AstraZeneca Crestor citizen petition 05 31 2016

Transcription

Case 1:16-cv-01336 Document 1-2 Filed 06/27/16 Page 1 of 79
ASTRAZENECA COMPLAINT (D.D.C.)
EXHIBIT B
May 31, 2016
By Electronic Filing
Food and Drug Administration
Division of Dockets Management (HFA-305)
5630 Fishers Lane, Room 1061
Rockville, Maryland 20852
RE:
Crestor® (rosuvastatin calcium) Pediatric Orphan Drug Exclusivity For
Treatment Of Pediatric Homozygous Familial Hypercholesterolemia
Dear Sir or Madam:
CITIZEN PETITION
AstraZeneca Pharmaceuticals LP and its affiliate iPR Pharmaceuticals, Inc. (collectively,
“AstraZeneca”) hereby submit this Citizen Petition pursuant to 21 U.S.C. § 355(q) and 21 C.F.R.
§ 10.30 to request that the Commissioner of Food and Drugs not approve any abbreviated new
drug application (“ANDA”) or section 505(b)(2) new drug application (“NDA”) referencing
Crestor® (rosuvastatin calcium) until the expiration of the orphan drug exclusivity for use of
Crestor® in the treatment of pediatric patients ages 7 to 17 with homozygous familial
hypercholesterolemia (“HoFH”).
Pediatric HoFH is a rare and extremely serious condition. If left untreated, HoFH causes
substantially elevated plasma cholesterol levels, which in turn lead to cardiovascular disease,
myocardial infarction, and premature death. As demonstrated in AstraZeneca’s Pediatric HoFH
Study (also known as HYDRA) and supplemental NDA (“sNDA”), No. 21-366/S-033, Crestor®
offers a safe and effective means for treating HoFH in pediatric patients. Crestor® statin therapy
helps reduce patients’ cholesterol levels, thereby helping prevent or delay the adverse
cardiovascular effects caused by HoFH. The Pediatric HoFH Study provides critical new
information on appropriate treatment for HoFH in children. On May 27, 2016, FDA approved
Crestor® “for treatment of pediatric patients 7 to 17 years of age with [HoFH] to reduce LDL-C,
total C, nonHDL-C and ApoB as an adjunct to diet, either alone or with other lipid-lowering
treatments.” Previously, on February 14, 2014, FDA’s Office of Orphan Products Development
granted AstraZeneca Orphan Drug Designation for Crestor® in the treatment of pediatric HoFH.
The Commissioner should grant this Citizen Petition for two principal reasons. First,
carving out AstraZeneca’s protected pediatric HoFH labeling from the labeling of a product
marketed under an ANDA or section 505(b)(2) NDA would present substantial safety and
efficacy risks. Although FDA may in some instances approve ANDAs that omit protected
pediatric labeling, FDA has made clear that a carve out is inappropriate when, as here, the
May 31, 2016
Page |2
protected pediatric labeling is “necessary for the safe use of the drug.”1 Crestor® is labeled for
treatment of HoFH in adult and pediatric patients, and for treatment of heterozygous familial
hypercholesterolemia (“HeFH”), a related but far less severe condition. In many instances, the
recommended dosage and course of treatment differ between adult HoFH and pediatric HoFH
patients, and likewise between HeFH and HoFH patients. Given these differences, there are
substantial risks that doctors would over- or under-treat pediatric HoFH patients if generic or
other rosuvastatin calcium omitted AstraZeneca’s protected pediatric HoFH labeling.
Second, irrespective of whether a carve out would present a safety risk, FDA lacks legal
authority to carve out pediatric labeling protected by orphan drug exclusivity. Together, the
Hatch-Waxman Act’s same-labeling requirement and FDA’s pediatric-labeling regulations
impose a categorical rule: pediatric labeling information subject to orphan drug exclusivity may
not be omitted from generic-drug labeling. The Best Pharmaceuticals for Children Act, 21
U.S.C. § 505A(o), permits the carve out of labeling protected only by patent and Hatch-Waxman
exclusivity—and therefore provides no basis for carving out labeling protected by orphan drug
exclusivity. FDA also possesses several other “general” carve-out authorities, see 21 C.F.R.
§§ 314.94(a)(8)(iv), 314.127(a)(7), but those authorities are inapposite in light of FDA’s
subsequently adopted pediatric-labeling rules and Congress’s enactment of section 505A(o).
Indeed, prior to the passage of section 505A(o), FDA concluded that it lacked authority to carve
out protected pediatric labeling in circumstances nearly identical to those presented here. FDA
and the United States District Court for the District of Maryland concluded in the Otsuka
litigation that FDA has authority to carve out pediatric labeling protected by orphan drug
exclusivity. However, that conclusion is incorrect for the reasons given above and in Part II.B of
this Citizen Petition.
ACTIONS REQUESTED
AstraZeneca respectfully requests that the Commissioner:
(1)
1
Determine that the labeling for any rosuvastatin calcium product must include the
pediatric orphan HoFH indication and prescribing information, including all data
and information derived from AstraZeneca’s Pediatric HoFH Study supporting
approval of the Crestor® pediatric orphan drug sNDA, to ensure the safe and
effective use of the product in pediatric HoFH patients; and
Letter from John R. Peters, M.D., Acting Director, Office of Generic Drugs, Center for Drug Evaluation
and Research, to Ralph S. Tyler, Venable LLP, at 10 n.27 (Apr. 27, 2015) (“Otsuka Letter”); see also id.
at 14 (labeling must be included “where carving it out would present a safety risk to pediatric patients
using the drug for its approved (non-protected adult) indication”).
May 31, 2016
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(2)
Refrain from approving any ANDA or section 505(b)(2) NDA referencing
Crestor® on or before May 27, 2023, if the labeling of the proposed product omits
the pediatric orphan HoFH labeling, including all data and information derived
from the Pediatric HoFH Study supporting approval of the Crestor® pediatric
orphan drug sNDA, which is protected by orphan exclusivity.
STATEMENT OF GROUNDS
I.
BACKGROUND
A. Background On The Development Of Rosuvastatin
Rosuvastatin is a synthetic 3-hydroxy-3-methylglutaryl coenzyme A (“HMG CoA”)
reductase inhibitor and a member of the statin class of lipid-lowering agents. Rosuvastatin is a
selective, potent, and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme
that converts HMG-CoA to mevalonate, a precursor of cholesterol. Rosuvastatin produces its
lipid-modifying effects in two ways: (i) it increases the number of hepatic cell surface lowdensity lipoprotein (“LDL”) receptors, enhancing uptake and catabolism of LDL; and (ii) it
inhibits the hepatic synthesis of very low-density lipoproteins (“VLDL”), thereby reducing both
VLDL and LDL. In an extensive clinical study program involving over 60,000 subjects, more
than 35,000 subjects received rosuvastatin and nearly 400 of these (not including the recent
Pediatric HoFH Study) subjects were children or adolescents. The clinical study program
demonstrated that rosuvastatin is a highly efficacious statin and favorably modifies plasma levels
of lipids, lipoproteins, and their ratios in adults and in pediatric patients with HeFH—a related,
but more common and far less serious condition—ages 6 to 17.
Crestor® (rosuvastatin calcium) was first approved for marketing in the Netherlands on
November 6, 2002. In the United States, Crestor® was approved for use in adult patients with
dyslipidemia, including HoFH, on August 12, 2003 (NDA 21-366). On October 15, 2009, based
on the results of Study D3561C00087 (also known as PLUTO), Crestor® was approved for the
treatment of HeFH in adolescent boys and postmenarchal girls, ages 10 to 17, to reduce total
cholesterol (“TC”), LDL-C, and Apolipoprotein B (“ApoB”) with a recommended dosing range
of 5 to 20 mg once daily. Based on the results of Study D3561C00002 (also known as
CHARON), AstraZeneca submitted a sNDA, No. 21-366/S-031, to support an expansion of the
age range for the HeFH indication to pediatric patients ages 8 to 17, with a recommended dosing
range of 5 to 10 mg once daily in patients 8 to less than 10 years old and 5 to 20 mg once daily in
patients 10 to 17 years old. In Europe, the dossier supporting the expanded age range of 6 to
17 years for the HeFH indication received approval from the Committee for Medicinal Products
for Human Use in April 2014, and the approval was adopted by the European Commission in
June 2014. In the United States, FDA approved AstraZeneca’s sNDA 21-366/S-031 on
November 20, 2015.
May 31, 2016
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In markets where Crestor® was approved prior to approval of the pediatric orphan drug
HoFH sNDA, it is indicated for one or more of the following indications: treatment of patients
with primary hypercholesterolemia (heterozygous familial and nonfamilial), mixed dyslipidemia,
primary dysbetalipoproteinemia, and isolated hypertriglyceridemia, as an adjunct to diet when
response to diet and exercise is inadequate. Crestor® also is indicated for the treatment of adult
patients with HoFH, either alone or as an adjunct to diet and other lipid-lowering treatments
(e.g., LDL-apheresis), and to reduce TC, LDL-C, and ApoB in children and adolescents ages 8 to
17 with HeFH. In some markets, rosuvastatin is approved to slow progression of atherosclerosis
and/or reduce the risk of major cardiovascular events.
In 2013, AstraZeneca executed an settlement agreement with Watson Laboratories, Inc.
(“Watson”) that granted Watson the ability to market generic rosuvastatin beginning on May 2,
2016. Watson began marketing its generic rosuvastatin product on or about May 2, 2016, and
has continued to market that product through the date of this Citizen Petition. As required under
the terms of the March 2013 settlement agreement, AstraZeneca has granted Watson a patent
license and a selective waiver of all periods of exclusivity applicable to FDA’s May 27, 2016,
approval of the pediatric HoFH indication and labeling with respect to Watson’s marketing of its
generic rosuvastatin product.2
B. Background On Homozygous Familial Hypercholesterolemia (HoFH)
HoFH adversely affects day-to-day functioning, morbidity, and mortality.3 If left
untreated, HoFH progresses from a serious condition to a severe condition and eventually leads
to premature death. Typically, children with HoFH have substantially elevated plasma
cholesterol levels and are predisposed to premature and progressive atherosclerotic
cardiovascular disease (Cuchel, et. al 20144). In the pediatric HoFH patient population, the
accumulation of cholesterol begins at birth and produces increasingly severe clinical
manifestations. Angina pectoris, myocardial infarction, and death in early childhood have been
reported, although the first major cardiovascular events usually occur during adolescence
(Wiegman, et. al 20155). Pediatric HoFH patients often develop accumulation of cholesterol in
2
See Exhibit A, Declaration of Sarah Walters ¶¶ 3–7 (“Walters Decl.”).
See Exhibit B, Declaration of Gregory F. Keenan, MD ¶¶ 4–6 (“Keenan Decl.”).
4
Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, et al.; European Atherosclerosis
Society Consensus Panel on Familial Hypercholesterolemia. Homozygous familial hypercholesterolemia:
new insights and guidance for clinicians to improve detection and clinical management. A position paper
from the Consensus Panel on Familial Hypercholesterolemia of the European Atherosclerosis Society.
Eur. Heart J. 2014 Aug 21; 35(32):2146-2157.
5
Wiegman A, Gidding SS, Watts GF, et al. Familial hypercholesterolemia in children and adolescents:
gaining decades of life by optimizing detection and treatment. Eur. Heart J. 2015 May 25 (Epub ahead of
print). doi:10.1093/eurheartj/ehv157.
3
May 31, 2016
Page |5
other parts of the body leading to cutaneous xanthomas within the first four years of life,
commonly serving as the first clue for diagnosis. Cholesterol retention in the arterial wall and
foam cell formation within the intima of arteries typically progresses to occlusive atherosclerosis
with angina pectoris and/or plaque rupture resulting in thrombotic occlusion of the coronary
artery (i.e., myocardial infarction). As a result, patients develop clinically significant
cardiovascular disease in early childhood, often leading to premature coronary death before the
patient turns 30 years old in untreated individuals (Nordestgaard et al 2013;6 Wierzbicki 20137).
The figure below depicts the concept of cumulative cholesterol burden in this pediatric orphan
population:
Fig. 1: LDL-C burden in individuals with or without familial hypercholesterolemia as a function of the age of
initiation of statin therapy. Data derived from Huijgen et al. and Starr et al. Abbreviations: LDL, low-density
lipoprotein; LDL-C, LDL cholesterol; HDL-C, high-density lipoprotein cholesterol; CHD, coronary heart disease;
FH, familial hypercholesterolemia.
Compared to healthy children, the day-to-day functioning of children with HoFH is
significantly impaired. Cholesterol deposits in the tendons and joints may lead to tendinitis and
joint pain, which impairs patients’ quality of life (Cuchel et al. 2014). Non-pharmacological
intervention includes lipoprotein apheresis, beginning at an early age.8 Typically lipoprotein
apheresis treatments take two to four hours and must be repeated every one to two weeks. The
children participating in the Pediatric HoFH Study who were treated with apheresis were all
6
Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. Familial
hypercholesterolemia is underdiagnosed and undertreated in the general population: guidance for
clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis
Society. Eur. Heart J. 2013; 34 (45):3478-90a.
7
Wierzbicki AS. Homozygous Familial Hypercholesterolemia. Clin. Lipidology. 2013;8(4):407-409.
8
See Keenan Decl. ¶ 8.
May 31, 2016
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scheduled to be on weekly apheresis treatments. Another non-pharmacological approach to
treatment of HoFH is liver transplantation (Goldberg et al 20119), which requires a suitable
donor organ and carries with it the complications of transplant surgery and recovery.
Recent guidance from the European Atherosclerosis Society Consensus Panel on Familial
Hypercholesterolemia focused on early diagnosis and treatment of patients with HoFH
(Cuchel et al 2014). The Panel recommended lifestyle intervention and maximal statin therapy
as the mainstays of treatment starting in the first year after a patient is diagnosed with HoFH.
The Panel also supported the addition of ezetimibe and recommended lipoprotein apheresis
starting by age 5, although, other than Crestor®, neither statin nor ezetimibe therapies are
approved for the treatment of pediatric patients with HoFH.
HoFH is related to HeFH, a more common and less serious form of familial
hypercholesterolemia.10 In contrast to HoFH, which arises when a patient inherits altered
hypercholesterolemia-causing genes from both parents, HeFH arises when a patient inherits an
altered hypercholesterolemia-causing gene from only one parent.11 HeFH is characterized by
elevated LDL-C levels that cause atherosclerotic plaque deposition in arteries and an increased
risk of coronary artery disease. Treatment for HeFH consists largely of dietary modification and
statin therapy—often in conjunction with ezetimibe, gemfibrozil, fenofibrate, or similar drugs.
Reflecting the substantial difference in disease severity, a lower daily dosage is recommended
for some patients with HeFH than patients of the same age with HoFH. For example, Crestor®’s
label indicates that the dosage range for HeFH patients ages 8 to less than 10 is 5 to 10 mg once
daily, whereas the dosage for HoFH patients in the same age range is 20 mg once daily.12 Larger
doses of rosuvastatin may be required for pediatric HoFH patients because these patients tend to
show 50 percent less response on LDL-C and are at a much greater risk of a cardiac event early
in life than patients with HeFH.13
9
Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, et al. Familial
hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical
guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J. Clin.
Lipidol 2011;5:133–140.
10
See Keenan Decl. ¶¶ 8–10.
11
Whereas HeFH affects approximately one in 500 people, HoFH is “extremely rare” and affects only
approximately one in one million people. See George Yuan, Jian Wang, & Robert A. Hegele,
Heterozygous familial hypercholesterolemia: an underrecognized cause of early cardiovascular disease,
Canadian
Medical
Ass’n
J.
(Apr.
11,
2006),
available
at
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1421462/.
12
See Keenan Decl. ¶¶ 9, 17. A copy of the current FDA-approved Crestor® label is attached as Exhibit 1
to the Keenan Declaration.
13
See id. ¶ 25.
May 31, 2016
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C. Background On The Development Of Rosuvastatin For Use In The Treatment
Of The Pediatric Orphan HoFH Population
In 2014, AstraZeneca initiated a trial of rosuvastatin in pediatric patients with HoFH ages
6 to 17 to address unmet medical needs of pediatric HoFH patients. Among other things, the
study focused on the greater degree of LDL-C reduction demonstrated with rosuvastatin
compared to some of the other approved statins in previous clinical studies of adults. This study,
No. D3561C00004, is referred to herein as the HYDRA study or the Pediatric HoFH Study, and
is formally entitled “A Randomized, Double-blind, Placebo-controlled, Multi-center, Cross-over
Study of Rosuvastatin in Children and Adolescents (aged 6 to <18 years) with Homozygous
Familial Hypercholesterolemia (HoFH).”
A critical question in designing the Pediatric HoFH Study concerned the appropriate
dosing regimen to study for pediatric HoFH patients, taking into account both the need for
adequate dosing to achieve efficacy and the potential safety risks to pediatric patients associated
with increased dosages. When AstraZeneca discussed the Pediatric HoFH Study design with
drug review personnel in the Division of Metabolism and Endocrinology Protections of FDA’s
Center for Drug Evaluation and Research, the FDA personnel inquired whether the Pediatric
HoFH Study should include doses of up to 40 mg. In response, AstraZeneca presented its views
that 20 mg was an appropriate dose for pediatric HoFH patients, and that there was insufficient
safety data on higher doses (including the 40 mg dose) to justify a change in study design.
Following further discussions of this issue, the Pediatric HoFH Study proceeded and evaluated
the 20 mg dose.14
In the Pediatric HoFH Study, rosuvastatin was studied in a randomized, double-blind,
placebo-controlled, multicenter, cross-over study with 20 mg once daily versus placebo (once
daily) in 14 children and adolescents (ages 6 to 17) with HoFH. The study design included an
active 4-week dietary lead-in phase during which all patients were treated with rosuvastatin 10 or
20 mg, a cross-over phase that included a six-week treatment period with rosuvastatin 20 mg
preceded or followed by a six-week placebo treatment period, and a 12-week maintenance phase
during which all patients were treated with rosuvastatin 20 mg. Patients who entered the study
on ezetimibe or apheresis therapy were permitted to continue the treatment throughout the
study.15
The Pediatric HoFH Study met its primary objective. In particular, the study identified a
clinically meaningful reduction in LDL-C among patients in the study group. The LS mean
relative difference in LDL-C after six weeks of treatment with rosuvastatin 20 mg compared to
placebo was -22.3 percent (absolute difference: -85.4 mg/dL; -2.2 mmol/L) in pediatric HoFH
14
15
See id. ¶¶ 15–16.
See id. ¶ 17.
May 31, 2016
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patients. This treatment effect was statistically significant (p=0.005). In treating HoFH, LDL
cholesterol is the primary target of therapy. The reduction in both cardiovascular and total
mortality is proportional to the degree of LDL cholesterol reduction (based on meta analysis of
the results of large, lipid lowering outcome studies in the general population), with every 1
mmol/L reduction being associated with a corresponding 22 percent reduction in cardiovascular
mortality and a 12 percent reduction in total mortality over five years. (Baigent et al 2010,16
Nordestgaard et al 2013,17 CTT Collaborators 2005,18 CTT Collaborators 2010,19 CTT
Collaborators 2012.20) Therefore, the magnitude of effect observed in the Pediatric HoFH Study
represents a clinically meaningful reduction in LDL-C among pediatric HoFH patients.
The levels of LDL-C observed after six weeks of treatment with rosuvastatin 20 mg were
maintained over a 12- to 18-week period. A positive treatment effect was seen across both of the
analyzed subgroups: males and females, and patients treated and not treated with apheresis. The
treatment effect on LDL-C was similar for males (-24.2%) and females (-20.1%). The treatment
effect was greater in patients not being treated with apheresis (-26.3%) than in those who were
treated with apheresis (-18.7%).
The Pediatric HoFH Study also met each of its key secondary objectives. Statistically
significant (p<0.05) LS mean relative differences in TC (-20.1%), non-HDL-C (-22.9%), and
ApoB (-17.1%) were observed in pediatric HoFH patients following six weeks of treatment with
rosuvastatin 20 mg versus placebo.
Positive treatment effects were also seen for HDL-C, TG, LDL-C/HDL-C, TC/HDL-C,
non-HDL-C/HDL-C, Apolipoprotein A-1 (“ApoA-1”), and ApoB/ApoA-1 following six weeks
of treatment with rosuvastatin 20 mg versus placebo in pediatric HoFH patients, with nominally
16
Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and safety of more
intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26
randomised trials. Lancet 2010;376:1670-1681.
17
Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al.
Familial hypercholesterolemia is underdiagnosed and undertreated in the general population: guidance for
clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis
Society. Eur. Heart. J. 2013;34 (45):3478-90a.
