rhabdomyolysis have been reported in patients using both products
concomitantly. Cases have
occurred more frequently in patients taking 40 mg
of rosuvastatin.
Intervention:
In patients taking concomitant ticagrelor, especially those
with additional risk factors for myopathy and rhabdomyolysis, monitor patients
for signs and symptoms of myopathy, particularly during initiation of therapy
and during upward dose titration of EZALLOR SPRINKLE.
7.2 Drug Interactions that Decrease the
Efficacy of EZALLOR SPRINKLE
Table 6 presents drug interactions that may decrease
the efficacy of EZALLOR SPRINKLE and instructions for preventing or managing
them.
Table 6: Drug
Interactions that Decrease the Efficacy of EZALLOR SPRINKLE
Table 6 has been revised;
see underlined text:
Antacids
Clinical Impact: Concomitant
aluminum and magnesium hydroxide combination antacid administration decreased
the mean exposure of rosuvastatin 50% [see Clinical Pharmacology (12.3)].
Intervention: In
patients taking antacid, administer EZALLOR SPRINKLE at least 2 hours before
the antacid.
7.3
EZALLOR SPRINKLE Effects on Other Drugs
Subsection title revised:
Additions
and/or revisions underlined:
Table
7 presents EZALLOR SPRINKLE effect on other drugs and instructions for
preventing or managing them.
.
. .
8
Use in Specific Populations
8.4 Pediatric Use
Additions and/or
revisions underlined:
. . .
The safety and effectiveness of rosuvastatin as an
adjunct to other LDL-C-lowering therapies to reduce LDL-C have been established
in pediatric patients 7 years of age and older with HoFH. Use of
rosuvastatin for this indication is based on a randomized, placebo-controlled,
cross-over study in 14 pediatric patients 7 years of age and older with HoFH [see Clinical
Studies (14)].
. . .
8.5 Geriatric Use
Additions and/or
revisions underlined:
Of the 10,275 patients in clinical studies with
rosuvastatin, 3,159 (31%) were 65 years and older, and 698 (6.8%) were 75
years and older. No overall differences in safety or effectiveness were
observed between these subjects and younger subjects.
. . .
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or
revisions underlined:
. . .
When taking EZALLOR SPRINKLE with an aluminum and
magnesium hydroxide combination antacid, administer EZALLOR SPRINKLE at
least 2 hours before the antacid [see
Drug Interactions (7.2)].
. . .
PATIENT INFORMATION
Patient Information has
undergone extensive changes; please refer to label for complete information
Approved Drug Label (PDF)
4
Contraindications
Additions
and/or revisions underlined:
EZALLOR
SPRINKLE is contraindicated in the following conditions:
5
Warnings and Precautions
5.1 Myopathy and Rhabdomyolysis
Additions
and/or revisions underlined:
EZALLOR
SPRINKLE 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 EZALLOR
SPRINKLE.
Risk
Factors for Myopathy
Risk
factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism,
renal impairment , concomitant use with certain
other drugs (including other lipid-lowering therapies and higher EZALLOR
SPRINKLE dosage. Asian patients on EZALLOR SPRINKLE may be at higher risk for
myopathy [see Drug Interactions (7.1) and
Use in Specific Populations (8.8)]. The myopathy risk is greater in
patients taking EZALLOR SPRINKLE 40 mg daily compared with lower EZALLOR
SPRINKLE dosages.
Steps
to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis
The
concomitant use of EZALLOR SPRINKLE with cyclosporine or gemfibrozil is not
recommended.
EZALLOR
SPRINKLE dosage modifications are recommended for patients taking certain
antiviral medications, darolutamide, and regorafenib [see Dosage and Administration (2.6)]. Niacin,
fibrates, and colchicine may also increase the risk of myopathy and
rhabdomyolysis [see Drug Interactions
(7.1)].
Discontinue EZALLOR
SPRINKLE if markedly elevated CK levels occur or if myopathy is either
diagnosed or suspected. Muscle symptoms and CK elevations may resolve if EZALLOR
SPRINKLE is discontinued. Temporarily discontinue EZALLOR SPRINKLE 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 or increasing the EZALLOR SPRINKLE dosage.
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
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 creatine kinase
that 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
EZALLOR SPRINKLE if IMNM is suspected.
5.3 Hepatic Dysfunction
Additions
and/or revisions underlined:
Increases
in serum transaminases have been reported with use of EZALLOR SPRINKLE [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.
In
a pooled analysis of placebo-controlled trials, increases in serum
transaminases to more than three times the ULN occurred in 1.1% of
patients taking EZALLOR SPRINKLE versus 0.5% of patients treated with
placebo. Marked persistent increases of hepatic transaminases have also
occurred with EZALLOR Sprinkle. There have been rare postmarketing reports
of fatal and non-fatal hepatic failure in patients taking statins, including EZALLOR
SPRINKLE.