18
Cholesterol Treatment Trialists’ Collaborators. Efficacy and safety of cholesterol-lowering treatment:
prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet
2005;366:1267-1278.
19
Cholesterol Treatment Trialists’ Collaborators. Efficacy and safety of more intensive lowering of LDL
cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet
2010;376:1670–1681.
20
Cholesterol Treatment Trialists’ Collaborators. The effects of lowering LDL cholesterol with statin
therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised
trials. Lancet 2012; 380:581–590.
May 31, 2016
Page |9
significant differences for all parameters except HDL-C and ApoA-1. These levels also were
maintained over a 12- to 18-week period of treatment with rosuvastatin.
In addition, as detailed in AstraZeneca’s pediatric orphan drug HoFH sNDA, in the eight
children and adolescents patients (ages 8 to 17) from the forced-titration open label study (Study
54) with HoFH, the reduction in LDL-C (21%), TC (18.6%), and non-HDL-C (20.2%) from
baseline following six weeks of treatment with rosuvastatin 20 mg was consistent with that
observed in the Pediatric HoFH Study.
D. AstraZeneca Diligently Pursued The Pediatric Orphan Drug HoFH
Development Program And Approval Of The Crestor® Pediatric Orphan Drug
HoFH sNDA
AstraZeneca diligently pursued each of the clinical and regulatory processes that provide
the basis for this Citizen Petition.21
1. The Orphan Drug HoFH sNDA. AstraZeneca filed its Crestor® pediatric orphan drug
HoFH sNDA on July 27, 2015—shortly after completion of the successful Pediatric HoFH
Study. To expedite the approval process, AstraZeneca filed a request for priority review of its
sNDA that fully met all FDA required criteria. See NDA 21-366/S-033 § 1.2.1. That request
showed that the Pediatric HoFH Study and its results meet the criteria for priority review set
forth in FDA’s Guidance for Industry Expedited Programs for Serious Conditions – Drugs and
Biologics (May 2014). Nevertheless, FDA informed AstraZeneca on October 9, 2015, that the
sNDA would receive standard, rather than expedited, review.22
AstraZeneca sought reconsideration of FDA’s decision not to grant priority review, and
requested in the alternative that FDA consider reviewing the application on an expedited basis
through the standard review process.23 In support of this request, AstraZeneca:
21
•
highlighted the policies and procedures for review of NDAs outlined in FDA’s
Manual of Policies and Procedures (MAPP 6020.3 Rev. 2), noting that supplemental
applications that propose labeling changes in accordance with a final pediatric study
report will automatically receive a priority review designation;
•
indicated that the pediatric orphan drug HoFH sNDA falls within a broad class of
pediatric applications for which the MAPP strongly encourages priority review; and
See id.¶ 19.
23
See id.
22
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•
showed that, following approval of REPATHA (evolocumab), approval of
rosuvastatin would address the significant treatment gap that still remained for
pediatric HoFH patients ages 6 to 12, as well as providing alternative and/or effective
combination treatment for pediatric HoFH patients ages 13 to 17.
Despite these arguments, FDA did not reconsider its initial review classification decision and
kept AstraZeneca’s pediatric orphan drug HoFH sNDA on a standard review track.24
FDA approved AstraZeneca’s pediatric orphan drug sNDA on May 27, 2016.25 This
approval will enable a significant improvement in the treatment of an orphan population for which
no statin therapy was previously approved. Indeed, even following the approval in 2015 of
REPATHA as an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL
apheresis) for the treatment of patients with HoFH who require additional lowering of LDL-C,
there were no approved statins for treatment of pediatric HoFH patients under age 13 prior to
FDA’s approval of AstraZeneca’s pediatric orphan drug sNDA in 2016.26
2. Crestor® Pediatric HoFH Labeling. AstraZeneca submitted a draft revised Crestor®
label with its sNDA, reflecting the pediatric HoFH indication being sought. In an additional
effort to accelerate the approval process, AstraZeneca followed up with FDA on May 2, 2016,
May 5, 2016, and on other occasions. On May 12, 2016, FDA forwarded a revised draft of the
Crestor label to AstraZeneca. AstraZeneca responded with a further revised draft Crestor® label
five days later, on May 17, 2016, and remained in regular contact with FDA through approval of
the label on May 27, 2016.27
3. Orphan Designation and Exclusivity. AstraZeneca applied for orphan designation for
Crestor® for the treatment of pediatric HoFH in November 2013. FDA granted that designation
on February 14, 2014. FDA’s approval of the pediatric HoFH sNDA thus triggers a grant of
seven years of orphan exclusivity to the new labeling, extending from May 27, 2016, to May 27,
2023.
*
*
*
In view of these efforts, AstraZeneca requests that FDA expedite its consideration of this
Citizen Petition and ensure that the issues raised herein are fully considered before FDA issues a
final approval determination with respect to ANDAs or section 505(b)(2) NDAs that reference
Crestor®.
24
See id.
See id. ¶ 17.
26
See id. ¶ 7.
27
See id. ¶ 19.
25
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II.
ARGUMENT
A. FDA May Not Carve Out AstraZeneca’s Protected Labeling Because Doing So
May Present Serious Safety and Efficacy Risks
FDA has adopted a safety and efficacy policy (the “Policy”) that squarely applies to
AstraZeneca’s protected pediatric HoFH labeling. Under the Policy, a generic drug is
“misbranded” and “will not [be] approve[d]” where
1. the reference-listed drug “is approved in adults and pediatric patients for the same
indication”;
2. “the pediatric information is protected by exclusivity and is significantly different
from the information regarding use in adults for the same indication”; and
3. “a carve-out of [the] pediatric information while the adult information is retained
in the ANDA labeling may result in a potential safety risk to pediatric patients.”
Otsuka Letter at 10.28
FDA highlighted three key aspects of the Policy last year in response to a citizen petition
filed by Otsuka Pharmaceutical.29 FDA first reasoned that generic applications may not be
approved so long as a carve out “may result in a potential safety risk.” Id. (emphases added).
This language errs on the side of safety and makes clear that certainty is not required. Rather,
the proper question is whether there is a meaningful prospect that a carve out would give rise to a
safety or efficacy risk.
The Otsuka Letter also notes that the Policy operates independently of the Agency’s
general carve-out regulations. Hence, a generic drug is not “considered safe and effective” if the
three criteria set forth above are met “even though the drug is otherwise subject to a carve out
under section 505(j)(2)(A)(v) of the [FDCA], and 21 CFR 314.92(a)(1), 314.94(a)(8)(iv) and
314.12(a)(7).” Id. at 10 (emphasis added).
Finally, the third criterion focuses on whether, when considering “both the information
that will be carved out and the information that will remain in the labeling once the carve out is
implemented,” the resulting label “would present a safety risk to pediatric patients using the drug
for its approved (non-protected adult) indication.” Id. at 14.30 According to the Otsuka Letter,
28
These same considerations should apply to a section 505(b)(2) product.
Otsuka’s citizen petition concerned Abilify (aripiprazole), a drug approved for treatment of Tourette’s
Disorder in pediatric patients, and for which Otsuka had obtained both Hatch-Waxman and orphan drug
exclusivity for the pediatric treatment data. See Otsuka Letter at 1, 13–15.
30
FDA also applies a comparative analysis, under which a carve out is impermissible if it “render[s] the
29
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“[t]he Glucophage precedent” illustrates how this comparison test works in practice. Id. at 10
n.27. Bristol Myers Squibb (“BMS”), Glucophage’s sponsor, conducted pediatric studies for an
indication for which Glucophage had already been approved in adults. These studies earned
BMS three years of Hatch-Waxman exclusivity for the resulting pediatric labeling. FDA
contends that it declined to
approve an ANDA for Glucophage even for the adult indication until the expiry
of the three-year exclusivity resulting from the pediatric studies because the
agency concluded that, given that the drug was approved for the same indication
in adults, the pediatric information was necessary for the safe use of the drug and
therefore could not be carved out.
Id. “As a result, the exclusivity awarded for the pediatric information provided a de facto
exclusivity for use of the drug in all populations.” Id.31 In contrast, Otsuka was not entitled to
the same “de facto exclusivity” because the label for its drug, Abilify (aripiprazole), “include[d]
no dosing information for Tourette’s Disorder in adults” and therefore failed the first of the
Policy’s three criteria. Id. at 14. In other words, once Abilify’s pediatric labeling was carved
out, there was no risk that a doctor would rely on adult dosing information when prescribing
generic aripiprazole to pediatric patients.
Unlike Abilify, Crestor® meets all three of the Policy’s criteria and is therefore entitled to
de facto exclusivity for the duration of AstraZeneca’s seven-year period of orphan drug
exclusivity.
Crestor® satisfies the Policy’s first criterion because it is approved for treatment of HoFH
in adults and pediatric patients ages 7 to 17. This approval distinguishes Crestor® from Abilify
and places Crestor® in the same position as Glucophage.
Crestor® meets the Policy’s second criterion because its labeling for treatment of
pediatric HoFH is protected by seven-year orphan drug exclusivity. This pediatric HoFH
labeling is significantly different from the labeling regarding treatment of HoFH in adult
patients, as illustrated in the table below. Whereas the dose range for adult HoFH patients “is 5
to 40 mg orally once daily” and the “usual starting dose in adult patients . . . is 20 mg once
daily,” Label § 2.1 (emphasis added), the only approved dose for pediatric HoFH patients “is 20
mg orally once daily,” id. § 2.2. Moreover, Crestor®’s label states that the 40 mg dose may be
used “for those patients who have not achieved their LDL-C goal utilizing the 20 mg dose,” and
proposed drug product less safe or effective than the listed drug for all remaining, nonprotected
conditions of use.” 21 C.F.R. § 314.27(a)(7) (emphasis added).
31
Notably, the Otsuka Letter fails to cite agency memoranda to support this account of its reasoning
regarding the Glucophage precedent. Instead, the Otsuka Letter points to a single page of the
Congressional Record as support for FDA’s interpretation of the Policy.
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that “[a]bout one third of the patients” in a prior study “benefited from increasing their dose from
20 mg to 40 mg, with further [cholesterol] lowering of greater than 6%.” Label §§ 2.1, 14.5
Dosage
Other
Information
HoFH - Adults
20 mg daily
recommended
starting dose;
40 mg dose
recommended for
patients who have
not achieved their
LDL-C goal
utilizing the 20 mg
dose
About one third of
patients in prior
study benefitted
from increasing
their dose from 20
mg to 40 mg
HoFH - Pediatrics
20 mg daily
recommended
dose for patients 7
to 17 years old
HeFH - Adults
5 to 40 mg daily
(based on general
dosing)
HeFH - Pediatrics
5 to 10 mg daily
for patients 8 to
less than 10 years
old; 5 to 20 mg
daily for patients
10 to 17 years old
Patients should be
titrated upwards
from starting 5 mg
dose to a
maximum dosage
of 20 mg once
daily
Fig. 2: Summary table of Crestor® current labeling information. Shaded material subject to seven-year orphan drug
protection. Source: Label §§ 2.1–2.2, 14.5.
As to the third criterion, there is strong evidence that carving out AstraZeneca’s protected
pediatric HoFH labeling “may result in a potential safety risk to pediatric patients.” Otsuka
Letter at 10. The attached declaration of Gregory Keenan, MD, a clinician familiar with the
Pediatric HoFH Study and with expertise in treatment of pediatric patients and pharmaceutical
development, bears this out in four principal ways.32
First, a carve out may lead specialists to over-treat pediatric HoFH patients. For
example, without access to AstraZeneca’s protected pediatric HoFH labeling, a specialist might
prescribe rosuvastatin doses in excess of 20 mg (the amount recommended in the protected
labeling) based on the adult HoFH indication, which ranges up to 40 mg. This risk is particularly
acute because Crestor®’s unprotected labeling states that the recommended “starting dose” for
adult patients is 20 mg and that an increased 40 mg dose may be used for patients who have not
achieved their LDL-C goal utilizing the 20 mg dose. Label § 2.1 (emphasis added). Physicians
might also over-treat pediatric HoFH patients based on the unprotected label’s statement that
32
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“[a]bout one third of the patients” in a recent study “benefited from increasing their dose from 20
mg to 40 mg, with further [cholesterol] lowering of greater than 6%.” Label § 14.5.33
Specialists may also be prone to over-treat pediatric HoFH patients by adjusting upward
from the dose for pediatric HeFH—a related but much less serious condition—recited in
Crestor®’s labeling.34 Specialists may take this course based on the knowledge that HoFH
patients are 50 percent less responsive to statin treatment than HeFH patients, and that pediatric
HoFH patients are at a much greater risk of a cardiac event early in life than HeFH patients.35
Second, a carve out may cause generalist doctors with limited experience in treating
HoFH to under-treat their pediatric patients. For example, a generalist might prescribe below the
protected 20 mg dosage based on the lower dose ranges for pediatric HeFH in Crestor®’s
labeling.36
Third, there is a risk that children ages 7 to 9 will be undertreated if AstraZeneca’s
protected pediatric HoFH data is carved out, because the Crestor® label recommends titrating
upwards from a 5 mg starting dose to a 10 mg dose for HeFH patients ages 8 to less than 10, and
titrating upwards from a 5 mg starting dose to a maximum dose of 20 mg for HeFH patients ages
10 to 17.37 In comparison, the protected pediatric labeling states that the recommended dose for
pediatric HoFH patients ages 7 to 17 is 20 mg. See Label § 2.2. Indeed, while the protected
labeling includes information on treatment of 7-year old HoFH patients, the HeFH labeling
includes no information at all about the treatment of 7-year olds.
Fourth, if the Pediatric HoFH Study information is omitted from the labeling for
rosuvastatin products other than Crestor®, the resulting safety risk would not be cured by a
general disclaimer referring to the existence of pediatric-use information in Crestor®’s labeling.
Such a disclaimer currently appears on the labeling for a licensed generic rosuvastatin product
marketed by Watson. Specifically, the Watson disclaimer states that
Pediatric use information for patients ages 8 to less than 10 years is approved for
AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets. However, due to
33
Crestor®’s unprotected labeling states that 20 percent (8 of 40) of the patients in this study were ages 8
to 17, thus providing a further risk that specialists may over-treat by prescribing 40 mg for pediatric
HoFH patients.
34
Crestor®’s label recommends a dose of 5 to 10 mg once daily for pediatric HeFH patients age 8 to less
than 10, and a dose of 5 to 20 mg once daily for pediatric HeFH patients age 10 to 17. In comparison, the
protected labeling recommends a dose of 20 mg once daily for all pediatric HoFH patients. Label § 2.2.
35
36
See id. ¶ 26.
37
See id. Some pediatric HeFH patients achieve treatment goals at doses below 20 mg, in which case the
20 mg dose of Crestor® is not administered. Id. ¶ 9.
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AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with
that pediatric information.
This language is based on the omission of labeling for pediatric HeFH, and will be understood as
a reference to the pediatric HeFH labeling in Crestor® given that the age range of patients ages 8
to less than 10 years tracks to the information in the Crestor® labeling for pediatric HeFH.38 The
disclaimer makes no reference to HoFH and omits 7-year olds altogether, who are within the
approved pediatric HoFH population. The disclaimer thus does not alert the physician to the
omission of critical information on use in pediatric HoFH.39
These risks present serious safety and efficacy concerns. Over-treatment of a pediatric
HoFH patient could lead to severe skeletal muscle effects (e.g., myopathy and rhabdomyolysis)
or acute renal failure. See Label § 5.1. The risk that physicians treating pediatric HoFH patients
will exceed the 20 mg dose shown effective in the Pediatric HoFH Study is exacerbated by the
severe potential consequences of inadequate treatment of HoFH, and the understanding that
HoFH patients generally have a lower and more unpredictable response to statin therapy.40 On
the other hand, under-treatment could allow the disease to progress rapidly, resulting in
accelerated onset of cardiovascular disease and increased risk of angina pectoris or myocardial
infarction.41
Because Crestor® satisfies all three of the criteria set forth in the Otsuka Letter,
AstraZeneca is entitled to “de facto exclusivity for use of the drug in all populations.” Otsuka
Letter at 10 n.27. Indeed, failure to grant AstraZeneca the benefit of this Policy would constitute
an unexplained departure from past agency practice, in violation of the Administrative Procedure
Act. See Ramaprakash v. FAA, 346 F.3d 1121, 1124–25 (D.C. Cir. 2003).
Although FDA relied in part on the Best Pharmaceuticals for Children Act (“BPCA”),
21 U.S.C. § 505A(o), in denying Otsuka’s citizen petition, that statute does not provide carve-out
authority, or authority to add a pediatric labeling disclaimer,42 here because it unambiguously
38
As required under the terms of the March 2013 settlement agreement, AstraZeneca granted Watson a
waiver of its Crestor® orphan drug exclusivity rights on May 31, 2016. See Walters Decl. ¶ 7. As a
result, the labeling for Watson’s generic rosuvastatin product includes (or will soon include) the key
Pediatric HoFH Study information described above. Id. ¶ 8.
39
See Id. ¶ 27.
40
Id. ¶ 24.
41
See id. ¶ 26.
42
Where section 505A(o) does apply, it authorizes FDA after carving out protected labeling to include an
affirmative disclaimer statement in the labeling to alert prescribers that the drug is not labeled for
pediatric use and to include “a statement of any appropriate pediatric contraindications, warnings,
precautions, or other information that the Secretary considers necessary to assure safe use.” 21 U.S.C.
§ 355a(o)(2).
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applies to labeling protected only by patent and Hatch-Waxman exclusivity. In particular,
section 505A(o)(1) provides that
A drug for which an application has been submitted or approved under section
355(j) of this title shall not be considered ineligible for approval under that
section or misbranded under section 352 of this title on the basis that the labeling
of the drug omits a pediatric indication or any other aspect of labeling pertaining
to pediatric use when the omitted indication or other aspect is protected by patent
or by exclusivity under clause (iii) or (iv) of section 355(j)(5)(F) of this title.
21 U.S.C. § 355A(o)(1) (emphasis added).
AstraZeneca’s pediatric HoFH labeling is not protected only “by patent or by exclusivity
under” 21 U.S.C. § 355(j)(5)(F). Instead, it is protected by orphan drug exclusivity, which arises
from section 355cc(a) of the FDCA—a provision not mentioned in any way in section 505A(o).
See 21 U.S.C. § 360cc(a) (providing seven years of exclusivity for drugs approved to treat “a
rare disease or condition”). Because section 505A(o)’s text is plain and unambiguous, FDA’s
“‘sole function . . . is to enforce [the statute] according to its terms.’” Sebelius v. Cloer, 133 S.
Ct. 1886, 1896 (2013) (quoting Hartford Underwriters Ins. Co. v. Union Planters Bank, N.A.,
530 U.S. 1, 6 (2000)).
FDA has consistently read section 505A(o) according to its plain terms. Immediately
following BPCA’s passage in 2002, FDA stated in response to a citizen petition filed by BMS
that section 505A(o) addresses pediatric labeling only protected by “patent exclusivity” or “3year exclusivity under section 505(j)(5)(D)(iii) & (iv) of the [FDCA].” Letter from Dennis E.
Baker, Associate Commissioner for Regulatory Affairs, to C. Boyden Gray, Wilmer Cutler &
Pickering, No. 01P-0586/CP1, at 1 & n.2 (Jan. 24, 2002). Similarly, officials in FDA’s Center
for Drug Evaluation and Research have twice acknowledged that section 505A(o) “does not
address the carve-out of protected pediatric information from [section] 505(b)(2) product
labeling” because section 505A(o) refers only to applications submitted under 21 U.S.C. §
355(j). Memorandum from Jeanine Best, MSN, RN, PNP, Senior Clinical Analyst – Pediatric
and Maternal Health Staff, to Division of Hematology Products, Ref. ID 2911472, at 3 (Feb. 28,
2011); Memorandum from Jeanine Best, MSN, RN, PNP, Senior Clinical Analyst – Pediatric
and Maternal Health Staff, to Division of Neurology Products et al., Ref. ID 3245307, at 8 (Jan.
15, 2013). Just as FDA has followed the plain language of section 505A(o) with respect to
section 505(b)(2) NDAs, it must follow the plain language authorizing a carve out of labeling
only protected by patent or Hatch-Waxman exclusivity, and not the orphan-drug-exclusivity
protected labeling at issue in this Citizen Petition.
Indeed, the “fix” enacted in section 505A(o) was a deliberate and carefully crafted step to
“override” FDA’s pediatric-labeling requirements, 147 Cong. Rec. H10210, but not when orphan
exclusivity applies. The legislative history is replete with references to three-year exclusivity, as
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that was the exclusivity protection afforded BMS for Glucophage, see, e.g., 147 Cong. Rec.
H8105 (“H.R. 2887 closes this potential loophole by instructing the FDA to approve generic
drugs without proprietary pediatric labeling awarded to product sponsors under the HatchWaxman Act.”); id. H10210 (statement of Rep. Eshoo) (“[T]he bill we will vote on today and
send to the President closes the ‘Glucophage loophole’ which allowed one company to get an
additional 3 years of marketing exclusivity.”).
Importantly, although Congress went beyond the specifics of the Glucophage precedent
in crafting section 505A(o), it added only a type of labeling protection not at issue here—that
provided by the patent laws. Congress took this step despite the fact that Glucophage had no
patent protection. See 147 Cong. Rec. H8551 (statement of Rep. Pallone) (“There are no patents
blocking the approval of generics in this case [Glucophage].”). This incremental step reflects
careful Congressional attention to the specific areas that Congress believed needed reform and
does not extend to labeling specially protected by orphan exclusivity.
*
*
*
In short, carving out AstraZeneca’s protected pediatric HoFH labeling may give rise to a
broad range of potential safety and efficacy risks, and FDCA section 505A(o) does not provide
authority for FDA to address the issue through alternate labeling. Because these risks satisfy all
the criteria for de facto exclusivity under the Policy set forth in FDA’s Otsuka Letter, FDA may
not carve out the protected labeling—and therefore may not approve generic rosuvastatin
ANDAs or section 505(b)(2) NDAs—prior to the expiration of Crestor®’s period of orphan drug
exclusivity.
B. FDA May Not Carve Out AstraZeneca’s Protected Labeling Because FDA Lacks
Authority To Carve Out Pediatric Labeling Protected By Orphan Drug
Exclusivity
FDA may not carve out AstraZeneca’s protected pediatric HoFH labeling for an
additional and independent reason: none of FDA’s carve-out authorities applies to pediatric
labeling protected by orphan drug exclusivity, regardless of a factual inquiry into whether the
omitted labeling raises a safety issue.
1. The FDCA And FDA’s Pediatric-Labeling Regulations Present A Barrier
To Generic-Drug Approvals
FDA’s pediatric-labeling regulations mandate that dosing, specific indications, and safety
data pertaining to pediatric uses “must appear in all prescription drug labeling.” 21 C.F.R.
§§ 201.57(a), (a)(6)–(7), (a)(13), (c)(2)(i)(B), (c)(3)(i)(H). Thus, “[i]f there is a specific pediatric
indication different from those approved for adults that is supported by adequate and wellcontrolled studies in the pediatric population, it must be described under the ‘Indications and
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Usage’ section, and appropriate pediatric dosage information must be given under the ‘Dosage
and Administration’ section.” Id. § 201.57(c)(9)(iv)(B). Similarly, if “there are specific
statements on pediatric use of the drug for an indication also approved for adults that are based
on adequate and well-controlled studies in the pediatric population,” that information must be
included in labeling in the “Pediatric use” subjection, discussed as applicable in detail under the
“Clinical Pharmacology” and “Clinical Studies” sections, pediatric dosage must be given under
the ‘‘Dosage and Administration’’ section, and the ‘‘Pediatric use’’ subsection of the labeling
must cite limitations on pediatric use. Id. § 201.57(c)(9)(iv)(C). FDA has explained that “[a]
drug product that is not in compliance with [the pediatric-labeling rules] would be considered
misbranded and an unapproved new drug under the [FDCA].” 59 Fed. Reg. 64,240, 64,247
(1994).43
These FDA pediatric-labeling regulations create a barrier to approval of a generic drug
when (i) the reference-listed drug is approved for one or more pediatric indications and (ii) at
least one of those pediatric indications is protected by patent, Hatch-Waxman, or some other
form of exclusivity.44 In this scenario, the generic manufacturer cannot secure approval: The
pediatric-labeling rules require the manufacturer to include the pediatric labeling, see 21 C.F.R.
§§ 201.57(a), (c)(9)(iv)(B), but that labeling is protected and thus unavailable. If FDA carved
the protected labeling out, the generic drug would be considered misbranded under the pediatriclabeling rules. See 59 Fed. Reg. at 64,247.
This was the scenario presented in the Glucophage (metformin) precedent. At the time,
“the only obstacle” to approval of generic metformin was a perceived “loophole in the WaxmanHatch [Act]” that provided total exclusivity whenever the sponsor of a reference-listed drug
obtained exclusivity with respect to one or more pediatric indications. 147 Cong. Rec. H8551
(Nov. 28, 2001) (statement of Rep. Pallone) (emphasis added). “FDA’s Office of Generic
Drugs” was “unable to allow . . . generics onto the market due to” the “monopoly” BMS
obtained under FDA regulations. Id.
The foregoing context shows why section 505A(o) was necessary and how the statute
was intended to operate within FDA’s overall regulatory framework. Section 505A(o) was
enacted because FDA’s carve-out authority was limited by operation of FDA’s own 1994
pediatric-labeling regulations. On the one hand, FDA had authority under its general 1992
carve-out regulations to allow generic drugs to omit certain labeling,45 but, on the other hand,
44
See also 147 Cong. Rec. H10209 (Dec. 18, 2001) (“In 1994, the FDA created an exception to [its
general carve-out] regulation[s], concerning acceptable label omissions, affording pioneer drug
manufacturers extended total marketing exclusivity based on the development of new pediatric use
indications. In particular, the FDA adopted regulations requiring that pediatric information be included in
the labeling of every prescription drug. See 21 C.F.R. § 201.57(f)(9)(ii).”).
45
Via regulations promulgated in 1992, FDA has interpreted section 505(j)(2)(A)(v)’s exception for
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FDA’s later-in-time 1994 pediatric-labeling regulations precluded omissions of pediatric
information by requiring such information to be included on the label or requiring the drug to be
considered misbranded. Congress understood this problem when it enacted section 505A(o).
Indeed, Congress did not act in a vacuum when it enacted section 505A(o). Rather, in
late 2001, Congress confronted a specific situation that demonstrated the need for a change in the
law, and that situation drove the enactment of section 505A(o). Under then-existing law, FDA’s
grant of three-year exclusivity for Glucophage resulted in “total marketing exclusivity” because,
under FDA’s 1994 pediatric-labeling regulations, generics could not omit the three-yearexclusive pediatric indication from their labels. See 147 Cong. Rec. H10209 (Dec. 18, 2001)
(“Under existing law, that grant resulted in total marketing exclusivity with respect to
Glucophage for the applicable period because BMS has acquired exclusive rights to the only
pediatric use indication that applied under the pediatric labeling requirements.”); id. at H8105
(Nov. 13, 2001) (statement of Rep. Dingell) (“Because FDA has granted three-year exclusivity to
the pediatric label of Glucophage, Bristol has argued that no generic may be marketed during the
pendency of its labeling exclusivity.”).
Congress clearly understood that the so-called Glucophage problem arose in the context
of the statutes and regulations discussed above. Indeed, a memorandum in the Congressional
Record explains that FDA’s 1994 pediatric-labeling regulations superseded the 1992 general
carve-out regulations by “requiring that pediatric information be included in the labeling of every
prescription drug.” 147 Cong. Rec. H10209 (Dec. 18, 2001). As reflected in that memorandum,
the practical effect of FDA’s 1994 pediatric-labeling regulations was to afford Glucophage a
three-year period of “total marketing exclusivity” for all uses, rather than just for the three-yearexclusive pediatric indication. See id.
2. Section 505A(o) Unambiguously Addresses Only Patent And HatchWaxman Exclusivity
Congress enacted section 505A(o) to close the Glucophage “loophole.” See, e.g., 147
Cong. Rec. H8105 (Nov. 13, 2001) (statement of Rep. Dingell) (“H.R. 2887 closes this potential
loophole by instructing the FDA to approve generic drugs without proprietary pediatric labeling
awarded to product sponsors under the Hatch-Waxman Act.”); id. at H8552 (Nov. 28, 2001)
(statement of Rep. Pallone) (“Mr. Speaker, there is currently a legislative fix in place in the
House and Senate version of the pediatric exclusivity bill that would close this loophole and
allow generic versions of this diabetes drug to compete with Bristol’s Glucophage.”); H.R. Rep.
No. 107-277 (2001), at 38 (“[Section 505A(o)] does make clear that if a manufacturer does claim
labeling changes made “because the new drug and the listed drug are produced or distributed by different
manufacturers” as allowing generic drugs to “omi[t] . . . an indication or other aspect of labeling” that is
“protected by patent or accorded exclusivity under section 505(j)(5)(F) of the Act.” 21 C.F.R. §
314.94(a)(8)(iv).
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supplemental exclusivity under section 505(j), the terms of that exclusivity will not prevent
generic competition for the indications or aspects of labeling which are not protected.”).
Notably, Congress did not amend or alter FDA’s longstanding pediatric-labeling
regulations, which remain in effect today, when it enacted section 505A(o). Instead, Congress
expanded FDA’s carve-out authority for pediatric labeling with respect to labeling protected only
by patent and Hatch-Waxman exclusivity. See 21 U.S.C. § 355A(o)(1) (referring to “labeling
pertaining to pediatric use” that is protected only “by patent or by exclusivity under
[§ 355(j)(5)(F)(iii) or (iv)]”). FDA has repeatedly acknowledged this limited scope, as noted in
Part II.A, supra.
Because section 505A(o) does not address other forms of exclusivity—including
exclusivity afforded by the Orphan Drug Act, 21 U.S.C. § 360cc(a)—the barrier to generic-drug
approvals presented in the Glucophage precedent remains with respect to orphan drug
exclusivity. Indeed, it is well-settled that agencies and courts shall construe statutes without
adding words to or modifying the statutory text. See Utility Air Regulatory Grp. v. EPA, 134 S.
Ct. 2427, 2446 (2014) (“an agency may not rewrite clear statutory terms to suit its own sense of
how the statute should operate”); 62 Cases, More or Less, Each Containing Six Jars of Jam v.
United States, 340 U.S. 593, 596 (1951) (“[O]ur problem is to construe what Congress has
written. After all, Congress expresses its purpose by words. It is for us to ascertain – neither to
add nor to subtract, neither to delete nor to distort.”).
3. FDA’s General Carve-Out Provisions Do Not Provide Authority To
Carve Out AstraZeneca’s Protected Labeling
In 1992, FDA promulgated a series of general “carve-out” regulations. See 57 Fed. Reg.
17,950, 17,984–86, 17,992 (1992). These regulations empower FDA to approve a generic drug
even when its label differs from the reference-listed drug in specified ways. For example, the
regulations provide that a generic drug label may differ from the reference-listed drug’s label by
the “omission of an indication or other aspect of labeling protected by patent or accorded
exclusivity under section 505(j)(5)(F) of the [FDCA]” so long as “such differences do not render
the proposed drug product less safe or effective than the listed drug for all remaining, nonprotected conditions of use.” 21 C.F.R. §§ 314.94(a)(8)(iv), 314.127(a)(7).
These general carve-out regulations do not fill the void left by section 505A(o) for at
least five reasons.
First, FDA understood that its general carve-out authorities were insufficient when it
evaluated generic metformin ANDAs in 2001. Were that not the case, section 505A(o) would
have been unnecessary. To the extent FDA is now of the view that it could have resolved the
Glucophage problem by exercising its general carve-out authorities, that view constitutes an
unexplained departure from past agency practice, in violation of the Administrative Procedure
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Act. See Ramaprakash, 346 F.3d at 1124–25.
Similarly, to the extent FDA now believes that the problem posed in the Glucophage
precedent was not a legal inability to carve out protected pediatric information, but rather an
inability to do so only when a carve out would (as a factual matter) present a safety risk, FDA’s
stance is revisionist history. The Congressional Record shows that the Glucophage problem was
the product of the same-label and pediatric-labeling requirements: “The FDA’s Office of Generic
Drugs has numerous generic versions of this diabetes drug awaiting approval. However, the
office is unable to allow these generics onto the market due to Bristol’s monopoly. There are no
patents blocking the approval of generics in this case. The only obstacle is a . . . loophole in the
Waxman-Hatch exclusivity.” 147 Cong. Rec. H8551 (Nov. 28, 2001) (statement of Rep.
Pallone).
Contemporaneous trade press coverage likewise shows that FDA interpreted its
regulations as prohibiting carve outs of protected pediatric labeling. Articles indicate that FDA
“delayed” and placed “on hold” approval of “[g]enerics for Bristol-Myers Squibb’s diabetes drug
Glucophage (metformin) and anti-anxiety agent BuSpar (buspirone) . . . because of
Waxman/Hatch exclusivity for pediatric labeling.” FDA Discontinued Label Guidance on Hold,
The Pink Sheet (Apr. 8, 2002).46 Gary Buehler, Director of FDA’s Office of Generic Drugs,
explained that FDA’s approval process for generic metformin ANDAs “stopped . . . because of a
problem with pediatric labeling,” and that “the ideal solution” for this problem was new
legislation by Congress. Glucophage Generics Should Be Addressed by Congress, OGD’s
Buehler Says, The Pink Sheet (Nov. 5, 2001). Congress responded to that call for action on the
understanding that, prior to the enactment of 21 U.S.C. § 505A(o), “[a] pharmaceutical company
[wa]s prohibited under the law . . . to market a dru[g] . . . without the pediatric indication being
on the label.” 147 Cong. Rec. H8101 (Nov. 13, 2001) (statement of Rep. Tauzin).
Second, Congress was aware of FDA’s conclusion that it lacked legal authority to carve
out protected pediatric information, yet did not provide authority to carve out labeling protected
by orphan drug exclusivity in section 505A(o). FDA must presume that the disparate inclusion
was intentional, particularly because Congress was considering orphan drug legislation during
the same time period. Cf. Russsello v. United States, 464 U.S. 16, 23 (1983) (“[I]t is generally
presumed that Congress acts intentionally and purposely in the disparate inclusion or exclusion”
of statutory terms.).
This reading finds further support in the expressio unius canon of statutory interpretation.
46
See also Bristol BuSpar Pediatric Labeling May Delay Second Round of Generics, The Pink Sheet
(Oct. 1, 2001) (FDA delayed approval of BuSpar ANDAs based on the argument that “FDA cannot
approve a generic that does not include the same pediatric labeling as the innovator”); see also id. (“The
FDA rhetoric . . . has been [that] they cannot approve a generic drug with the label that doesn’t have a
pediatric indication for it if in fact the innovator product does have a pediatric indication.”).
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See Leatherman v. Tarrant Narcotics Intelligence & Coordination Unit, 507 U.S. 163, 168
(1993); TRW Inc. v. Andrews, 534 U.S. 19, 28–29 (2001). The negative phrasing employed in
section 505A(o) defines FDA’s approval authority no less than positive phrasing would have
done. Cf. Marine Space Enclosures, Inc. v. Fed. Maritime Comm’n, 420 F.2d 577, 583-84 (D.C.
Cir. 1969) (interpreting a statute that required a hearing prior to the Commission’s decision to
“disapprove, cancel or modify any agreement” to require a hearing prior to approval of an
agreement).
Here, Congress simply chose to define FDA’s approval authority by limiting the
circumstances in which FDA cannot deny approval when it comes to carve outs of pediatric
labeling, rather than defining when FDA shall grant approval in the face of such carve outs.
Under either formulation, however, the outcome is the same. Congress directed when FDA shall
approve generic drugs (i.e., “shall not be considered ineligible for approval . . . or misbranded”),
assuming that other conditions for approval are satisfied. When the statute directs FDA not to
disapprove an ANDA that omits labeling protected only by patent or three-year-exclusivity, FDA
has no license to grant approvals omitting, as here, pediatric indications or information protected
by other forms exclusivity.47
Third, section 505A(o) speaks directly to the question of when FDA may carve out
pediatric labeling information, whereas other statutory provisions (e.g., the “different
manufacturer” exception to the same-labeling statute) address carve-out authority only generally.
Thus, under the “commonplace [canon] of statutory construction that the specific governs the
general,” section 505A(o) provides the exclusive means by which protected pediatric labeling
may be carved out. RadLAX Gateway Hotel, LLC v. Amalgamated Bank, 132 S.Ct. 2065, 2071
(2012). Because section 505A(o) does not address orphan drug exclusivity, FDA lacks carve-out
authority with respect to AstraZeneca’s protected orphan drug labeling.
Indeed, the absence of any reference to orphan drug exclusivity in section 505A(o)
reflects an intentional Congressional choice to omit orphan drug exclusivity from the categories
of pediatric information that may be omitted from generic drug labeling. This conclusion is
reinforced because orphan drug exclusivity long predated section 505A(o). See United States v.
Langley, 62 F.3d 602, 605 (4th Cir. 1995) (“Congress acts with knowledge of existing law, and
. . . absent a clear manifestation of contrary intent, a newly-enacted or revised statute is presumed
to be harmonious with existing law and its judicial construction.” (quotation marks omitted)).
47
Congress’s expression of FDA’s approval authority in a double negative (i.e., “shall not be considered
ineligible or misbranded”) acts as a positive constraint. In other words, in the absence of satisfying the
double negative condition, FDA cannot grant approval. See Adams v. State Livestock Facilities Siting
Review Bd., 787 N.W. 2d 941 (Wisc. Ct. App. 2010); Ford Motor Co. v. Kahne, 379 F. Supp. 2d 857,
861 n.3 (E.D. Mich. 2005). Moreover, there are no “contrary indications that adopting a particular rule or
statute was probably not meant to signal any exclusion” of orphan drug exclusivity. See Marx v. Gen.
Revenue Corp., 133 S. Ct. 1166, 1175 (2013).
May 31, 2016
P a g e | 23
Moreover, language elsewhere in section 505A(o) demonstrates that Congress was well aware of
orphan drug exclusivity. Specifically, in sections 505A(b) and 505A(c), in addressing the
interaction of pediatric exclusivity with patent and regulatory protections, Congress specifically
mentioned orphan drug exclusivity in other contexts not relevant to the issue at hand. See 21
U.S.C. §§ 355A(b)(1)(A)(ii), 355A(c)(1)(A)(ii).
Accordingly, Congress would have specifically included orphan drug exclusivity in
section 505A(o) had Congress intended orphan drug exclusivity to be a category of exclusivity
that may be omitted from generic drug labeling. Indeed, when it enacted section 505A(o),
Congress was not picking from an endless universe of patent and regulatory protections; there
are only a handful of such categories, two of which are specified in section 505A(o).
Had Congress intended that all exclusivities could be carved out from a generic drug’s
label, Congress could have spoken broadly and used the term “exclusivity” alone without
specifically referring to “orphan drug exclusivity.” Congress intentionally chose not to use such
a broad, catch-all term in section 505A(o), even though it has done so elsewhere. Compare
21 U.S.C. § 355(j)(10)(A)(i) (a drug shall “be eligible for approval and shall not be considered
misbranded . . . if the application is otherwise eligible for approval under this subsection but for
expiration of patent, an exclusivity period, or of a delay in approval” (emphasis added)).
Congress’s failure to employ such terminology provides further evidence that section 505A(o)
was not intended to sweep in all forms of exclusivity.
Fourth, FDA’s pediatric-labeling rules trump the general carve-out rules. The pediatriclabeling rules are categorical; they say that all pediatric labeling must be included. And these
rules were adopted in 1994, after FDA adopted its general carve-out rules in 1992. See 57 Fed.
Reg. 17,950, 17,984-86, 17,992 (1992). Thus, the later-in-time labeling rules override the carveout rules to the extent the two conflict. See, e.g., Boudette v. Barnette, 923 F.2d 754, 757 (9th
Cir. 1991) (“When two statutes conflict the general rule is that the statute last in time prevails.”);
Maceren v. INS, 509 F.2d 934, 941 (9th Cir. 1974) (when regulations conflict, “the earlier
regulation should give way to the later in time”).48
Fifth, and finally, the Orphan Drug Act (“ODA”) has always provided a seven-year
period of exclusivity for approved orphan drugs since its enactment 33 years ago. See Pub. L.
No. 97-414, § 527, 96 Stat. 2049, 2051 (1983) (codified at 21 U.S.C. § 360cc). Similarly, ever
since their adoption, FDA’s orphan drug regulations have provided that, when a drug receives
48
To the extent FDA interprets its pediatric-labeling and general-carve-out regulations differently, its
interpretation is erroneous. Auer deference does not apply because FDA’s regulations are not ambiguous.
See Christensen v. Harris Cnty., 529 U.S. 576, 588 (2000) (“Auer deference is warranted only when the
language of the regulation is ambiguous.”). Even if it did apply, an interpretation of the regulations that
allowed a carve out here would be “plainly erroneous or inconsistent with the regulation[s].” Auer v.
Robbins, 519 U.S. 452, 461 (1997).