Patients
who consume substantial quantities of alcohol and/or have a history of liver
disease may be at increased risk for hepatic injury [see Use in Specific Populations (8.7)].
Consider liver enzyme
testing before EZALLOR SPRINKLE initiation and when clinically indicated
thereafter. EZALLOR SPRINKLE 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 EZALLOR SPRINKLE
5.5 Increases in HbA1c and Fasting Serum Glucose Levels
Additions
and/or revisions underlined:
Increases
in HbA1c and fasting serum glucose levels have been reported with statins,
including EZALLOR SPRINKLE. Based on clinical trial data with EZALLOR
SPRINKLE, in some instances these increases may exceed the threshold for
the diagnosis of diabetes mellitus [see
Adverse Reactions (6.1)]. 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 important adverse reactions are
described below and elsewhere in the labeling:
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)]
Proteinuria and Hematuria [see Warnings and
Precautions (5.4)]
Increases in HbA1c and Fasting Serum Glucose Levels
[see Warnings and Precautions (5.5)]
6.1 Clinical
Trials Experience
Extensive
additions and/or revisions, please refer to label for complete information.
6.2 Postmarketing
Experience
Additions and/or revisions underlined:
…
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.
…
Skin and
Subcutaneous Tissue Disorders: drug reaction with eosinophilia and
systemic symptoms (DRESS), lichenoid drug eruption
7
Drug Interactions
7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with EZALLOR
Additions and/or revisions underlined:
Rosuvastatin is a substrate of CYP2C9 and
transporters (such as OATP1B1, BCRP). Rosuvastatin plasma levels can be
significantly increased with concomitant administration of inhibitors of CYP2C9
and transporters. Table 5 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with
EZALLOR SPRINKLE and instructions for preventing managing them or [see Warnings and Precautions (5.1) and
Clinical Pharmacology (12.3)].
Table 5: Drug Interactions that Increase the Risk
of Myopathy and Rhabdomyolysis with EZALLOR SPRINKLE
Please refer to label to view Table 5.
7.2 Drug Interactions that Decrease the Efficacy of EZALLOR SPRINKLE
Additions
and/or revisions underlined:
Table
6 presents drug interactions that may decrease the efficacy of EZALLOR SPRINKLE
and instructions for preventing or managing them.
Table
6: Drug Interactions that Decrease the Efficacy of EZALLOR SPRINKLE
Please
refer to label to view Table 6.
7.3 Rosuvastatin Effects on Other Drugs
Additions
and/or revisions underlined:
Table
7 presents rosuvastatin’s effect on other drugs and instructions for preventing
or managing them.
Table 7:
Rosuvastatin Effects on Other Drugs
Please
refer to label to view Table 7.
8
Use in Specific Populations
8.4 Pediatric Use
Additions and/or revisions underlined:
The safety and effectiveness of
rosuvastatin as an adjunct to diet to reduce LDL-C have been established in
pediatric patients 8 years of age and older with HeFH. Use of rosuvastatin for
this indication is based on one 12-week controlled trial with a 40-week
open-label extension period in 176 pediatric patients 10 years of age and older
with HeFH and one 2-year open-label, uncontrolled trial in 175 pediatric
patients 8 years of age and older with HeFH [see
Clinical Studies (14)]. In the 1-year
trial with a 12-week controlled phase, there was no detectable effect of
rosuvastatin on growth, weight, BMI (body mass index), or sexual maturation in
patients aged 10 to 17 years.
The safety and effectiveness of
rosuvastatin as an adjunct to other LDL-C-lowering therapies to reduce LDL-C
have been established pediatric patients 7 years of age and older with HoFH.
Use of rosuvastatin for this indication is based on a randomized,
placebo-controlled, cross-over study in 14 pediatric patients
7 years of age and older with HoFH [see Clinical
Studies (14)].
The safety and effectiveness of
rosuvastatin have not been established in pediatric patients younger than 8
years of age with HeFH, younger than 7 years of age with HoFH, or in pediatric
patients with other types of hyperlipidemia (other than HeFH or HoFH).
8.5 Geriatric Use
Additions and/or revisions underlined:
Of the total number of
rosuvastatin-treated patients in clinical studies, 3,159 (31%) were 65
years and older, and 698 (6.8%) were 75 years and older. No overall differences
in safety or effectiveness were observed between these subjects and younger
subjects.
Advanced age (greater than
or equal to 65 years) is a risk factor for rosuvastatin-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 EZALLOR SPRINKLE for the increased risk of
myopathy [see Warnings and
Precautions (5.1)].