May 31, 2016
P a g e | 24
orphan drug exclusivity, “no approval will be given to a subsequent sponsor of the same drug for
the same use or indication for 7 years.” 21 C.F.R. § 316.3(b)(12); see also 57 Fed. Reg. 62,076,
62,086 (1992). These provisions, including the incentives provided to drug companies to
develop drugs for the treatment of rare diseases and the policy reasons for those incentives, are
well-known to Congress, and apply with special force to a pediatric orphan disease or
condition.49 Those incentives and policy considerations were not merely in the background but
instead were under active consideration by Congress when section 505A(o) was enacted.
In fact, the legislative record reflects that Congress was considering orphan drug
exclusivity contemporaneously with its debate over section 505A(o). On August 1, 2001, the
Senate Health, Education, Labor and Pensions (“HELP”) Committee held a markup of the
BPCA. See S. Rep. No. 107-79 (2001), at 5. Two days later, on August 3, 2001, Senator
Kennedy, Chairman of the HELP Committee, introduced a bill entitled “Rare Diseases Act of
2001,” to provide statutory authorization for the existing Office of Rare Diseases at the National
Institutes of Health (“NIH”) and to increase the funding for FDA’s Orphan Product Research
Grant program. S. 1379, 107th Cong. (2001); 147 Cong. Rec. S8952 (Aug. 3, 2001). In
commenting on the bill, Chairman Kennedy noted “that Congress has had a longstanding interest
in rare diseases” and “[i]n 1983, . . . enacted the Orphan Drug Act to promote the development of
treatments for rare diseases and disorders.” 147 Cong. Rec. S8952.
The text of Senator Kennedy’s bill itself reflected an understanding of the continuing
need to strongly incentivize drug manufacturers to develop drugs for orphan diseases. The
findings in the bill stated, “[f]or many years, the 25,000,000 Americans suffering from the over
6,000 rare diseases and disorders were denied access to effective medicines because prescription
drug manufacturers could rarely make a profit from marketing drugs for such small groups of
patients. The prescription drug industry did not adequately fund research into such treatments.”
S. 1379, 107th Cong., 1st Sess., at 2. “The Orphan Drug Act created financial incentives for the
research and production of such orphan drugs. New federal programs at the National Institutes
of Health and the Food and Drug Administration encouraged clinical research and commercial
product development for products that target rare diseases.” Id. at 3. The legislation recognized
that, “[d]espite the tremendous success of the [ODA], rare diseases and disorders deserve greater
emphasis,” and so the legislation had the purpose of establishing an Office of Rare Diseases at
the NIH and “increas[ing] the national investment in the development of diagnostics and
treatments for patients with rare diseases and disorders.” Id. at 3–4.
In parallel with its consideration of these orphan drug exclusivity provisions, on October
4, 2001, the HELP Committee issued a report on S. 838, an early version of BPCA. See S. Rep.
No. 107-79 (2001). Shortly thereafter, on October 16, 2001, the HELP Committee marked up
the Rare Diseases Act. See id. at 5. Only two days later, the Senate passed BPCA (S. 838) with
49
See, e.g., 21 U.S.C. § 360ff (establishing rare pediatric disease priority review voucher program).
May 31, 2016
P a g e | 25
an amendment containing what is now codified in section 505A(o). See 147 Cong. Rec.
S10816–19 (Oct. 18, 2001); id. S10844–46 (Oct. 18, 2001). On December 12, 2001, the Senate
considered and passed the BPCA legislative vehicle that ultimately was enacted (S. 1789)
containing what is now codified in section 505A(o). See 147 Cong. Rec. S13070–76 (Dec. 12,
2001). Six days later, on December 18, 2001, the Senate HELP Committee issued a report on
the Rare Diseases Act, which was enacted later in 2002. See S. Rep. No. 107-129; Rare Diseases
Act of 2002, Pub. L. No. 107-280, 116 Stat. 1988 (Nov. 6, 2002). The first paragraph of that
December 18, 2001, Senate HELP Committee Report clearly evidences the HELP Committee’s
understanding and recognition of the importance of the Orphan Drug Act, including its orphan
drug exclusivity incentive afforded to drug manufacturers: “To address a longstanding unmet
need to develop new treatments, diagnostics, and cures for rare diseases and disorders, Congress
enacted the Orphan Drug Act of 1983 (Pub. L. 97-414). This Act created financial incentives,
such as market exclusivity, tax credits, and research grants, for the research and production of
orphan drugs, and established the Orphan Products Board at the [FDA]. Congress sought through
the Act to encourage the development of new ‘orphan’ treatments, diagnostics, and cures for the
millions of Americans with rare diseases who did not have access to effective medicines because
prescription drug manufacturers were unlikely to develop and market drugs for such small
groups of patients.” S. Rep. No. 107-129, at 1–2 (emphasis added). That same December 18th
HELP Committee Report noted that “[t]he Orphan Drug Act provided seven years of market
exclusivity and expanded tax credits to companies for the development and marketing of orphan
drugs.” Id. at 3 (emphasis added).50
In short, Congress was, at the very same time, actively considering in parallel both
orphan drug exclusivity and the pediatric labeling omission provisions in section 505A(o). The
same Senators who enacted section 505A(o) knew exactly what they were doing by limiting it to
labeling protected only by patent protection and three-year exclusivity, and by not including
orphan drug exclusivity within the scope of section 505A(o). Indeed, the foregoing legislative
history of Congress’ consideration of orphan drug exclusivity in parallel with Congress’
consideration of pediatric labeling omissions in section 505A(o) reflects precisely why Congress
omitted orphan drug exclusivity from section 505A(o): Congress understood the value and
impact of orphan drug exclusivity and eschewed enactment of language that would in any way
diminish that protection in the case of a pediatric orphan disease or condition.
The Pediatric HoFH Study provides an example of how the incentives created by the
50
A comparable legislative record is found in the House of Representatives. For example, during an
October 11, 2001, markup of the BPCA legislation (H.R. 2887) by the House Committee on Energy and
Commerce, Representative Waxman noted that drug manufacturers “get even more exclusivity” for
orphan drugs. Tr. of Record of Markup on H.R. 2985 American Spirit Fraud Prevention Act of 2001,
H.R. 2887, Best Pharmaceuticals for Children Act, and H.R. 2983 Price-Anderson Reauthorization Act of
2001, House of Representatives, Committee on Energy and Commerce, at 68 (Oct. 11, 2011).
May 31, 2016
P a g e | 26
Orphan Drug Act and FDA’s pediatric-labeling regulations work in practice. Pediatric HoFH is
an important public-health issue with unmet medical need. Although the market for HoFH
treatment is small (due to the small number of pediatric HoFH patients), AstraZeneca agreed to
invest time and resources in the Pediatric HoFH Study based in large part on the incentives
created by Congress and FDA regulations.51 Without those incentives, it is not realistic to expect
that a drug manufacturer would invest time and resources in investigating treatment for small
pediatric patient populations.
*
*
*
For all the foregoing reasons, FDA lacks legal authority to carve out AstraZeneca’s
protected labeling, and may not lawfully approve ANDAs or section 505(b)(2) NDAs for generic
rosuvastatin calcium until (i) AstraZeneca’s orphan drug exclusivity expires, (ii) FDA revises its
pediatric-labeling rules through notice-and-comment rulemaking, or (iii) Congress amends
section 505A(o) to cover orphan drug exclusivity. Although FDA and the United States District
Court for the District of Maryland concluded in the Otsuka litigation that FDA has authority to
carve out pediatric labeling protected by orphan drug exclusivity,52 that conclusion is incorrect
and should be overturned for the reasons given above.
ENVIRONMENTAL IMPACT
The actions requested in this Petition are subject to categorical exclusion under 21 C.F.R.
§ 25.31.
ECONOMIC IMPACT
Information on the economic impact of this Petition will be submitted upon request of the
Commissioner.
CERTIFICATION
I certify that, to my best knowledge and belief: (a) this Petition includes all information
and views upon which the Petition relies; (b) this Petition includes representative data and/or
information known to the Petitioner which are unfavorable to the Petition; and (c) I have taken
reasonable steps to ensure that any representative data and/or information which are unfavorable
to the Petition were disclosed to me. I further certify that the information upon which I have
51
See Keenan Decl. ¶ 20.
See Otsuka Letter at 10–15; see also Otsuka Pharm. Co. v. Burwell, No. GJH-15-852, 2015 WL
1962240 (D. Md. Apr. 29, 2015)
52
ASTRAZENECA CITIZEN PETITION
EXHIBIT A
DECLARATION OF SARAH WALTERS
I, Sarah Walters, provide this declaration in support of a Citizen Petition
being submitted to the FDA by AstraZeneca Pharmaceuticals LP ("AstraZeneca")
and to provide information concerning licensing of AstraZeneca's CRESTOR®
(rosuvastatin calcium) drug.
I declare further as follows:
Professional Background and Qualifications
1.
I am an Executive Director, Cardiovascular, at AstraZeneca, based in
Wilmington, Delaware. I have a BS degree from The Pennsylvania State University
and a MBA from the University of Pennsylvania.
2.
At AstraZeneca, I am responsible for U.S. commercial oversight of the
CV portfolio, which includes Crestor.
With respect to development activities for
Crestor, my responsibilities have included counsel regarding Crestor development
plans.
Watson's Licensed Generic Rosuvastatin Product
3.
On March 23, 2013, in connection with resolution of a patent
infringement dispute, AstraZeneca's affiliate iPR Pharmaceuticals, Inc. ("IPR") and
other AstraZeneca entities executed an agreement with Watson Laboratories, Inc.
("Watson") regarding the marketing of generic rosuvastatin products.
This
agreement granted Watson a license to market generic rosuvastatin beginning on
May 2, 2016.
4.
Watson began marketing a generic rosuvastatin product on or about
May 2, 2016, and has continued to market that product through the date of this
declaration.
5.
On May 27, 2016, FDA approved a new Crestor label, which lists
Crestor as a treatment for homozygous familial hypercholesterolemia ("HoFH) in
patients ages 7 to 17.
6.
The Crestor labeling for treatment of pediatric HoFH patients is
protected by orphan drug exclusivity, such that FDA "may not approve" abbreviated
new drug applications or section 505(b)(2) new drug applications "for such drug for
such disease or condition ... until the expiration of seven years from" May 27, 2016.
21 U.S.C. § 360cc(a).
As a result, of this orphan drug exclusivity, generic
rosuvastatin products may not include AstraZeneca's protected pediatric HoFH
labeling until May 27, 2023.
7.
As required under the terms of the March 2013 settlement agreement
with Watson, by letter dated May 31, 2016, IPR granted Watson a selective waiver
of all exclusivities applicable to Crestor pediatric HoFH labeling with respect to
Watson's marketing of generic rosuvastatin products.
This waiver will permit
Watson to include the protected pediatric HoFH labeling in its generic rosuvastatin
product.
8.
Based on IPR's granting Watson a waiver of its Crestor orphan drug
exclusivity rights on May 31, 2016, the labeling for Watson's generic rosuvastatin
-2-
product includes (or will soon include) labeling information for pediatric HoFH
patients derived from AstraZeneca's Pediatric HoFH Study.
I declare under penalty of perjury, that the foregoing is true and correct to the best
of my knowledge. Executed this 31st day ofM~aware.
-3-
ASTRAZENECA CITIZEN PETITION
EXHIBIT B
DECLARATION OF GREGORY KEENAN, MD
I, Gregory F. Keenan, MD, provide this declaration in support of a Citizen Petition
being submitted to the FDA by AstraZeneca Pharmaceuticals LP (“AstraZeneca”) and to
provide information concerning AstraZeneca’s development of CRESTOR® (rosuvastatin
calcium)
for
the
hypercholesterolemia
treatment
(“HoFH”).
of
pediatric
As
explained
patients
further
with
below,
homozygous
AstraZeneca
familial
studied
rosuvastatin for pediatric HoFH in close communication with FDA, and has generated critical
data for prescribers regarding the safe and effective treatment of pediatric patients with this
serious condition.
I declare further as follows:
Professional Background and Qualifications
1.
I am the Vice President for Medical Affairs of AstraZeneca, based in
Gaithersburg, Maryland.
I have a MD from Albany Medical College and am trained in
internal medicine and pediatrics. I have over 16 years of pharmaceutical industry experience
and have worked at AstraZeneca for over 3 and one half years on the development of drug
treatments for various cardiovascular disorders and other diseases and conditions.
2.
At AstraZeneca, I am responsible for Medical Affairs in the United States and
support AstraZeneca’s cardiovascular drug portfolio including development activities for
Crestor.
Pediatric HoFH
3.
HoFH is a rare and serious inherited disorder in which patients present with
significantly reduced functional low-density lipoprotein (“LDL”) receptors and other
abnormalities.
Reduced receptor-mediated catabolism of LDL causes high plasma LDL
cholesterol (“LDL-C”) and premature coronary artery disease, potentially leading to
myocardial infarction and death.
Cholesterol retention in the arterial wall and foam cell
–1–
formation within the intima of arteries typically progresses to occlusive atherosclerosis with
angina pectoris and/or plaque rupture resulting in thrombotic occlusion of the coronary artery
(i.e., myocardial infarction).
4.
In children, HoFH causes the accumulation of cholesterol beginning at birth and
produces increasingly severe clinical manifestations. The signs and symptoms of HoFH in
children may include:
a. Peripheral vascular disease, cerebrovascular disease, and/or coronary
artery disease;
b. Tendonitis and/or arthralgias;
c. Unusual skin lesions (xanthomas);
d. Corneal arcus; and
e. Aortic stenosis.
5.
Pediatric HoFH patients face significantly impaired day-to-day functioning, and
typically do not survive beyond 30 years of age in the absence of a successful treatment
intervention (Nordestgaard et al 2013;1 Wierzbicki 20132).
Historically, off-label statin
treatment following initiation of diet modification has been the preferred initial
pharmacological treatment in children with HoFH starting as early as possible (Daniels et al.
2011,3 Cuchel et. al 20144). Other treatment options include apheresis, liver transplantation,
and ileal bypass surgery.
1
Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. Familial
hypercholesterolemia is underdiagnosed and undertreated in the general population: guidance for clinicians
to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur. Heart
J. 2013; 34 (45):3478-90a.
2
Wierzbicki AS. Homozygous Familial Hypercholesterolemia. Clin. Lipidology. 2013;8(4):407-409.
3
Daniels SR, Gidding SS, de Ferranti SD, et al. Pediatric aspects of familial hypercholesterolemias:
recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J.
Clin. Lipidol. 2011;5(3 Suppl):S30-7.
4
Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, et al.; European Atherosclerosis
Society Consensus Panel on Familial Hypercholesterolemia. Homozygous familial hypercholesterolemia:
new insights and guidance for clinicians to improve detection and clinical management. A position paper
–2–
6.
Prior to Crestor, and the recent approval of PCSK9 drugs for adolescents, there
were no FDA-approved pharmacological treatments for pediatric HoFH, and physicians used
statin therapy and other lipid-lowering agents to treat patients off-label (Cuchel et. al 2014).
Even after the approval in 2015 of REPATHA (evolocumab) as an adjunct to diet and other
LDL-lowering therapies for the treatment of patients with HoFH who require additional
lowering of LDL-C, there were no approved statins for treatment of pediatric HoFH patients
under age 13 prior to FDA’s approval of Crestor for pediatric HoFH patients in 2016.
7.
Heterozygous
familial
hypercholesterolemia
(“HeFH”)
is
a
related
but
considerably less severe form of familial hypercholesterolemia. In HeFH, pediatric patients
generally do not have symptoms of coronary heart disease. Treatment of pediatric HeFH
generally consists of dietary modification and statin therapy beginning at age 8 (thereafter
tailored to the age of the patient), often in conjunction with other lipid-modifying agents
(Daniels et al. 2011).
8.
Because HeFH is less severe than HoFH, physicians typically treat pediatric
HeFH patients with Crestor by titrating upwards from a 5 mg starting dose to a 10 mg dose in
patients ages 8 to less than 10, and from 5 mg to a maximum recommended dose of 20 mg in
patients ages 10 to 17. Some pediatric HeFH patients achieve treatment goals at doses below
20 mg, in which case the 20 mg dose of Crestor is not administered.
9.
Physicians generally prescribe statin therapy much earlier and more
aggressively in pediatric HoFH patients than pediatric HeFH patients, in part because the
risk of an early cardiac event is considerably higher in pediatric HoFH patients.
Development of Rosuvastatin for Pediatric HoFH and Interactions with FDA
10.
Rosuvastatin is a selective, potent, and competitive inhibitor of synthetic 3-
hydroxy-3-methylglutaryl coenzyme A (“HMG CoA”) reductase, the rate-limiting enzyme that
from the Consensus Panel on Familial Hypercholesterolemia of the European Atherosclerosis Society. Eur.
Heart J. 2014 Aug 21; 35(32):2146-2157.
–3–
converts HMG-CoA to mevalonate, a precursor of cholesterol. Clinical testing in over 60,000
subjects, with more than 35,000 subjects receiving Crestor, has demonstrated that Crestor is a
highly effective statin and favorably modifies plasma levels of lipids, lipoproteins, and their
ratios.
For adults, Crestor is approved for six indications:
dyslipidemia;
hypertriglyceridemia;
primary
hyperlipidemia and mixed
dysbetalipoproteinemia
(Type
II
hyperlipoproteinemia); HoFH; slowing the progression of atherosclerosis; and primary
prevention of cardiovascular disease.
11.
AstraZeneca affiliate iPR Pharmaceuticals, Inc. (“IPR”) owns the New Drug
Approval (“NDA”) for Crestor. Throughout this declaration, references to AstraZeneca are
intended to include IPR.
12.
Crestor was first approved in the United States for pediatric use in HeFH,
initially down to age 10 and then to age eight based on the results of study D3561C00002, also
known as the CHARON study. Based on the CHARON data, on November 20, 2015, FDA
approved expanded labeling for Crestor for use in pediatric patients with HeFH down to age
eight, with a recommended dosing range of 5 to 10 mg once daily in patients 8 to less than 10
years old and 5 to 20 mg once daily in patients 10 to 17 years old.
13.
After consultation with FDA, in 2014 AstraZeneca initiated study number
D3561C00004, formally entitled “A Randomized, Double-blind, Placebo-controlled, Multicenter, Cross-over Study of Rosuvastatin in Children and Adolescents (aged 6 to <18 years)
with Homozygous Familial Hypercholesterolemia (HoFH),” and referred to in shorthand as the
HYDRA study or the Pediatric HoFH Study.
14.
One critical question in designing the Pediatric HoFH Study concerned the
appropriate dosing regimen to study for pediatric HoFH patients, balancing the need for
adequate dosing to achieve efficacy with potential safety issues for higher doses.
When
AstraZeneca discussed the study design with FDA drug review personnel in the Division of
–4–
Metabolism and Endocrinology Products of the Center for Drug Evaluation and Research, the
FDA personnel inquired whether the Pediatric HoFH Study should include doses up to 40 mg.
15.
In response to FDA’s inquiry regarding the propriety of studying doses up to 40
mg, AstraZeneca presented its views that 20 mg was a safe and appropriate dose, and that
there was insufficient safety data regarding the higher 40 mg dose for pediatric patients.
Following further discussions and consideration, the Pediatric HoFH Study proceeded and
evaluated the 20 mg dose.
As stated in the FDA-approved labeling for Crestor, serious
adverse reactions, including myopathy and rhabdomyolysis with acute renal failure have been
reported with statins, including Crestor, and are increased at the 40 mg (highest) dose. These
risks could be heightened in pediatric patients, where greater sensitivity and critical
assessment is required with respect to safety concerns, data on doses greater than 20 mg are
limited, and higher doses (including the highest dose of 40 mg) have not been studied in a
sufficient number of pediatric patients or for a sufficient duration of therapy to establish
safety.
16.
The Pediatric HoFH Study went forward with patients ages 6 to 17 receiving
Crestor 20 mg once daily or placebo. The Pediatric HoFH Study concluded in 2015, and met
the primary and key secondary endpoints. Crestor 20 mg significantly reduced LDL-C, total
cholesterol, apolipoprotein B (“ApoB”), and non-high density lipoprotein cholesterol (“nonHDLC”) compared to placebo. Based on these findings and the subsequent supplemental new drug
application (“sNDA”) submitted by AstraZeneca, on May 27, 2016, FDA approved Crestor “for
treatment of pediatric patients 7 to 17 years of age with homozygous familial
hypercholesterolemia (HoFH) to reduce LDL-C, total C, nonHDL-C and ApoB as an adjunct to
diet, either alone or with other lipid-lowering treatments.” Whereas the recommended dosing
for pediatric HeFH is 5 to 10 mg once daily for patients 8 to less than 10 years of age and 5 to
20 mg once daily in patients 10 to 17 years of age, with dosing titrated to achieve therapeutic
–5–
goals, the recommended dosing for pediatric HoFH “is 20 mg orally once daily in patients 7 to
17 years of age.” A true and correct copy of the Crestor label approved by FDA on May 27,
2016, is attached as Exhibit 1.
Orphan Drug Status and Protected Pediatric Labeling
17.
On February 14, 2014, FDA granted AstraZeneca orphan drug designation for
Crestor for the treatment of pediatric HoFH. The orphan drug designation led to the award of
seven years of orphan exclusivity with FDA’s May 27, 2016, approval of Crestor for pediatric
HoFH for patients ages 7 to 17.
18.
AstraZeneca attempted to expedite approval of Crestor for pediatric HoFH
patients in several ways. First, AstraZeneca filed a request for priority review of its sNDA for
treatment of pediatric HoFH patients that fully met all FDA required criteria. Second, when
FDA declined to grant priority review for AstraZeneca’s pediatric HoFH sNDA, AstraZeneca
sought reconsideration and gave additional reasons why priority review was warranted—
including that the pediatric HoFH sNDA (i) fully met the criteria established in FDA’s
Guidance for Industry Expedited Programs for Serious Conditions-Drugs and Biologics (May
2014) and MAPP 6020.3, and (ii) and sought approval for treatment of a rare and serious
condition in a pediatric orphan population. AstraZeneca also requested that the FDA consider
reviewing its application on an expedited basis through the standard review process. Lastly,
AstraZeneca diligently pursued labeling negotiations with FDA. AstraZeneca followed up with
FDA regarding the revised Crestor label on May 2, 2016, May 5, 2016, and on other occasions.
FDA did not provide a substantive response to these inquiries until May 12, 2016, when FDA
forwarded a revised draft of the Crestor label. AstraZeneca responded with a further revised
draft Crestor label five days later, on May 17, 2016, and remained in regular contact with FDA
through approval of the label on May 27, 2016.
–6–
19.
Orphan drug exclusivity and the other protections that apply to the
development of important new public health information for a medicine under U.S. food and
drug laws create incentives to invest time and resources into clinical studies. Pediatric HoFH
is an important public health issue with unmet medical need. One of the reasons AstraZeneca
conducted the Pediatric HoFH Study to try to address that public health need, among other
competing potential research priorities, was the potential protections for Crestor that would
arise from orphan exclusivity and the new labeling for pediatric HoFH if the study was
successful in demonstrating that Crestor would produce health benefits for these patients.
Risk of Omitting The Pediatric HoFH Study Data from Drug Labeling
20.
The Pediatric HoFH Study data and associated dosing recommendations in the
FDA-approved Crestor labeling provide a critical evidence-based guide for physicians treating
pediatric HoFH patients with rosuvastatin. Without the benefit of such labeling, there is a
substantial risk that physicians will treat their pediatric HoFH patients with doses beyond
levels that have been established as safe.
21.
For adult HoFH patients, section 2.1 of Crestor’s approved labeling provides
that the recommended “starting dose . . . is 20 mg once daily.” (Emphasis added). The general
dosing guidelines in section 2.1 also provide that the patient should be titrated up according to
the patient’s response, and that the 40 mg dose may be considered for patients who have not
achieved their LDL-C goal utilizing the 20 mg dose. In addition, section 14.5 of the Crestor
label summarizes an early clinical study in HoFH patients. That section states in pertinent
part: “About one-third of the patients benefited from increasing their dose from 20 mg to 40
mg with further LDL-C lowering of greater that 6%.” There is a real risk that a physician
treating a pediatric HoFH patient will follow these dosing recommendations from the labeling
for adult HoFH if the physician is not given the benefit of the labeling from the Pediatric
–7–
HoFH Study showing significant efficacy at 20 mg and recommending 20 mg as the dose, not
just the starting dose for pediatric HoFH patients.
22.
The Pediatric HoFH Study data establish the efficacy and favorable benefit-risk
of the 20 mg dose for pediatric HoFH patients.
If a physician instead treats his or her
pediatric HoFH patients at higher doses such as 40 mg, because the physician does not have
the Pediatric HoFH Study information, patients will be put at heightened potential risk for
adverse effects such as myopathy and rhabdomyloysis.
23.
The risk that physicians treating pediatric HoFH patients will exceed the 20 mg
dose shown effective in the Pediatric HoFH Study is exacerbated by the severe potential
consequences of inadequate treatment of HoFH, and the understanding that HoFH patients
generally have a lower and more unpredictable response to statin therapy.
24.
The risk that physicians will prescribe excessive doses of rosuvastatin for their
pediatric HoFH patients in the absence of the labeling based on the Pediatric HoFH Study
also arises to the extent that physicians base treatment decisions for pediatric HoFH on the
labeling for pediatric HeFH. As stated above, the rosuvastatin labeling recommends doses up
to 20 mg for HeFH patients 10 to 17 years of age. Physicians understand that patients with
HoFH tend to show an average of approximately 50 percent less response on LDL-C reduction
than patients with HeFH. Accordingly, a physician consulting labeling recommending up to
20 mg rosuvastatin for HeFH patients 10 to 17 years of age logically might deduce that doses
above 20 mg are appropriate for HoFH patients in this age range, and only the labeling based
on the Pediatric HoFH Study would inform the physician not to exceed 20 mg.
25.
There is also a risk that physicians could under-treat pediatric HoFH patients if
the Pediatric HoFH Study information is omitted from the labeling for rosuvastatin.
A
physician with limited experience in treating HoFH patients may rely on the rosuvastatin
labeling for pediatric HeFH patients, which recommends titrating upwards from a 5 mg
–8–
starting dose to a 10 mg dose in patients ages 8 to less than 10 and to a 20 mg dose in patients
ages 10 to 17. This approach would result in pediatric HoFH patients receiving less than the
20 mg recommended dose shown to be safe and effective in the Pediatric HoFH Study and
AstraZeneca’s sNDA. Pediatric patients receiving less than the recommended dose would be
at increased risk of developing cardiovascular and other conditions associated with HoFH.
26.
If the Pediatric HoFH Study information is omitted from the labeling of a
rosuvastatin product other than Crestor, the resulting risks would not be cured by a general
disclaimer referencing the existence of pediatric use information for Crestor such as that
appearing in the current labeling for the approved generic rosuvastatin calcium product. The
generic-drug disclaimer states:
Pediatric use information for patients ages 8 to less than 10 years is
approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets.
However, due to AstraZeneca’s marketing exclusivity rights, this drug
product is not labeled with that pediatric information.
This language was based on the omission of labeling for pediatric HeFH, and will be
understood as a reference to the pediatric HeFH labeling in Crestor given that the age range
of 8 to 10 year olds tracks to the information in the Crestor labeling for pediatric HeFH. The
disclaimer makes no reference to HoFH and omits 7-year olds altogether, who are within the
approved pediatric HoFH population. The disclaimer thus does not alert the physician to the
omission of critical information on use in pediatric HoFH.
27.
In summary, the Pediatric HoFH Study data and resulting FDA-approved
labeling provide a roadmap to physicians for the treatment of pediatric HoFH patients with
rosuvastatin. Carving the Pediatric HoFH Study information out of the rosuvastatin labeling
would leave physicians without an evidence-based approach to proper dosing and treatment.
No disclaimer can serve as an adequate substitute for the Pediatric HoFH Study information,
especially not one that that is tied to HeFH or that otherwise does not specifically address
HoFH.
–9–
KEENAN DECLARATION
EXHIBIT 1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
CRESTOR safely and effectively. See full prescribing information for
CRESTOR.
x Active liver disease, which may include unexplained persistent elevations
in hepatic transaminase levels (4)
x Pregnancy (4, 8.1, 8.3)
x Lactation (4, 8.2)
CRESTOR (rosuvastatin calcium) tablets
Initial U.S. Approval: 2003
------------------------ WARNINGS AND PRECAUTIONS -------------------x Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks
increase with use of 40 PJ GRVH DGYDQFHG DJH K\pothyroidism,
renal impairment, and combination use with cyclosporine,
atazanavir/ritonavir, lopinavir/ritonavir, or simeprevir. Cases of myopathy
and rhabdomyolysis with acute renal failure secondary to myoglobinuria
have been reported. Advise patients to promptly report to their physician
unexplained and/or persistent muscle pain, tenderness, or weakness and
discontinue CRESTOR if signs or symptoms appear. (5.1, 7.5, 7.6)
x Liver enzyme abnormalities: Persistent elevations in hepatic
transaminases can occur. Perform liver enzyme tests before initiating
therapy and as clinically indicated thereafter. (5.2)
------------------------ RECENT MAJOR CHANGES --------------------------Indications and Usage (1.2)
5/2016
Dosage and Administration (2.2)
5/2016
Contraindications (4)
5/2016
------------------------ INDICATIONS AND USAGE ---------------------------CRESTOR is an HMG Co-A reductase inhibitor indicated for:
x adult patients with primary hyperlipidemia and mixed dyslipidemia as an
adjunct to diet to reduce elevated total-C, LDL-C, ApoB, nonHDL-C, and
TG levels and to increase HDL-C (1.1)
x pediatric patients 8 to 17 years of age with heterozygous familial
hypercholesterolemia (HeFH) to reduce elevated total-C, LDL-C and
ApoB after failing an adequate trial of diet therapy (1.2)
x pediatric patients 7 to 17 years of age with homozygous familial
hypercholesterolemia (HoFH) to reduce LDL-C, total-C, nonHDL-C and
ApoB as an adjunct to diet, either alone or with other lipid-lowering
treatments (1.2)
x adult patients with hypertriglyceridemia as an adjunct to diet (1.3)
x adult patients with primary dysbetalipoproteinemia (Type III
hyperlipoproteinemia) as an adjunct to diet (1.4)
x adult patients with homozygous familial hypercholesterolemia (HoFH) to
reduce LDL-C, total-C, and ApoB (1.5)
x slowing the progression of atherosclerosis as part of a treatment strategy
to lower total-C and LDL-C as an adjunct to diet (1.6)
x risk reduction of MI, stroke, and arterial revascularization procedures in
patients without clinically evident CHD, but with multiple risk factors
(1.7)
Limitations of use (1.8): CRESTOR has not been studied in Fredrickson
Type I and V dyslipidemias.
------------------------------- ADVERSE REACTIONS --------------------------Most frequent adverse reactions (rate >2%) are headache, myalgia, abdominal
pain, asthenia, and nausea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------- DRUG INTERACTIONS --------------------------x Cyclosporine: Combination increases rosuvastatin exposure. Limit
CRESTOR dose to 5 mg once daily. (2.4, 5.1, 7.1, 12.3)
x Gemfibrozil: Combination should be avoided. If used together, limit
CRESTOR dose to 10 mg once daily. (2.4, 5.1, 7.2)
x Atazanavir/ritonavir, lopinavir/ritonavir, or simeprevir: Combination
increases rosuvastatin exposure. Limit CRESTOR dose to 10 mg once
daily. (2.4, 5.1, 7.3, 12.3)
x Coumarin anticoagulants: Combination prolongs INR. Achieve stable
INR prior to starting CRESTOR. Monitor INR frequently until stable
upon initiation or alteration of CRESTOR therapy. (5.3, 7.4)
x Concomitant lipid-lowering therapies: Use with fibrates or lipidPRGLI\LQJ GRVHV g/day) of niacin increases the risk of adverse
skeletal muscle effects. Caution should be used when prescribing with
CRESTOR. (5.1, 7.5, 7.6)
----------------------- DOSAGE AND ADMINISTRATION -------------------x CRESTOR can be taken with or without food, at any time of day. (2.1)
x Dose range: 5-40 mg once daily. Use 40 mg dose only for patients not
reaching LDL-C goal with 20 mg. (2.1)
x Adult HoFH: Starting dose 20 mg/day (2.1)
x Pediatric patients with HeFH: 5 to 10 mg/day for patients 8 to less than
10 years of age, and 5 to 20 mg/day for patients 10 to 17 years of
age.(2.2)
x Pediatric patients with HoFH: 20 mg/day for patients 7 to 17 years of age
(2.2)
----------------------- USE IN SPECIFIC POPULATIONS --------------------x Females of reproductive potential: Advise females of reproductive
potential to use effective contraception during treatment with CRESTOR
(8.3)
x Severe renal impairment (not on hemodialysis): Starting dose is 5 mg,
not to exceed 10 mg. (2.5, 5.1, 8.6)
x Asian population: Consider 5 mg starting dose. (2.3, 8.8)
---------------------- DOSAGE FORMS AND STRENGTHS -----------------Tablets: 5 mg, 10 mg, 20 mg, and 40 mg (3)
See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling.
Revised: 5/2016
------------------------------- CONTRAINDICATIONS --------------------------x Known hypersensitivity to product components (4)
FULL PRESCRIBING INFORMATION: CONTENTS*
1
2
3
4
5
5.5 Endocrine Effects
ADVERSE REACTIONS
6.1 Clinical Studies Experience
6.2 Postmarketing Experience
7
DRUG INTERACTIONS
7.1 Cyclosporine
7.2 Gemfibrozil
7.3 Protease Inhibitors
7.4 Coumarin Anticoagulants
7.5 Niacin
7.6 Fenofibrate
7.7 Colchicine
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
8.8 Asian Patients
INDICATIONS AND USAGE
1.1 Hyperlipidemia and Mixed Dyslipidemia
1.2 Pediatric Patients with Familial Hypercholesterolemia
1.3 Hypertriglyceridemia
1.4 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)
1.5 Adult Patients with Homozygous Familial Hypercholesterolemia
1.6 Slowing of the Progression of Atherosclerosis
1.7 Primary Prevention of Cardiovascular Disease
1.8 Limitations of Use
DOSAGE AND ADMINISTRATION
2.1 General Dosing Information
2.2 Pediatric Dosing
2.3 Dosing in Asian Patients
2.4 Use with Concomitant Therapy
2.5 Dosing in Patients with Severe Renal Impairment
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
5.1 Skeletal Muscle Effects
5.2 Liver Enzyme Abnormalities
5.3 Concomitant Coumarin Anticoagulants
5.4 Proteinuria and Hematuria
6
1
Reference ID: 3937746
14.2 Heterozygous Familial Hypercholesterolemia
14.5 Homozygous Familial Hypercholesterolemia
14.6 Pediatric Patients with Homozygous Familial Hypercholesterolemia
14.7 Pediatric Patients with Heterozygous Familial Hypercholesterolemia
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
10
11
12
OVERDOSAGE
DESCRIPTION
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.5 Pharmacogenomics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14
CLINICAL STUDIES
*Sections or subsections omitted from the full prescribing information are not listed.
2
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Hyperlipidemia and Mixed Dyslipidemia
CRESTOR is indicated as adjunctive therapy to diet to reduce elevated Total-C, LDL-C, ApoB,
nonHDL-C, and triglycerides and to increase HDL-C in adult patients with primary
hyperlipidemia or mixed dyslipidemia. Lipid-altering agents should be used in addition to a diet
restricted in saturated fat and cholesterol when response to diet and nonpharmacological
interventions alone has been inadequate.
1.2
Pediatric Patients with Familial Hypercholesterolemia
CRESTOR is indicated as an adjunct to diet to:
x
reduce Total-C, LDL-C and ApoB levels in children and adolescents 8 to17 years of age
with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy
the following findings are present: LDL-C >190 mg/dL, or >160 mg/dL along with a
positive family history of premature cardiovascular disease (CVD) or two or more other
CVD risk factors.
x
reduce LDL-C, Total-C, nonHDL-C and ApoB in children and adolescents 7 to 17 years
of age with homozygous familial hypercholesterolemia, either alone or with other lipidlowering treatments (e.g., LDL apheresis).
1.3
Hypertriglyceridemia
CRESTOR is indicated as adjunctive therapy to diet for the treatment of adult patients with
hypertriglyceridemia.
1.4
Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)
CRESTOR is indicated as an adjunct to diet for the treatment of adult patients with primary
dysbetalipoproteinemia (Type III Hyperlipoproteinemia).
1.5
Adult Patients with Homozygous Familial Hypercholesterolemia
CRESTOR is indicated as adjunctive therapy to other lipid-lowering treatments (e.g., LDL
apheresis) or alone if such treatments are unavailable to reduce LDL-C, Total-C, and ApoB in
adult patients with homozygous familial hypercholesterolemia.
1.6
Slowing of the Progression of Atherosclerosis
CRESTOR is indicated as adjunctive therapy to diet to slow the progression of atherosclerosis in
adult patients as part of a treatment strategy to lower Total-C and LDL-C to target levels.
3
1.7
Primary Prevention of Cardiovascular Disease
In individuals without clinically evident coronary heart disease but with an increased risk of
cardiovascular disease based on DJH \HDUVROGLQPHQDQG years old in women,
hsCRP mg/L, and the presence of at least one additional cardiovascular disease risk factor
such as hypertension, low HDL-C, smoking, or a family history of premature coronary heart
disease, CRESTOR is indicated to:
x
x
x
1.8
reduce the risk of stroke
reduce the risk of myocardial infarction
reduce the risk of arterial revascularization procedures
Limitations of Use
CRESTOR has not been studied in Fredrickson Type I and V dyslipidemias.
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Information
The dose range for CRESTOR in adults is 5 to 40 mg orally once daily. The usual starting dose
is 10 to 20 mg once daily. The usual starting dose in adult patients with homozygous familial
hypercholesterolemia is 20 mg once daily.
The maximum CRESTOR dose of 40 mg should be used only for those patients who have not
achieved their LDL-C goal utilizing the 20 mg dose [see Warnings and Precautions (5.1)].
CRESTOR can be administered as a single dose at any time of day, with or without food. The
tablet should be swallowed whole.
When initiating CRESTOR therapy or switching from another HMG-CoA reductase inhibitor
therapy, the appropriate CRESTOR starting dose should first be utilized, and only then titrated
according to the patient’s response and individualized goal of therapy.
After initiation or upon titration of CRESTOR, lipid levels should be analyzed within
2 to 4 weeks and the dosage adjusted accordingly.
2.2
Pediatric Dosing
In heterozygous familial hypercholesterolemia, the recommended dose range is 5 to 10 mg orally
once daily in patients 8 to less than 10 years of age, and 5 to 20 mg orally once daily in patients
10 to 17 years of age.
In homozygous familial hypercholesterolemia, the recommended dose is 20 mg orally once daily
in patients 7 to 17 years of age.
4
2.3
Dosing in Asian Patients
In Asian patients, consider initiation of CRESTOR therapy with 5 mg once daily due to
increased rosuvastatin plasma concentrations. The increased systemic exposure should be taken
into consideration when treating Asian patients not adequately controlled at doses up to
20 mg/day [see Use in Specific Populations (8.8) and Clinical Pharmacology (12.3)].
2.4
Use with Concomitant Therapy
Patients taking cyclosporine
The dose of CRESTOR should not exceed 5 mg once daily [see Warnings and Precautions (5.1),
Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
Patients taking gemfibrozil
Avoid concomitant use of CRESTOR with gemfibrozil. If concomitant use cannot be avoided,
initiate CRESTOR at 5 mg once daily. The dose of CRESTOR should not exceed 10 mg once
daily [see Warnings and Precautions (5.1), Drug Interactions (7.2) and Clinical Pharmacology
(12.3)].
Patients taking atazanavir and ritonavir, lopinavir and ritonavir, or simeprevir
Initiate CRESTOR therapy with 5 mg once daily. The dose of CRESTOR should not exceed
10 mg once daily [see Warnings and Precautions (5.1), Drug Interactions (7.3) and Clinical
Pharmacology (12.3)].
2.5
Dosing in Patients with Severe Renal Impairment
For patients with severe renal impairment (CLcr <30 mL/min/1.73 m2) not on hemodialysis,
dosing of CRESTOR should be started at 5 mg once daily and not exceed 10 mg once daily [see
Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
3
DOSAGE FORMS AND STRENGTHS
5 mg: Yellow, round, biconvex, coated tablets. Debossed “CRESTOR” and “5” on one side of
the tablet.
10 mg: Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “10” on one side of
the tablet.
20 mg: Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “20” on one side of
the tablet.
40 mg: Pink, oval, biconvex, coated tablets. Debossed “CRESTOR” on one side and “40” on the
other side of the tablet.
5
4
CONTRAINDICATIONS
CRESTOR is contraindicated in the following conditions:
x
x
x
x
Patients with a known hypersensitivity to any component of this product. Hypersensitivity
reactions including rash, pruritus, urticaria, and angioedema have been reported with
CRESTOR [see Adverse Reactions (6.1)].