8.6 Renal Impairment
Additions
and/or revisions underlined:
Rosuvastatin
exposure is not influenced by mild to moderate renal impairment (CLcr greater
than or equal to 30 mL/min/1.73 m2). Exposure to rosuvastatin is
increased to a clinically significant extent in patients with severe renal
impairment (CLcr <30 mL/min/1.73 m2) who are not receiving
hemodialysis [see Clinical Pharmacology (12.3)].
Renal
impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all
patients with renal impairment for development of myopathy. In patients with
severe renal impairment not on hemodialysis, the recommended starting dosage is
5 mg daily and should not exceed 10 mg daily [see
Dosage and Administration (2.5) and Warnings and Precautions (5.1)].
8.7 Hepatic Impairment
Additions
and/or revisions underlined:
EZALLOR
SPRINKLE is contraindicated in patients with acute liver failure or
decompensated cirrhosis. Chronic alcohol liver disease is known to increase
rosuvastatin exposure. Patients who consume substantial quantities of
alcohol and/or have a history of liver disease may be at increased risk
for hepatic injury [see
Contraindications (4), Warning and Precautions (5.3) and Clinical Pharmacology
(12.3)].
8.1 Pregnancy
Additions and/or revisions underlined:
Risk Summary
Discontinue EZALLOR SPRINKLE
when pregnancy is recognized. Alternatively, consider the ongoing
therapeutic needs of the individual patient.
patients based on the mechanism of action [see Clinical Pharmacology (12.1)]. In
addition, treatment of hyperlipidemia is not generally necessary during
pregnancy. Atherosclerosis is a chronic process and the discontinuation of
lipid-lowering drugs during pregnancy should have little impact on the outcome
of long-term therapy of primary hyperlipidemia for most patients. EZALLOR SPRINKLE decreases synthesis of cholesterol and possibly
other biologically active substances derived from cholesterol; therefore,
EZALLOR SPRINKLE may cause fetal harm when administered to pregnant.
Available data from case series and prospective and
retrospective observational cohort studies over decades of use with statins in
pregnant women have not identified a drug-associated
risk of major congenital malformations. Published data from prospective and
retrospective observational cohort studies with rosuvastatin use in pregnant
women are insufficient to determine if there is a drug-associated risk of
miscarriage (see Data).
In animal reproduction studies, no adverse
developmental effects were observed in pregnant rats or rabbits orally
administered rosuvastatin during the period of organogenesis at doses
that resulted in systemic exposures equivalent to human exposures at the
maximum recommended human dose (MRHD) of 40 mg/day, based on AUC and body
surface area (mg/m2) respectively (see Data).
…
Data
Human Data
A Medicaid cohort linkage study of 1,152
statin-exposed pregnant women compared to 886,996 controls did not find a
significant teratogenic effect from maternal use of statins in the first
trimester of pregnancy, after adjusting for potential confounders – including
maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco
use – using propensity score-based methods. The relative risk of congenital
malformations between the group with statin use and the group with no statin
use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37)
after controlling for confounders, particularly preexisting diabetes mellitus.
There were also no statistically significant increases in any of the organ-
specific malformations assessed after accounting for confounders. In the
majority of pregnancies, statin treatment was
initiated prior to pregnancy and was discontinued at some point in the first
trimester when pregnancy was identified. Study limitations include reliance
on physician coding to define the presence of a malformation, lack of control
for certain confounders such as body mass index, use of prescription dispensing
as verification for the use of a statin, and lack of information on non-live
births.
Animal Data
…
Rosuvastatin crosses the placenta in rats and
rabbits and is found in fetal tissue and amniotic fluid at 3% and 20%,
respectively, of the maternal plasma concentration following a single 25 mg/kg
oral gavage dose on gestation day 16 in rats. In rabbits, fetal tissue
distribution was 25% of maternal plasma concentration was observed in rabbits
after a single oral gavage dose of 1 mg/kg on gestation day 18.
8.2 Lactation
Additions and/or revisions underlined:
Risk Summary
Limited data from case reports in published literature indicate that rosuvastatin is present in human milk. There is no
available information on the effects of the drug on the breastfed infant or the
effects of the drug on milk production. Statins, including EZALLOR SPRINKLE,
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 EZALLOR SPRINKLE [see Use in Specific Populations (8.1) and Clinical Pharmacology
(12.1)].
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 and
Instructions for Use).
Myopathy and
Rhabdomyolysis
Advise
patients that EZALLOR SPRINKLE may cause myopathy and rhabdomyolysis. Inform
patients that the risk is also increased when taking certain types of
medication and they should discuss all medication, both prescription and over
the counter, with their healthcare provider. 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), and Drug Interactions (7.1)].