Patients with active liver disease, which may include unexplained persistent elevations of
hepatic transaminase levels [see Warnings and Precautions (5.2)].
Pregnancy [see Use in Specific Populations (8.1, 8.3)].
Lactation. Limited data indicate that CRESTOR is present in human milk. Because statins
have the potential for serious adverse reactions in nursing infants, women who require
CRESTOR treatment should not breastfeed their infants [see Use in Specific Populations
(8.2)].
5
WARNINGS AND PRECAUTIONS
5.1
Skeletal Muscle Effects
Cases of myopathy and rhabdomyolysis with acute renal failure secondary to
myoglobinuria have been reported with HMG-CoA reductase inhibitors, including
CRESTOR. These risks can occur at any dose level, but are increased at the highest dose
(40 mg).
CRESTOR should be prescribed with caution in patients with predisposing factors for myopathy
(e.g., age 65 years, inadequately treated hypothyroidism, renal impairment).
The risk of myopathy during treatment with CRESTOR may be increased with concurrent
administration of some other lipid-lowering therapies (fibrates or niacin), gemfibrozil,
cyclosporine, atazanavir/ritonavir, lopinavir/ritonavir, or simeprevir [see Dosage and
Administration (2) and Drug Interactions (7)]. Cases of myopathy, including rhabdomyolysis,
have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered
with colchicine, and caution should be exercised when prescribing CRESTOR with colchicine
[see Drug Interactions (7.7)].
CRESTOR therapy should be discontinued if markedly elevated creatine kinase levels occur or
myopathy is diagnosed or suspected. CRESTOR therapy should also be temporarily withheld in
any patient with an acute, serious condition suggestive of myopathy or predisposing to the
development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension,
dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or
uncontrolled seizures).
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an
autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle
6
weakness and elevated serum creatine kinase, which persist despite discontinuation of statin
treatment; muscle biopsy showing necrotizing myopathy without significant inflammation;
improvement with immunosuppressive agents.
All patients should be advised to promptly report to their physician unexplained muscle pain,
tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and
symptoms persist after discontinuing CRESTOR.
5.2
Liver Enzyme Abnormalities
It is recommended that liver enzyme tests be performed before the initiation of CRESTOR, and
if signs or symptoms of liver injury occur.
Increases in serum transaminases [AST (SGOT) or ALT (SGPT)] have been reported with
HMG-CoA reductase inhibitors, including CRESTOR. In most cases, the elevations were
transient and resolved or improved on continued therapy or after a brief interruption in therapy.
There were two cases of jaundice, for which a relationship to CRESTOR therapy could not be
determined, which resolved after discontinuation of therapy. There were no cases of liver failure
or irreversible liver disease in these trials.
In a pooled analysis of placebo-controlled trials, increases in serum transaminases to >3 times
the upper limit of normal occurred in 1.1% of patients taking CRESTOR versus 0.5% of patients
treated with placebo.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients
taking statins, including rosuvastatin. If serious liver injury with clinical symptoms and/or
hyperbilirubinemia or jaundice occurs during treatment with CRESTOR, promptly interrupt
therapy. If an alternate etiology is not found, do not restart CRESTOR.
CRESTOR should be used with caution in patients who consume substantial quantities of
alcohol and/or have a history of chronic liver disease [see Clinical Pharmacology (12.3)]. Active
liver disease, which may include unexplained persistent transaminase elevations, is a
contraindication to the use of CRESTOR [see Contraindications (4)].
5.3
Concomitant Coumarin Anticoagulants
Caution should be exercised when anticoagulants are given in conjunction with CRESTOR
because of its potentiation of the effect of coumarin-type anticoagulants in prolonging the
prothrombin time/INR. In patients taking coumarin anticoagulants and CRESTOR
concomitantly, INR should be determined before starting CRESTOR and frequently enough
during early therapy to ensure that no significant alteration of INR occurs [see Drug Interactions
(7.4)].
7
5.4
Proteinuria and Hematuria
In the CRESTOR clinical trial program, dipstick-positive proteinuria and microscopic hematuria
were observed among CRESTOR treated patients. These findings were more frequent in patients
taking CRESTOR 40 mg, when compared to lower doses of CRESTOR or comparator
HMG-CoA reductase inhibitors, though it was generally transient and was not associated with
worsening renal function. Although the clinical significance of this finding is unknown, a dose
reduction should be considered for patients on CRESTOR therapy with unexplained persistent
proteinuria and/or hematuria during routine urinalysis testing.
5.5
Endocrine Effects
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA
reductase inhibitors, including CRESTOR. Based on clinical trial data with CRESTOR, in some
instances these increases may exceed the threshold for the diagnosis of diabetes mellitus [see
Adverse Reactions (6.1)].
Although clinical studies have shown that CRESTOR alone does not reduce basal plasma
cortisol concentration or impair adrenal reserve, caution should be exercised if CRESTOR is
administered concomitantly with drugs that may decrease the levels or activity of endogenous
steroid hormones such as ketoconazole, spironolactone, and cimetidine.
6
ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the
label:
x
Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy (including
myositis) [see Warnings and Precautions (5.1)]
x
Liver enzyme abnormalities [see Warnings and Precautions (5.2)]
6.1
Clinical Studies Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in clinical practice.
In the CRESTOR controlled clinical trials database (placebo or active-controlled) of
5394 patients with a mean treatment duration of 15 weeks, 1.4% of patients discontinued due to
adverse reactions. The most common adverse reactions that led to treatment discontinuation
were:
x
myalgia
x
abdominal pain
8
x
nausea
7KHPRVWFRPPRQO\UHSRUWHGDGYHUVHUHDFWLRQVLQFLGHQFHLQWKH&5(6725FRQWUROOHG
clinical trial database of 5394 patients were:
x
headache
x
myalgia
x
abdominal pain
x
asthenia
x
nausea
$GYHUVHUHDFWLRQVUHSRUWHGLQ2% of patients in placebo-controlled clinical studies and at a rate
greater than placebo are shown in Table 1. These studies had a treatment duration of up to
12 weeks.
Table 1. Adverse Reactions1 5HSRUWHGLQRI3DWLHQWV7UHDWHGZLWK&5(6725and
> Placebo in Placebo-Controlled Trials (% of Patients)
Adverse
Reactions
CRESTOR CRESTOR CRESTOR
5 mg
10 mg
20 mg
N=291
N=283
N=64
Headache
5.5
4.9
3.1
Nausea
3.8
3.5
6.3
Myalgia
3.1
2.1
6.3
Asthenia
2.4
3.2
4.7
Constipation
2.1
2.1
4.7
1
Adverse reactions by COSTART preferred term.
CRESTOR
40 mg
N=106
8.5
0
1.9
0.9
2.8
Total CRESTOR
5 mg-40 mg
N=744
5.5
3.4
2.8
2.7
2.4
Placebo
N=382
5.0
3.1
1.3
2.6
2.4
Other adverse reactions reported in clinical studies were abdominal pain, dizziness,
hypersensitivity (including rash, pruritus, urticaria, and angioedema) and pancreatitis. The
following laboratory abnormalities have also been reported: dipstick-positive proteinuria and
microscopic hematuria [see Warnings and Precautions (5.4)]; elevated creatine phosphokinase,
transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid
function abnormalities.
In the METEOR study, involving 981 participants treated with rosuvastatin 40 mg (n=700) or
placebo (n=281) with a mean treatment duration of 1.7 years, 5.6% of subjects treated with
CRESTOR versus 2.8% of placebo-treated subjects discontinued due to adverse reactions. The
most common adverse reactions that led to treatment discontinuation were: myalgia, hepatic
enzyme increased, headache, and nausea [see Clinical Studies (14.8)].
$GYHUVHUHDFWLRQVUHSRUWHGLQ2% of patients and at a rate greater than placebo are shown in
Table 2.
9
Table 2. Adverse Reactions1 Reported in 2% of Patients Treated with
CRESTOR and > Placebo in the METEOR Trial (% of Patients)
Adverse Reactions
CRESTOR 40 mg
N=700
Myalgia
12.7
Arthralgia
10.1
Headache
6.4
Dizziness
4.0
Increased CPK
2.6
Abdominal pain
2.4
ALT >3x ULN2
2.2
1
Adverse reactions by MedDRA preferred term.
2
Frequency recorded as abnormal laboratory value.
Placebo
N=281
12.1
7.1
5.3
2.8
0.7
1.8
0.7
In the JUPITER study, 17,802 participants were treated with rosuvastatin 20 mg (n=8901) or
placebo (n=8901) for a mean duration of 2 years. A higher percentage of rosuvastatin-treated
patients versus placebo-treated patients, 6.6% and 6.2%, respectively, discontinued study
medication due to an adverse event, irrespective of treatment causality. Myalgia was the most
common adverse reaction that led to treatment discontinuation.
In JUPITER, there was a significantly higher frequency of diabetes mellitus reported in patients
taking rosuvastatin (2.8%) versus patients taking placebo (2.3%). Mean HbA1c was significantly
increased by 0.1% in rosuvastatin-treated patients compared to placebo-treated patients. The
number of patients with a HbA1c >6.5% at the end of the trial was significantly higher in
rosuvastatin-treated versus placebo-treated patients [see Warnings and Precautions (5.5) and
Clinical Studies (14.9)].
Adverse reactions reported in 2% of patients and at a rate greater than placebo are shown in
Table 3.
Table 3. Adverse Reactions1 5HSRUWHGLQRI3DWLHQWV7UHDWHGZLWK
CRESTOR and > Placebo in the JUPITER Trial (% of Patients)
Adverse Reactions
CRESTOR 20 mg
N=8901
Myalgia
7.6
Arthralgia
3.8
Constipation
3.3
Diabetes mellitus
2.8
Nausea
2.4
1
Treatment-emergent adverse reactions by MedDRA preferred term.
Placebo
N=8901
6.6
3.2
3.0
2.3
2.3
Pediatric Patients with Heterozygous Familial Hypercholesterolemia
In a 12-week controlled study in boys and postmenarcheal girls 10 to 17 years of age with
heterozygous familial hypercholesterolemia with CRESTOR 5 to 20 mg daily [see Use in
Specific Populations (8.4) and Clinical Studies (14.7)], elevations in serum creatine
phosphokinase (CK) >10 x ULN were observed more frequently in rosuvastatin compared with
10
placebo-treated children. Four of 130 (3%) children treated with rosuvastatin (2 treated with
10 mg and 2 treated with 20 mg) had increased CK >10 x ULN, compared to 0 of 46 children on
placebo.
6.2
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of CRESTOR:
arthralgia, fatal and non-fatal hepatic failure, hepatitis, jaundice, thrombocytopenia, depression,
sleep disorders (including insomnia and nightmares), peripheral neuropathy and gynecomastia.
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.
There have been rare reports of immune-mediated necrotizing myopathy associated with statin
use [see Warnings and Precautions (5.1)].
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss,
forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These
cognitive issues have been reported for 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).
7
DRUG INTERACTIONS
7.1
Cyclosporine
Cyclosporine increased rosuvastatin exposure (AUC) 7-fold. Therefore, in patients taking
cyclosporine, the dose of CRESTOR should not exceed 5 mg once daily [see Dosage and
Administration (2.4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
7.2
Gemfibrozil
Gemfibrozil significantly increased rosuvastatin exposure. Due to an observed increased risk of
myopathy/rhabdomyolysis, combination therapy with CRESTOR and gemfibrozil should be
avoided. If used together, the dose of CRESTOR should not exceed 10 mg once daily [see
Clinical Pharmacology (12.3)].
7.3
Protease Inhibitors
Coadministration of rosuvastatin with certain protease inhibitors has differing effects on
rosuvastatin exposure. Simeprevir, which is a hepatitis C virus (HCV) protease inhibitor, or
combinations of atazanavir/ritonavir or lopinavir/ritonavir, which are HIV-1 protease inhibitors,
increase rosuvastatin exposure (AUC) up to threefold [see Table 4 – Clinical Pharmacology
(12.3)]. For these protease inhibitors, the dose of CRESTOR should not exceed 10 mg once
daily. The combinations of fosamprenavir/ritonavir or tipranavir/ritonavir, which are HIV-1
11
protease inhibitors, produce little or no change in rosuvastatin exposure. Caution should be
exercised when rosuvastatin is coadministered with protease inhibitors [see Dosage and
Administration (2.4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
7.4
Coumarin Anticoagulants
CRESTOR significantly increased INR in patients receiving coumarin anticoagulants. Therefore,
caution should be exercised when coumarin anticoagulants are given in conjunction with
CRESTOR. In patients taking coumarin anticoagulants and CRESTOR concomitantly, INR
should be determined before starting CRESTOR and frequently enough during early therapy to
ensure that no significant alteration of INR occurs [see Warnings and Precautions (5.3) and
Clinical Pharmacology (12.3)].
7.5
Niacin
The risk of skeletal muscle effects may be enhanced when CRESTOR is used in combination
with lipid-PRGLI\LQJGRVHV g/day) of niacin; caution should be used when prescribing with
CRESTOR [see Warnings and Precautions (5.1)].
7.6
Fenofibrate
When CRESTOR was coadministered with fenofibrate, no clinically significant increase in the
AUC of rosuvastatin or fenofibrate was observed. Because it is known that the risk of myopathy
during treatment with HMG-CoA reductase inhibitors is increased with concomitant use of
fenofibrates, caution should be used when prescribing fenofibrates with CRESTOR [see
Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
7.7
Colchicine
Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase
inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be
exercised when prescribing CRESTOR with colchicine [see Warnings and Precautions (5.1)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
CRESTOR is contraindicated for use in pregnant women since safety in pregnant women has not
been established and there is no apparent benefit to therapy with CRESTOR during pregnancy.
Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the
synthesis of other biologically active substances derived from cholesterol, CRESTOR may cause
fetal harm when administered to pregnant women. CRESTOR should be discontinued as soon as
pregnancy is recognized [see Contraindications (4)]. Limited published data on the use of
12
rosuvastatin are insufficient to determine a drug-associated risk of major congenital
malformations or miscarriage. In animal reproduction studies, there were no adverse
developmental effects with oral administration of rosuvastatin during organogenesis at systemic
exposures equivalent to a maximum recommended human dose (MRHD) of 40 mg/day in rats or
rabbits (based on AUC and body surface area, respectively). In rats and rabbits, decreased
pup/fetal survival occurred at 12 times and equivalent, respectively, to the MRHD of 40 mg/day
[see Data].
The estimated background risk of major birth defects and miscarriage for the indicated
population is unknown. In the U.S. general population, the estimated background risk of major
birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
respectively.
Data
Human Data
Limited published data on rosuvastatin have not shown an increased risk of major congenital
malformations or miscarriage. Rare reports of congenital anomalies have been received
following intrauterine exposure to other statins. In a review of approximately 100 prospectively
followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of
congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what
would be expected in the general population. The number of cases is adequate to exclXGHDWR
4-fold increase in congenital anomalies over the background incidence. In 89% of the
prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was
discontinued at some point in the first trimester when pregnancy was identified.
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. A higher fetal tissue distribution (25%
maternal plasma concentration) was observed in rabbits after a single oral gavage dose of
1 mg/kg on gestation day 18.
Rosuvastatin administration did not indicate a teratogenic effect LQUDWVDWPJNJGD\RULQ
UDEELWV3 mg/kg/day (doses equivalent to the MRHD of 40 mg/day based on AUC and body
surface area, respectively).
In female rats given 5, 15 and 50 mg/kg/day before mating and continuing through to gestation
day 7 resulted in decreased fetal body weight (female pups) and delayed ossification at
50 mg/kg/day (10 times the human exposure at the MRHD dose of 40 mg/day based on AUC).
In pregnant rats given 2, 10 and 50 mg/kg/day of rosuvastatin from gestation day 7 through
lactation day 21 (weaning), decreased pup survival occurred at 50 mg/kg/day (dose equivalent to
12 times the MRHD of 40 mg/day based body surface area).
13
In pregnant rabbits given 0.3, 1, and 3 mg/kg/day of rosuvastatin from gestation day 6 to day 18,
decreased fetal viability and maternal mortality was observed at 3 mg/kg/day (dose equivalent to
the MRHD of 40 mg/day based on body surface area).
8.2
Lactation
Risk Summary
Rosuvastatin use is contraindicated during breastfeeding [see Contraindications (4)]. Limited
data indicate that CRESTOR 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. Because
of the potential for serious adverse reactions in a breastfed infant, advise patients that
breastfeeding is not recommended during treatment with CRESTOR.
8.3
Females and Males of Reproductive Potential
Contraception
CRESTOR may cause fetal harm when administered to a pregnant woman [see Use in Specific
Populations (8.1)]. Advise females of reproductive potential to use effective contraception
during treatment with CRESTOR.
8.4
Pediatric Use
In children and adolescents 8 to 17 years of age with heterozygous familial
hypercholesterolemia, the safety and effectiveness of CRESTOR as an adjunct to diet to reduce
total cholesterol, LDL-C, and ApoB levels when, after an adequate trial of diet therapy, LDL-C
exceeds 190 mg/dL or when LDL-C exceeds 160 mg/dL and there is a positive family history of
premature CVD or two or more other CVD risk factors, were established in one controlled trial
and in one open-label, uncontrolled trial [see Clinical Studies (14.7)]. The long-term efficacy of
CRESTOR therapy initiated in childhood to reduce morbidity and mortality in adulthood has not
been established.
The safety and effectiveness of CRESTOR in children and adolescents 10 to 17 years of age with
heterozygous familial hypercholesterolemia were evaluated in a controlled clinical trial of
12 weeks duration followed by 40 weeks of open-label exposure. Patients treated with 5 mg,
10 mg, and 20 mg daily CRESTOR had an adverse experience profile generally similar to that of
patients treated with placebo. There was no detectable effect of CRESTOR on growth, weight,
BMI (body mass index), or sexual maturation [see Clinical Studies (14.7)] in children and
adolescents (10 to 17 years of age).
CRESTOR has not been studied in controlled clinical trials involving prepubertal patients or
patients younger than 10 years of age with heterozygous familial hypercholesterolemia.
However, the safety and effectiveness of CRESTOR were evaluated in a two year open-label
uncontrolled trial that included children and adolescents 8 to 17 years of age with heterozygous
familial hypercholesterolemia [see Clinical Studies (14.7)]. The safety and efficacy of
14
CRESTOR in lowering LDL-C appeared generally consistent with that observed for adult
patients, despite limitations of the uncontrolled study design.
Children and adolescents 7 to 15 years of age with homozygous familial hypercholesterolemia
were studied in a 6-week randomized, placebo-controlled, cross-over study with CRESTOR
20 mg once daily followed by 12 weeks of open-label treatment [see Clinical Studies (14.6)]. In
general, the safety profile in this trial was consistent with that of the previously established safety
profile in adults.
Although not all adverse reactions identified in the adult population have been observed in
clinical trials of children and adolescent patients, the same warnings and precautions for adults
should be considered for children and adolescents. Adolescent females should be counseled on
appropriate contraceptive methods while on CRESTOR therapy [see Use in Specific Populations
(8.1)].
8.5
Geriatric Use
Of the 10,275 patients in clinical studies with CRESTOR, 3159 (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, and other reported clinical experience has
not identified differences in responses between the elderly and younger patients, but greater
sensitivity of some older individuals cannot be ruled out.
Elderly patients are at higher risk of myopathy and CRESTOR should be prescribed with caution
in the elderly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
8.6
Renal Impairment
Rosuvastatin exposure is not influenced by mild to moderate renal impairment
(CLcr 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 and dose adjustment is required [see Dosage and Administration (2.5),
Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
8.7
Hepatic Impairment
CRESTOR is contraindicated in patients with active liver disease, which may include
unexplained persistent elevations of hepatic transaminase levels. Chronic alcohol liver disease is
known to increase rosuvastatin exposure; CRESTOR should be used with caution in these
patients [see Contraindications (4), Warning and Precautions (5.2) and Clinical Pharmacology
(12.3)].
8.8
Asian Patients
Pharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure
to rosuvastatin in Asian subjects when compared with Caucasian controls. CRESTOR dosage
15
should be adjusted in Asian patients [see Dosage and Administration (2.3) and Clinical
Pharmacology (12.3)].
10
OVERDOSAGE
There is no specific treatment in the event of overdose. In the event of overdose, the patient
should be treated symptomatically and supportive measures instituted as required. Hemodialysis
does not significantly enhance clearance of rosuvastatin.
11
DESCRIPTION
CRESTOR (rosuvastatin calcium) is a synthetic lipid-lowering agent for oral administration.
The chemical name for rosuvastatin calcium is bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2[methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]
calcium salt with the following structural formula:
The empirical formula for rosuvastatin calcium is (C22H27FN3O6S)2Ca and the molecular weight
is 1001.14. Rosuvastatin calcium is a white amorphous powder that is sparingly soluble in water
and methanol, and slightly soluble in ethanol. Rosuvastatin calcium is a hydrophilic compound
with a partition coefficient (octanol/water) of 0.13 at pH of 7.0.
CRESTOR Tablets for oral administration contain 5, 10, 20, or 40 mg of rosuvastatin and the
following inactive ingredients: Each tablet contains: microcrystalline cellulose NF, lactose
monohydrate NF, tribasic calcium phosphate NF, crospovidone NF, magnesium stearate NF,
hypromellose NF, triacetin NF, titanium dioxide USP, yellow ferric oxide, and red ferric oxide
NF.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
CRESTOR is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting
enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of
cholesterol. In vivo studies in animals, and in vitro studies in cultured animal and human cells
have shown rosuvastatin to have a high uptake into, and selectivity for, action in the liver, the
16
target organ for cholesterol lowering. In in vivo and in vitro studies, rosuvastatin produces its
lipid-modifying effects in two ways. First, it increases the number of hepatic LDL receptors on
the cell-surface to enhance uptake and catabolism of LDL. Second, rosuvastatin inhibits hepatic
synthesis of VLDL, which reduces the total number of VLDL and LDL particles.
12.3 Pharmacokinetics
Absorption
In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were
reached 3 to 5 hours following oral dosing. Both Cmax and AUC increased in approximate
proportion to CRESTOR dose. The absolute bioavailability of rosuvastatin is approximately
20%.
Administration of CRESTOR with food did not affect the AUC of rosuvastatin.
The AUC of rosuvastatin does not differ following evening or morning drug administration.
Distribution
Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters.
Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and
independent of plasma concentrations.
Metabolism
Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is
recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed
principally by cytochrome P450 \ 2C9, and in vitro studies have demonstrated that N-desmethyl
rosuvastatin has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity
of the parent compound. Overall, greater than 90% of active plasma HMG-CoA reductase
inhibitory activity is accounted for by the parent compound.
Excretion
Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces
(90%). The elimination half-life (t1/2) of rosuvastatin is approximately 19 hours.
After an intravenous dose, approximately 28% of total body clearance was via the renal route,
and 72% by the hepatic route.
Specific Populations
Race
A population pharmacokinetic analysis revealed no clinically relevant differences in
pharmacokinetics among Caucasian, Hispanic, and Black or Afro-Caribbean groups. However,
pharmacokinetic studies, including one conducted in the US, have demonstrated an approximate
17
2-fold elevation in median exposure (AUC and Cmax) in Asian subjects when compared with a
Caucasian control group.
Gender
There were no differences in plasma concentrations of rosuvastatin between men and women.
Pediatric
In a population pharmacokinetic analysis of two pediatric trials involving patients with
heterozygous familial hypercholesterolemia 10 to 17 years of age and 8 to 17 years of age,
respectively, rosuvastatin exposure appeared comparable to or lower than rosuvastatin exposure
in adult patients.
Geriatric
There were no differences in plasma concentrations of rosuvastatin between the nonelderly and
HOGHUO\SRSXODWLRQVDJH65 years).
Renal Impairment
Mild to moderate renal impairment (CLcr 30 mL/min/1.73 m2) had no influence on plasma
concentrations of rosuvastatin. However, plasma concentrations of rosuvastatin increased to a
clinically significant extent (about 3-fold) in patients with severe renal impairment (CLcr <30
mL/min/1.73 m2) not receiving hemodialysis compared with healthy subjects
(CLcr >80 mL/min/1.73 m2).
Hemodialysis
Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were
approximately 50% greater compared with healthy volunteer subjects with normal renal function.
Hepatic Impairment
In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were
modestly increased.
In patients with Child-Pugh A disease, Cmax and AUC were increased by 60% and 5%,
respectively, as compared with patients with normal liver function. In patients with Child-Pugh
B disease, Cmax and AUC were increased 100% and 21%, respectively, compared with patients
with normal liver function.
Drug-Drug Interactions
Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically
significant extent.
Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake
transporter organic anion-transporting polyprotein 1B1 (OATP1B1) and efflux transporter breast
cancer resistance protein (BCRP). Concomitant administration of CRESTOR with medications
18
that are inhibitors of these transporter proteins (e.g. cyclosporine, certain HIV protease
inhibitors) may result in increased rosuvastatin plasma concentrations and an increased risk of
myopathy [see Dosage and Administration (2.4)]. It is recommended that prescribers consult the
relevant product information when considering administration of such products together with
CRESTOR.
Table 4. Effect of Coadministered Drugs on Rosuvastatin Systemic Exposure
Coadministered drug and dosing
regimen
Rosuvastatin
Mean Ratio
(ratio with/without
coadministered drug)
No Effect=1.0
Dose (mg)1
Change in
AUC
Change in Cmax
Cyclosporine – stable dose required
(75 mg – 200 mg BID)
10 mg QD for
10 days
7.12
112
Atazanavir/ritonavir combination
300 mg/100 mg QD for 8 days
10 mg
3.12
72
10 mg, single
dose
20 mg QD for
7 days
2.82
(2.3-3.4)3
2.12
(1.7-2.6)3
1.92
(1.6-2.2)3
1.6
(1.4-1.7)3
1.5
(1.0-2.1)3
1.4
(1.2-1.6)3
3.22
(2.6-3.9)3
52
(3.4-6.4)3
2.22
(1.8-2.7)3
2
(1.8-2.3)3
2.4
(1.6-3.6)3
2.2
(1.8-2.7)3
Simeprevir 150 mg QD, 7 days
Lopinavir/ritonavir combination
400 mg/100 mg BID for 17 days
Gemfibrozil 600 mg BID for 7 days
Eltrombopag 75 mg QD, 5 days
Darunavir 600 mg/ritonavir 100 mg
BID, 7 days
Tipranavir/ritonavir combination
500 mg/200mg BID for 11 days
Dronedarone 400 mg BID
80 mg
10 mg
10 mg QD for 7
days
10 mg
10 mg
1.4
Itraconazole 200 mg QD, 5 days
10 mg QD for
14 days
1.4
(1.2-1.6)3
1.3
(1.1-1.4)3
1.2
(0.9-1.6)3
1.4
(1.2-1.5)3
1.2
(0.9-1.4)3
1.2
(0.8-1.6)3
10 mg
1.1
1.5
10 mg
ļ
1.2
(1.1-1.3)3
10 mg or 80 mg
Ezetimibe 10 mg QD, 14 days
Fosamprenavir/ritonavir
700 mg/100 mg BID for 7 days
Fenofibrate 67 mg TID for 7 days
19
Table 4. Effect of Coadministered Drugs on Rosuvastatin Systemic Exposure
Coadministered drug and dosing
regimen
Rifampicin 450 mg QD, 7 days
Aluminum & magnesium hydroxide
combination antacid
Administered simultaneously
Administered 2 hours apart
Rosuvastatin
20 mg
ļ
40 mg
40 mg
0.52
(0.4-0.5)3
0.8
(0.7-0.9)3
1.0
(0.8-1.2)3
1.1
(1.0-1.3)3
0.8
(0.7-0.9)3
Ketoconazole 200 mg BID for 7 days
80 mg
Fluconazole 200 mg QD for 11 days
80 mg
Erythromycin 500 mg QID for 7 days
80 mg
0.52
(0.4-0.6)3
0.8
(0.7-1.0)3
1.0
(0.7-1.3)3
1.1
(0.9-1.4)3
0.7
(0.5-0.9)3
1
Single dose unless otherwise noted.
Clinically significant [see Dosage and Administration (2) and Warnings and Precautions (5)]
3
Mean ratio with 90% CI (with/without coadministered drug, e.g., 1= no change, 0.7 = 30% decrease,
11=11 fold increase in exposure)
2
Table 5. Effect of Rosuvastatin Coadministration on Systemic Exposure to Other Drugs
Rosuvastatin Dosage
Regimen
Coadministered Drug
Mean Ratio
(ratio with/without
coadministered drug)
No Effect=1.0
Name and Dose
40 mg QD for 10 days
Warfarin1
25 mg single dose
40 mg QD for 12 days
Digoxin
0.5 mg single dose
40 mg QD for 28 days Oral Contraceptive
(ethinyl estradiol 0.035 mg & norgestrel 0.180,
0.215 and 0.250 mg) QD for 21 Days
Change in
AUC
R- Warfarin
1.0
(1.0-1.1)2
S-Warfarin
1.1
(1.0-1.1)2
1.0
(0.9-1.2)2
Change in
Cmax
R-Warfarin
1.0
(0.9-1.0)2
S-Warfarin
1.0
(0.9-1.1)2
1.0
(0.9-1.2)2
EE 1.3
(1.2-1.3)2
NG 1.3
(1.3-1.4)2
EE 1.3
(1.2-1.3)2
NG 1.2
(1.1-1.3)2
EE = ethinyl estradiol, NG = norgestrel
1
Clinically significant pharmacodynamic effects [see Warnings and Precautions (5.3)]
2
Mean ratio with 90% CI (with/without coadministered drug, e.g., 1= no change, 0.7=30% decrease,
11=11-fold increase in exposure)
20
12.5 Pharmacogenomics
Disposition of HMG-CoA reductase inhibitors, including rosuvastatin, involves OATP1B1 and
other transporter proteins. Higher plasma concentrations of rosuvastatin have been reported in
very small groups of patients (n=3 to 5) who have two reduced function alleles of the gene that
encodes OATP1B1 (SLCO1B1 521T > C). The frequency of this genotype (i.e., SLCO1B1 521
C/C) is generally lower than 5% in most racial/ethnic groups. The impact of this polymorphism
on efficacy and/or safety of rosuvastatin has not been clearly established.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60, or 80 mg/kg/day by oral
gavage, the incidence of uterine stromal polyps was significantly increased in females at
80 mg/kg/day at systemic exposure 20 times the human exposure at 40 mg/day based on AUC.
Increased incidence of polyps was not seen at lower doses.
In a 107-week carcinogenicity study in mice given 10, 60, or 200 mg/kg/day by oral gavage, an
increased incidence of hepatocellular adenoma/carcinoma was observed at 200 mg/kg/day at
systemic exposures 20 times the human exposure at 40 mg/day based on AUC. An increased
incidence of hepatocellular tumors was not seen at lower doses.
Rosuvastatin was not mutagenic or clastogenic with or without metabolic activation in the Ames
test with Salmonella typhimurium and Escherichia coli, the mouse lymphoma assay, and the
chromosomal aberration assay in Chinese hamster lung cells. Rosuvastatin was negative in the in
vivo mouse micronucleus test.
In rat fertility studies with oral gavage doses of 5, 15, 50 mg/kg/day, males were treated for
9 weeks prior to and throughout mating and females were treated 2 weeks prior to mating and
throughout mating until gestation day 7. No adverse effect on fertility was observed at
50 mg/kg/day (systemic exposures up to 10 times the human exposure at 40 mg/day based on
AUC). In testicles of dogs treated with rosuvastatin at 30 mg/kg/day for one month, spermatidic
giant cells were seen. Spermatidic giant cells were observed in monkeys after 6-month treatment
at 30 mg/kg/day in addition to vacuolation of seminiferous tubular epithelium. Exposures in the
dog were 20 times and in the monkey 10 times the human exposure at 40 mg/day based on body
surface area. Similar findings have been seen with other drugs in this class.
13.2 Animal Toxicology and/or Pharmacology
Central Nervous System Toxicity
CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell
infiltration of perivascular spaces, have been observed in dogs treated with several other
members of this drug class. A chemically similar drug in this class produced dose-dependent
21
optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at a dose
that produced plasma drug levels about 30 times higher than the mean drug level in humans
taking the highest recommended dose. Edema, hemorrhage, and partial necrosis in the
interstitium of the choroid plexus was observed in a female dog sacrificed moribund at day 24 at
90 mg/kg/day by oral gavage (systemic exposures 100 times the human exposure at 40 mg/day
based on AUC). Corneal opacity was seen in dogs treated for 52 weeks at 6 mg/kg/day by oral
gavage (systemic exposures 20 times the human exposure at 40 mg/day based on AUC).
Cataracts were seen in dogs treated for 12 weeks by oral gavage at 30 mg/kg/day (systemic
exposures 60 times the human exposure at 40 mg/day based on AUC). Retinal dysplasia and
retinal loss were seen in dogs treated for 4 weeks by oral gavage at 90 mg/kg/day (systemic
exposures 100 times the human exposure at 40 PJGD\EDVHGRQ$8&'RVHV mg/kg/day
V\VWHPLFH[SRVXUHV times the human exposure at 40 mg/day based on AUC) did not reveal
retinal findings during treatment for up to one year.
Juvenile Toxicology Study
In a juvenile study, rats were dosed by oral gavage with 10 or 50 mg/kg/day from weaning for 9
weeks prior to pairing, throughout pairing and up to the day before necropsy for males or up to
gestation day 7 for females. No effects on sexual development, testicular and epididymal
appearance or fertility were observed at either dose level (2 times or up to 24 times the human
exposure (AUC) at the maximum pediatric dose of 20 mg/day).
14
CLINICAL STUDIES
CRESTOR reduces Total-C, LDL-C, ApoB, nonHDL-C, and TG, and increases HDL-C, in adult
patients with hyperlipidemia and mixed dyslipidemia.
Dose-Ranging Study: In a multicenter, double-blind, placebo-controlled, dose-ranging study in
patients with hyperlipidemia CRESTOR given as a single daily dose for 6 weeks significantly
reduced Total-C, LDL-C, nonHDL-C, and ApoB, across the dose range (Table 6).
Table 6. Dose-Response in Patients with Hyperlipidemia (Adjusted Mean % Change
from Baseline at Week 6)
Dose
Placebo
CRESTOR 5 mg
CRESTOR 10 mg
CRESTOR 20 mg
CRESTOR 40 mg
N
13
17
17
17
18
Total-C
-5
-33
-36
-40
-46
LDL-C
-7
-45
-52
-55
-63
22
Non-HDL-C
-7
-44
-48
-51
-60
ApoB
-3
-38
-42
-46
-54
TG
-3
-35
-10
-23
-28
HDL-C
3
13
14
8
10
Active-Controlled Study: CRESTOR was compared with the HMG-CoA reductase inhibitors
atorvastatin, simvastatin, and pravastatin in a multicenter, open-label, dose-ranging study of
2240 patients with hyperlipidemia or mixed dyslipidemia. After randomization, patients were
treated for 6 weeks with a single daily dose of either CRESTOR, atorvastatin, simvastatin, or
pravastatin (Figure 1 and Table 7).
Figure 1. Percent LDL-C Change by Dose of CRESTOR, Atorvastatin, Simvastatin, and
Pravastatin at Week 6 in Patients with Hyperlipidemia or Mixed Dyslipidemia
Box plots are a representation of the 25th, 50th, and 75th percentile values, with whiskers
representing the 10th and 90th percentile values. Mean baseline LDL-C: 189 mg/dL
Table 7. Percent Change in LDL-C From Baseline to Week 6 (LS Mean1) by
Treatment Group (Sample Sizes Ranging from 156–167 Patients Per Group)
Treatment
Treatment Daily Dose
10 mg
20 mg
40 mg
80 mg
CRESTOR
-462
-523
-554
--Atorvastatin
-37
-43
-48
-51
Simvastatin
-28
-35
-39
-46
Pravastatin
-20
-24
-30
--1
Corresponding standard errors are approximately 1.00
2
CRESTOR 10 mg reduced LDL-C significantly more than atorvastatin 10 mg; pravastatin 10 mg,
20 mg, and 40 mg; simvastatin 10 mg, 20 mg, and 40 mg. (p<0.002)
3
CRESTOR 20 mg reduced LDL-C significantly more than atorvastatin 20 mg and 40 mg;
pravastatin 20 mg and 40 mg; simvastatin 20 mg, 40 mg, and 80 mg. (p<0.002)
4
CRESTOR 40 mg reduced LDL-C significantly more than atorvastatin 40 mg; pravastatin 40 mg;
simvastatin 40 mg, and 80 mg. (p<0.002)
14.2 Heterozygous Familial Hypercholesterolemia
Active-Controlled Study: In a study of patients with heterozygous FH (baseline mean LDL of
291), patients were randomized to CRESTOR 20 mg or atorvastatin 20 mg. The dose was
23
increased by 6-week intervals. Significant LDL-C reductions from baseline were seen at each
dose in both treatment groups (Table 8).
Table 8. Mean LDL-C Percentage Change from Baseline
Atorvastatin (n=187)
CRESTOR (n=435)
LS Mean1 (95% CI)
LS Mean1 (95% CI)
Week 6
20 mg
-47% (-49%, -46%)
-38% (-40%, -36%)
Week 12
40 mg
-55% (-57%, -54%)
-47% (-49%, -45%)
Week 18
80 mg
NA
-52% (-54%, -50%)
1
LS Means are least square means adjusted for baseline LDL-C
Dose-Response Study: In a double-blind, placebo-controlled dose-response study in patients
with baseline TG levels from 273 to 817 mg/dL, CRESTOR given as a single daily dose
(5 to 40 mg) over 6 weeks significantly reduced serum TG levels (Table 9).
Table 9. Dose-Response in Patients with Primary Hypertriglyceridemia over 6 Weeks
Dosing Median (Min, Max) Percent Change from Baseline
Dose
Placebo
(n=26)
Triglycerides
nonHDL-C
VLDL-C
Total-C
LDL-C
HDL-C
1 (-40, 72)
2 (-13, 19)
2 (-36, 53)
1 (-13, 17)
5 (-30, 52)
-3 (-25, 18)
CRESTOR
5 mg
(n=25)
-21 (-58, 38)
-29 (-43, -8)
-25 (-62, 49)
-24 (-40, -4)
-28 (-71, 2)
3 (-38, 33)
CRESTOR
10 mg
(n=23)
-37 (-65, 5)
-49 (-59, -20)
-48 (-72, 14)
-40 (-51, -14)
-45 (-59, 7)
8 (-8, 24)
CRESTOR
20 mg
(n=27)
-37 (-72, 11)
-43 (-74, 12)
-49 (-83, 20)
-34 (-61, -11)
-31 (-66, 34)
22 (-5, 50)
CRESTOR
40 mg
(n=25)
-43 (-80, -7)
-51 (-62, -6)
-56 (-83, 10)
-40 (-51, -4)
-43 (-61, -3)
17 (-14, 63)
In a randomized, multicenter, double-blind crossover study, 32 patients (2ZLWKɽɽDQG with
apo E mutation [Arg145Cys] with primary dysbetalipoproteinemia (Type III
Hyperlipoproteinemia) entered a 6-week dietary lead-in period on the NCEP Therapeutic
Lifestyle Change (TLC) diet. Following dietary lead-in, patients were randomized to a sequence
of treatments in conjunction with the TLC diet for 6 weeks each: rosuvastatin 10 mg followed by
rosuvastatin 20 mg or rosuvastatin 20 mg followed by rosuvastatin 10 mg. CRESTOR reduced
non HDL-C (primary end point) and circulating remnant lipoprotein levels. Results are shown in
the table below.
Table 10. Lipid-modifying Effects of Rosuvastatin 10 mg and 20 mg in Primary
Dysbetalipoproteinemia (Type III hyperlipoproteinemia) After Six Weeks by Median
Percent Change (95% CI) from Baseline (N=32)
Total-C
Median at
Baseline
(mg/dL)
342.5
Median percent change
from baseline (95% CI)
CRESTOR 10 mg
-43.3
24
Median percent change from
baseline (95% CI) CRESTOR
20 mg
-47.6
Table 10. Lipid-modifying Effects of Rosuvastatin 10 mg and 20 mg in Primary
Dysbetalipoproteinemia (Type III hyperlipoproteinemia) After Six Weeks by Median
Percent Change (95% CI) from Baseline (N=32)
Median at
Baseline
(mg/dL)
Triglycerides
503.5
NonHDL-C
294.5
VLDL-C + IDL-C
209.5
LDL-C
112.5
HDL-C
35.5
RLP-C
82.0
Apo-E
16.0
from baseline (95% CI)
CRESTOR 10 mg
(-46.9, – 37.5)
-40.1
(-44.9, -33.6)
-48.2
(-56.7, -45.6)
-46.8
(-53.7, -39.4)
-54.4
(-59.1, -47.3)
10.2
(1.9, 12.3)
-56.4
(-67.1, -49.0)
-42.9
(-46.3, -33.3)
Median percent change from
baseline (95% CI) CRESTOR
20 mg
(-51.6,-42.8)
-43.0
(-52.5, -33.1)
-56.4
(-61.4, -48.5)
-56.2
(-67.7, -43.7)
-57.3
(-59.4, -52.1)
11.2
(8.3, 20.5)
-64.9
(-74.0, -56.6)
-42.5
(-47.1, -35.6)
14.5 Homozygous Familial Hypercholesterolemia
Dose-Titration Study: In an open-label, forced-titration study, homozygous FH patients (n=40,
8-63 years) were evaluated for their response to CRESTOR 20 to 40 mg titrated at a 6-week
interval. In the overall population, the mean LDL-C reduction from baseline was 22%. About
one-third of the patients benefited from increasing their dose from 20 mg to 40 mg with further
LDL lowering of greater than 6%. In the 27 patients with at least a 15% reduction in LDL-C, the
mean LDL-C reduction was 30% (median 28% reduction). Among 13 patients with an LDL-C
reduction of <15%, 3 had no change or an increase in LDL-C. Reductions in LDL-C of 15% or
greater were observed in 3 of 5 patients with known receptor negative status.