Hepatic
Dysfunction
Inform patients that EZALLOR SPRINKLE 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 EZALLOR SPRINKLE. Encourage patients to
optimize lifestyle measures, including regular exercise, maintaining a healthy
body weight, and making healthy food choices [see Warnings and Precautions
(5.5)].
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
EZALLOR SPRINKLE should be discontinued [see Use in Specific Populations
(8.1)].
Lactation
Advise patients that breastfeeding during treatment
with EZALLOR SPRINKLE is not recommended [see Use in Specific Populations
(8.2)].
…
Missed
Doses
If a dose is missed, advise patients not to take an
extra dose. Just resume the usual schedule [see Drug Interactions (2.1)].
PATIENT
INFORMATION
Extensive
additions and/or revisions, please refer to label for complete information.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Skeletal Muscle Effects
![]()
(Additions
underlined)
…
The risk of myopathy during treatment with
EZALLOR Sprinkle may be increased with concurrent administration of gemfibrozil,
some other lipid-lowering therapies (other fibrates or niacin),
cyclosporine, darolutamide, regorafenib, atazanavir/ritonavir, lopinavir/ritonavir,
simeprevir or combination of sofosbuvir/velpatasvir/voxilaprevir,
dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir,
sofosbuvir/velpatasvir,
glecaprevir/pibrentasvir, all combinations with
ledipasvir (including
ledipasvir/sofosbuvir) [see Dosage
and Administration (2) and Drug Interactions (7)].
![]()
…
5.2 Immune-Mediated Necrotizing Myopathy
(New
subsection added)
There have been rare reports of
immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated
with statin use. IMNM is characterized by: proximal muscle weakness and
elevated serum creatine kinase, 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. Consider
risk of IMNM carefully prior to initiation of a different statin. If therapy is
initiated with a different statin, monitor for signs and symptoms of IMNM.
7
Drug Interactions
7.3 Anti-viral Medications
(Subsection
revised; additions underlined)
Coadministration
of rosuvastatin with certain anti-viral drugs has differing effects on
rosuvastatin exposure and may increase risk of myopathy.
The
combination of sofosbuvir/velpatasvir/voxilaprevir which are anti-Hepatitis C virus (anti-HCV)
drugs, increases rosuvastatin exposure. Similarly, the combination of
ledipasvir/sofosbuvir may significantly increase rosuvastatin exposure. For
these combinations of anti-HCV drugs, concomitant use with EZALLOR Sprinkle is
not recommended.
Simeprevir
and combinations of dasabuvir/ombitasvir/paritaprevir/ritonavir,
elbasvir/grazoprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir which
are anti-HCV drugs, increase rosuvastatin exposure. Combinations of
atazanavir/ritonavir and lopinavir/ritonavir, which are anti-HIV-1 drugs,
increase rosuvastatin exposure [see Table
4 – Clinical Pharmacology (12.3)]. For these anti-viral drugs, the
dose of EZALLOR Sprinkle should not exceed 10 mg once daily.
The
combinations of fosamprenavir/ritonavir or tipranavir/ritonavir, which are anti-HIV-1
drugs, produce little or no change in rosuvastatin exposure. No dose
adjustment is needed for concomitant use with these combinations [see Dosage and Administration (2.3),
Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
7.4 Darolutamide
(New subsection added)
Darolutamide
increased rosuvastatin exposure more than 5 fold. Therefore, in patients taking
darolutamide, the dose of EZALLOR Sprinkle should not exceed 5 mg once daily [see Dosage and Administration (2.3),
Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
7.5 Regorafenib
(New subsection
added)
Regorafenib
increased rosuvastatin exposure and may increase the risk of myopathy. If used
together, the dose of EZALLOR Sprinkle should not exceed 10 mg once daily [see Dosage and Administration (2.3),
Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
(Additions underlined)
…
Tell your doctor
about all the medicines you take, including prescription and
over-the-counter medicines, vitamins, and herbal supplements. Talk to your
doctor before you start taking any new medicines.
…
Especially
tell your doctor if you take:
cyclosporine
(a medicine for your immune system)
gemfibrozil
(a fibric acid medicine for lowering cholesterol)
darolutamide (a medicine for the treatment of prostate
cancer)
regorafenib (a medicine used to treat cancer of the
colon and rectum)
anti-viral
medicines including HIV or hepatitis C virus drugs such as:
lopinavir,
ritonavir, fosamprenavir, tipranavir, atazanavir, simeprevir
combination of
sofosbuvir/velpatasvir/voxilaprevir
dasabuvir/ombitasvir/paritaprevir/ritonavir
elbasvir/grazoprevir
sofosbuvir/velpatasvir
glecaprevir/pibrentasvir
and
all other
combinations with ledipasvir including ledipasvir/sofosbuvir
…
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