14.6 Pediatric Patients with Homozygous Familial
Hypercholesterolemia
CRESTOR was studied in a randomized, double-blind, placebo-controlled, multicenter, crossover study in 14 children and adolescents with homozygous familial hypercholesterolemia. The
study included a 4-week dietary lead-in phase during which patients received CRESTOR 10 mg
daily, a cross-over phase that included two 6-week treatment periods with either CRESTOR
20 mg or placebo in random order, followed by a 12-week open-label phase during which all
patients received CRESTOR 20 mg. Patients ranged in age from 7 to 15 years of age (median 11
years), 50% were male, 71% were Caucasian, 21% were Asian, 7% were Black, and no patients
were of Hispanic ethnicity. Fifty percent were on apheresis therapy and 57% were taking
ezetimibe. Patients who entered the study on apheresis therapy or ezetimibe continued the
25
treatment throughout the entire study. Mean LDL-C at baseline was 416 mg/dL (range 152 to
716 mg/dL). A total of 13 patients completed both treatment periods of the randomized crossover phase; one patient withdrew consent due to inability to have blood drawn during the crossover phase.
CRESTOR 20 mg significantly reduced LDL-C, total cholesterol, ApoB, and non-HDL-C
compared to placebo (Table 11).
Table 11. Lipid-modifying Effects of Rosuvastatin in Pediatric Patients 7 to 15 years of
Age with Homozygous Familial Hypercholesterolemia After 6 Weeks
Placebo
CRESTOR 20 mg
Percent difference (95% CI)
(N=13)
(N=13)
LDL-C (mg/dL)
481
396
-22.3% (-33.5, -9.1)1
Total-C (mg/dL)
539
448
-20.1% (-29.7, -9.1)2
Non-HDL-C (mg/dL)
505
412
-22.9% (-33.7, -10.3)2
ApoB (mg/dL)
268
235
-17.1% (-29.2, -2.9)3
% Difference estimates are based on transformations of the estimated mean difference in log LDL
measurements between CRESTOR and placebo using a mixed model adjusted for study period
1
p=0.005, 2 p=0.003, 3 p=0.024
14.7 Pediatric Patients with Heterozygous Familial
Hypercholesterolemia
In a double blind, randomized, multicenter, placebo-controlled, 12 week study, 176 (97 male and
79 female) children and adolescents with heterozygous familial hypercholesterolemia were
randomized to rosuvastatin 5, 10 or 20 mg or placebo daily. Patients ranged in age from 10 to
17 years (median age of 14 years) with approximately 30% of the patients 10 to 13 years and
approximately 17%, 18%, 40%, and 25% at Tanner stages II, III, IV, and V, respectively.
Females were at least 1 year postmenarche. Mean LDL-C at baseline was 233 mg/dL (range of
129 to 399). The 12-week double blind phase was followed by a 40 week open label dosetitration phase, where all patients (n=173) received 5 mg, 10 mg or 20 mg rosuvastatin daily.
Rosuvastatin significantly reduced LDL-C (primary end point), total cholesterol and ApoB levels
at each dose compared to placebo. Results are shown in Table 12 below.
Table 12. Lipid-Modifying Effects of Rosuvastatin in Pediatric Patients 10 to
17 years of Age with Heterozygous Familial Hypercholesterolemia (Least-Squares
Mean Percent Change from Baseline To Week 12)
Dose (mg)
N
LDL-C
HDL-C
Total-C
TG1
ApoB
Placebo
46
-1%
+7%
0%
-7%
-2%
26
Table 12. Lipid-Modifying Effects of Rosuvastatin in Pediatric Patients 10 to
17 years of Age with Heterozygous Familial Hypercholesterolemia (Least-Squares
Mean Percent Change from Baseline To Week 12)
1
2
Dose (mg)
N
LDL-C
HDL-C
Total-C
TG1
ApoB
5
42
-38%
+4%2
-30%
-13%2
-32%
10
44
-45%
+11%2
-34%
-15%2
-38%
20
44
-50%
+9%2
-39%
16%2
-41%
Difference from placebo not statistically significant
At the end of the 12-week, double blind treatment period, the percentage of patients achieving
the LDL-C goal of less than 110 mg/dL (2.8 mmol/L) was 0% for placebo, 12% for rosuvastatin
5 mg, 41% for rosuvastatin 10 mg and 41% for rosuvastatin 20 mg. For the 40-week, open-label
phase, 71% of the patients were titrated to the maximum dose of 20 mg and 41% of the patients
achieved the LDL-C goal of 110 mg/dL.
Rosuvastatin was also studied in a two year open-label, uncontrolled, titration to goal trial that
included 175 children and adolescents with heterozygous familial hypercholesterolemia who
were 8 to 17 years old (79 boys and 96 girls). All patients had a documented genetic defect in the
LDL receptor or in Apo B. Approximately 89% were Caucasian, 7% were Asian, 1% were
Black, and fewer than 1% were Hispanic. Mean LDL-C at baseline was 236 mg/dL. Fifty-eight
(33%) patients were prepubertal at baseline. The starting rosuvastatin dosage for all children and
adolescents was 5 mg once daily. Children 8 to less than 10 years of age (n=41 at baseline) could
titrate to a maximum dosage of 10 mg once daily, and children and adolescents 10 to 17 years of
age could titrate to a maximum dosage of 20 mg once daily.
The reductions in LDL-C from baseline were generally consistent across age groups within the
trial as well as with previous experience in both adult and pediatric controlled trials.
The long-term efficacy of rosuvastatin therapy initiated in childhood to reduce morbidity and
mortality in adulthood has not been established.
In the Measuring Effects on Intima Media Thickness: an Evaluation Of Rosuvastatin 40 mg
(METEOR) study, the effect of therapy with CRESTOR on carotid atherosclerosis was assessed
by B-mode ultrasonography in patients with elevated LDL-C, at low risk (Framingham risk
<10% over ten years) for symptomatic coronary artery disease and with subclinical
atherosclerosis as evidenced by carotid intimal-medial thickness (cIMT). In this double-blind,
placebo-controlled clinical study 984 patients were randomized (of whom 876 were analyzed) in
27
a 5:2 ratio to CRESTOR 40 mg or placebo once daily. Ultrasonograms of the carotid walls were
used to determine the annualized rate of change per patient from baseline to two years in mean
maximum cIMT of 12 measured segments. The estimated difference in the rate of change in the
maximum cIMT analyzed over all 12 carotid artery sites between patients treated with
CRESTOR and placebo-treated patients was -0.0145 mm/year (95% CI –0.0196, –0.0093;
p <0.0001).
The annualized rate of change from baseline for the placebo group was +0.0131 mm/year
(p <0.0001). The annualized rate of change from baseline for the group treated with CRESTOR
was -0.0014 mm/year (p=0.32).
At an individual patient level in the group treated with CRESTOR, 52.1% of patients
demonstrated an absence of disease progression (defined as a negative annualized rate of
change), compared to 37.7% of patients in the placebo group.
In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial
Evaluating Rosuvastatin (JUPITER) study, the effect of CRESTOR (rosuvastatin calcium) on
the occurrence of major cardiovascular (CV) disease events was assessed in 17,802 men
50 \HDUVDQGZRPHQ 60 years) who had no clinically evident cardiovascular disease,
LDL-C levels <130 mg/dL (3.3 mmol/l) and hs-&53OHYHOV2 mg/L. The study population had
an estimated baseline coronary heart disease risk of 11.6% over 10 years based on the
Framingham risk criteria and included a high percentage of patients with additional risk factors
such as hypertension (58%), low HDL-C levels (23%), cigarette smoking (16%), or a family
history of premature CHD (12%). Study participants had a median baseline LDL-C of
108 mg/dL and hsCRP of 4.3 mg/L. Study participants were randomly assigned to placebo
(n=8901) or rosuvastatin 20 mg once daily (n=8901) and were followed for a mean duration of
2 years. The JUPITER study was stopped early by the Data Safety Monitoring Board due to
meeting predefined stopping rules for efficacy in rosuvastatin-treated subjects.
The primary end point was a composite end point consisting of the time-to-first occurrence of
any of the following major CV events: CV death, nonfatal myocardial infarction, nonfatal stroke,
hospitalization for unstable angina or an arterial revascularization procedure.
Rosuvastatin significantly reduced the risk of major CV events (252 events in the placebo group
vs. 142 events in the rosuvastatin group) with a statistically significant (p< 0.001) relative risk
reduction of 44% and absolute risk reduction of 1.2% (see Figure 2). The risk reduction for the
primary end point was consistent across the following predefined subgroups: age, sex, race,
smoking status, family history of premature CHD, body mass index, LDL-C, HDL-C, and
hsCRP levels.
28
Figure 2. Time to First Occurrence of Major Cardiovascular Events in JUPITER
The individual components of the primary end point are presented in Figure 3. Rosuvastatin
significantly reduced the risk of nonfatal myocardial infarction, nonfatal stroke, and arterial
revascularization procedures. There were no significant treatment differences between the
rosuvastatin and placebo groups for death due to cardiovascular causes or hospitalizations for
unstable angina.
Rosuvastatin significantly reduced the risk of myocardial infarction (6 fatal events and 62
nonfatal events in placebo-treated subjects vs. 9 fatal events and 22 nonfatal events in
rosuvastatin-treated subjects) and the risk of stroke (6 fatal events and 58 nonfatal events in
placebo-treated subjects vs. 3 fatal events and 30 nonfatal events in rosuvastatin-treated
subjects).
In a post-hoc subgroup analysis of JUPITER subjects (n=1405; rosuvastatin=725, placebo=680)
with a hsCRP 2 mg/L and no other traditional risk factors (smoking, BP 140/90 or taking
antihypertensives, low HDL-C) other than age, after adjustment for high HDL-C, there was no
significant treatment benefit with rosuvastatin treatment.
29
Figure 3. Major CV Events by Treatment Group in JUPITER
At one year, rosuvastatin increased HDL-C and reduced LDL-C, hsCRP, total cholesterol and
serum triglyceride levels (p <0.001 for all versus placebo).
16
HOW SUPPLIED/STORAGE AND HANDLING
CRESTOR® (rosuvastatin calcium) Tablets are supplied as:
x
x
x
x
x
x
NDC 0310-0755-90: 5 mg. Yellow, round, biconvex, coated tablets. Debossed
“CRESTOR” and “5” on one side; bottle of 90 tablets
NDC 0310-0751-90: 10 mg. Pink, round, biconvex, coated tablets. Debossed
“CRESTOR” and “10” on one side; bottle of 90 tablets
“CRESTOR” and “10” on one side; unit dose packages of 100
“CRESTOR” and “20” on one side; bottles of 90
“CRESTOR” and “20”on one side; unit dose packages of 100
NDC 0310-0754-30: 40 mg. Pink, oval, biconvex, coated tablets. Debossed “CRESTOR”
on one side and “40” on the other side; bottles of 30
Storage
Store at controlled room temperature, 20-25ºC (68-77ºF) [see USP Controlled Room
Temperature]. Protect from moisture.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
30
Patients should be instructed not to take 2 doses of CRESTOR within 12 hours of each other.
Skeletal Muscle Effects
Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness,
particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after
discontinuing CRESTOR.
Concomitant Use of Antacids
When taking CRESTOR with an aluminum and magnesium hydroxide combination antacid, the
antacid should be taken at least 2 hours after CRESTOR administration.
Embryofetal Toxicity
Advise females of reproductive potential of the risk to a fetus, to use effective contraception
during treatment, and to inform their healthcare provider of a known or suspected pregnancy.
[see Contraindications (4) and Use in Specific Populations (8.1, 8.3)].
Lactation
Advise women not to breastfeed during treatment with CRESTOR [see Contraindications (4)
and Use in Specific Populations (8.2)].
Liver Enzymes
It is recommended that liver enzyme tests be performed before the initiation of CRESTOR and if
signs or symptoms of liver injury occur. All patients treated with CRESTOR should be advised
to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right
upper abdominal discomfort, dark urine or jaundice.
CRESTOR is a trademark of the AstraZeneca group of companies.
© AstraZeneca 2015, 2016
Licensed from SHIONOGI & CO., LTD., Osaka, Japan
Distributed by:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
ASTRAZENECA
Rev. May 2016
31
PATIENT INFORMATION
CRESTOR®(Kres-tor)
rosuvastatin calcium
Tablets
Read this Patient Information carefully before you start taking CRESTOR and each
time you get a refill. If you have any questions about CRESTOR, ask your doctor.
Only your doctor can determine if CRESTOR is right for you.
What is CRESTOR?
CRESTOR is a prescription medicine that contains a cholesterol-lowering medicine
called rosuvastatin calcium. Most of the cholesterol in your blood is made in the liver.
CRESTOR works by reducing cholesterol in two ways: CRESTOR blocks an enzyme in
the liver causing the liver to make less cholesterol, and CRESTOR increases the
uptake and breakdown by the liver of cholesterol already in the blood.
x
x
CRESTOR is used along with diet to:
o lower the level of your “bad” cholesterol (LDL)
o increase the level of your “good” cholesterol (HDL)
o lower the level of fat in your blood (triglycerides)
o slow the buildup of fatty deposits (plaque) in the walls of blood vessels
CRESTOR is used to treat:
o adults who cannot control their cholesterol levels by diet and exercise alone
o children 8 to 17 years of age with heterozygous familial hypercholesterolemia (an
inherited condition that causes high levels of LDL)
o children 7 to 17 years of age with homozygous familial hypercholesterolemia (an
inherited condition that causes high levels of LDL).
CRESTOR is not approved for use in children with heterozygous familial
hypercholesterolemia younger than 8 years of age or for use in children with
homozygous familial hypercholesterolemia younger than 7 years of age.
CRESTOR is used to reduce the risk of heart attacks and strokes in men 50 years of
age and older and women 60 years of age and older who do not have known heart
disease but do have certain additional risk factors.
It is not known if CRESTOR is safe and effective in people who have Fredrickson Type
I and V dyslipidemias.
Who should not take CRESTOR?
Do not take CRESTOR if you:
x are allergic to rosuvastatin calcium or any of the ingredients in CRESTOR. See
the end of this leaflet for a complete list of ingredients in CRESTOR.
x have liver problems.
x are pregnant or think you may be pregnant, or are planning to become
pregnant. CRESTOR may harm your unborn baby. If you become pregnant,
stop taking CRESTOR and call your doctor right away. If you are not planning
to become pregnant you should use effective birth control (contraception)
while you are taking CRESTOR.
x are breastfeeding. Medicines like CRESTOR can pass into your breast milk and
may harm your baby.
32
What should I tell my doctor before and while taking CRESTOR?
Tell your doctor if you:
x have unexplained muscle aches or weakness
x have or have had kidney problems
x have or have had liver problems
x drink more than 2 glasses of alcohol daily
x have thyroid problems
x are 65 years of age or older
x are of Asian descent
x are pregnant or think you may be pregnant, or are planning to become
pregnant
x are breastfeeding
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.
Taking CRESTOR with certain other medicines may affect each other causing side
effects. CRESTOR may affect the way other medicines work, and other medicines
may affect how CRESTOR works.
Especially tell your doctor if you take:
x cyclosporine (a medicine for your immune system)
x gemfibrozil (a fibric acid medicine for lowering cholesterol)
x anti-viral medicines including HIV or hepatitis C protease inhibitors (such as
lopinavir, ritonavir, fosamprenavir, tipranavir, atazanavir, or simeprevir)
x certain anti-fungal medicines (such as itraconazole, ketoconazole and
fluconazole)
x coumarin anticoagulants (medicines that prevent blood clots, such as
warfarin)
x niacin or nicotinic acid
x fibric acid derivatives (such as fenofibrate)
x colchicine (a medicine used to treat gout)
Ask your doctor or pharmacist for a list of these medicines if you are not sure.
Know all of the medicines you take. Keep a list of them to show your doctor and
pharmacist when you get new medicine.
How should I take CRESTOR?
x Take CRESTOR exactly as your doctor tells you to take it.
x Take CRESTOR, by mouth, 1 time each day. Swallow the tablet whole.
x CRESTOR can be taken at any time of day, with or without food.
x Do not change your dose or stop CRESTOR without talking to your doctor,
even if you are feeling well.
x Your doctor may do blood tests to check your cholesterol levels before and
during your treatment with CRESTOR. Your doctor may change your dose of
CRESTOR if needed.
x Your doctor may start you on a cholesterol lowering diet before giving you
CRESTOR. Stay on this diet when you take CRESTOR.
x Wait at least 2 hours after taking CRESTOR to take an antacid that contains a
combination of aluminum and magnesium hydroxide.
x If you miss a dose of CRESTOR, take it as soon as you remember. However,
33
do not take 2 doses of CRESTOR within 12 hours of each other.
x If you take too much CRESTOR or overdose, call your doctor or go to the
nearest hospital emergency room right away.
What are the Possible Side Effects of CRESTOR?
CRESTOR may cause serious side effects, including:
x Muscle pain, tenderness and weakness (myopathy). Muscle problems,
including muscle breakdown, can be serious in some people and rarely cause
kidney damage that can lead to death. Tell your doctor right away if:
o
you have unexplained muscle pain, tenderness, or
weakness, especially if you have a fever or feel more
tired than usual, while you take CRESTOR.
o
you have muscle problems that do not go away even after your
doctor has told you to stop taking CRESTOR. Your doctor may
do further tests to diagnose the cause of your muscle problems.
Your chances of getting muscle problems are higher if you:
o are taking certain other medicines while you take CRESTOR
o are 65 years of age or older
o have thyroid problems (hypothyroidism) that are not controlled
o have kidney problems
o are taking higher doses of CRESTOR
x Liver problems. Your doctor should do blood tests to check your liver before
you start taking CRESTOR and if you have symptoms of liver problems while you
take CRESTOR. Call your doctor right away if you have any of the following
symptoms of liver problems:
o feel unusually tired or weak
o loss of appetite
o upper belly pain
o dark urine
o yellowing of your skin or the whites of your eyes
The most common side effects may include: headache, muscle aches and pains,
abdominal pain, weakness, and nausea.
Additional side effects that have been reported with CRESTOR include memory loss
and confusion.
Tell your doctor if you have any side effect that bothers you or that does not go
away.
These are not all the possible side effects of CRESTOR. For more information, ask
your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
How should I store CRESTOR?
• Store CRESTOR at room temperature, between 68°F to 77°F (20°C to 25°C) and
in a dry place.
• Safely throw away medicine that is out of date or no longer needed.
Keep CRESTOR and all medicines out of the reach of children.
What are the Ingredients in CRESTOR?
Active Ingredient: rosuvastatin as rosuvastatin calcium
Inactive Ingredients: microcrystalline cellulose NF, lactose monohydrate NF,
tribasic calcium phosphate NF, crospovidone NF, magnesium stearate NF,
34
hypromellose NF, triacetin NF, titanium dioxide USP, yellow ferric oxide, and red
ferric oxide NF.
General Information about the safe and effective use of CRESTOR
Medicines are sometimes prescribed for purposes other than those listed in a Patient
Information leaflet. Do not use CRESTOR for a condition for which it was not
prescribed. Do not give CRESTOR to other people, even if they have the same
medical condition you have. It may harm them.
You can ask your pharmacist or doctor for information about CRESTOR that is written
for health professionals.
CRESTOR is a trademark of the AstraZeneca group of companies.
© AstraZeneca 2015, 2016
Licensed from SHIONOGI & CO., LTD., Osaka, Japan
Distributed by:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
For more information, go to the CRESTOR website at www.crestor.com or call 1-800-CRESTOR
This Patient Information has been approved by the U.S. Food and Drug Administration
35
Revised 5/16

AstraZeneca Crestor citizen petition 05 31 2016

Transcription

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