[Federal Register Volume 76, Number 32 (Wednesday, February 16, 2011)]
[Proposed Rules]
[Pages 8942-8945]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-3437]
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CONSUMER PRODUCT SAFETY COMMISSION
16 CFR Part 1700
[CPSC Docket No. CPSC-2011-0007]
Poison Prevention Packaging Requirements; Proposed Exemption of
Powder Formulations of Colesevelam Hydrochloride and Sevelamer
Carbonate
AGENCY: Consumer Product Safety Commission.
ACTION: Proposed rule.
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SUMMARY: The Consumer Product Safety Commission (``CPSC,''
``Commission,'' or ``we'') is proposing to amend its child-resistant
packaging requirements to exempt powder formulations of two oral
prescription drugs, colesevelam hydrochloride and sevelamer carbonate.
Colesevelam hydrochloride, currently
[[Page 8943]]
marketed as Welchol[supreg], is available in a new powder formulation
and is indicated to reduce elevated LDL cholesterol levels and improve
glycemic control in adults with type 2 diabetes mellitus. Sevelamer
carbonate, currently marketed as Renvela[supreg], is available as a new
powder formulation and is indicated for the control of elevated serum
phosphorus in chronic kidney disease patients on dialysis. The proposed
rule would exempt these prescription drug products on the basis that
child-resistant packaging is not needed to protect young children from
serious injury or illness from powder formulations of colesevelam
hydrochloride and sevelamer carbonate because the products are not
acutely toxic, lack adverse human experience associated with acute
ingestion, and in powder form, are not likely to be ingested in large
quantities by children under 5 years of age.
DATES: Comments on the proposal should be submitted no later than May
2, 2011.
ADDRESSES: You may submit comments, identified by Docket No. CPSC-2011-
0007, by any of the following methods:
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: http://www.regulations.gov. Follow the
instructions for submitting comments.
To ensure timely processing of comments, the Commission is no
longer accepting comments submitted by electronic mail (e-mail) except
through http://www.regulations.gov.
Written Submissions
Submit written submissions in the following way:
Mail/Hand delivery/Courier (for paper, disk, or CD-ROM
submissions), preferably in five copies, to: Office of the Secretary,
U.S. Consumer Product Safety Commission, Room 820, 4330 East West
Highway, Bethesda, MD 20814; telephone (301) 504-7923.
Instructions: All submissions received must include the agency name
and docket number for this rulemaking. All comments received may be
posted without change, including any personal identifiers, contact
information, or other personal information provided, to http://www.regulations.gov. Do not submit confidential business information,
trade secret information, or other sensitive or protected information
electronically. Such information should be submitted in writing.
Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov.
FOR FURTHER INFORMATION CONTACT: Adrienne Layton, PhD, Division of
Health Sciences, Directorate for Health Sciences, Consumer Product
Safety Commission, Bethesda, MD 20814-4408; telephone (301) 504-7576;
[email protected].
SUPPLEMENTARY INFORMATION:
A. Background
1. The Poison Prevention Packaging Act of 1970 and Implementing
Regulations
The Poison Prevention Packaging Act of 1970 (``PPPA''), 15 U.S.C.
1471-1476, gives the Commission authority to establish standards for
the ``special packaging'' of household substances, such as drugs, when
child-resistant (``CR'') packaging is necessary to protect children
from serious personal injury or illness due to the substance and the
special packaging is technically feasible, practicable, and appropriate
for such substance. Accordingly, CPSC regulations require that oral
prescription drugs be in CR packaging. 16 CFR 1700.14(a)(10). The
powder forms of cholestyramine and colestipol, two drugs that are
chemically similar to colesevelam hydrochloride and sevelamer
carbonate, currently are exempt from CR packaging. Id.
1700.14(a)(10)(v) and (xv).
CPSC regulations allow companies to petition the Commission for
exemption from CR requirements. 16 CFR part 1702. Among the possible
grounds for granting an exemption are that the degree or nature of the
hazard that the substance poses to children is such that special
packaging is not required to protect children against serious personal
injury or serious illness (16 CFR 1702.17).
2. The Products for Which Exemptions Are Sought
a. Welchol[supreg] (Colesevelam Hydrochloride)
On February 24, 2009, Daiichi Sankyo, Inc. (``Daiichi'') petitioned
the Commission to exempt the powdered form of colesevelam
hydrochloride, which it markets as Welchol[supreg], from the special
packaging requirements for oral prescription drugs. The petitioner
stated that the exemption is justified because of lack of toxicity and
lack of adverse human experience with the drug. Welchol[supreg] has
been marketed in tablet form and dispensed in CR packaging. On October
2, 2009, the U.S. Food and Drug Administration (``FDA'') approved a new
powder formulation of the drug. The petition requested an exemption
only for the powder dosage form of Welchol[supreg]. Tablets would
continue to be in CR packaging.
Welchol[supreg] (colesevelam hydrochloride) is a bile acid
sequestrant indicated as an adjunct to: (1) Reduce elevated low-density
lipoprotein cholesterol (LDL-C) levels; and (2) improve glycemic
control in adults with type 2 diabetes mellitus. The new dosage form of
Welchol[supreg] provides 1.875 g or 3.75 g of the powdered drug in unit
dose packages to be mixed with water and taken orally as a suspension.
(A unit dose package of Welchol[supreg] or Renvela[supreg] is a pouch
that contains an individual dose.)
b. Renvela[supreg] (Sevelamer Carbonate)
On March 6, 2009, Genzyme Corporation (``Genzyme'') petitioned the
Commission to exempt the powdered form of sevelamer carbonate, which it
markets as Renvela[supreg], from the special packaging requirements for
oral prescription drugs. The petitioner stated that the exemption is
justified because of lack of toxicity and lack of adverse human
experience with the drug.
Renvela,[supreg] sevelamer carbonate, is a phosphate binder
indicated for the control of serum phosphorus in patients with chronic
kidney disease on dialysis. The tablets are marketed with a pill
crusher for patients who have trouble swallowing the tablets. The
company reformulated Renvela[supreg] as a powder to be taken as an oral
suspension and received approval from FDA for this powder formulation
on August 12, 2009. The new dosage form of Renvela[supreg] provides
either 0.8 g or 2.4 g of Renvela[supreg] powder in unit dose packages
to be mixed with 2 ounces of water.
B. Toxicity and Human Experience Data
Welchol[supreg] and Renvela[supreg] have similar chemical
structures, biological properties, and powder formulations. Therefore,
we are considering the two petitions together, and staff reviewed
related toxicity data together. CPSC staff found that colesevelam
hydrochloride and sevelamer carbonate are not absorbed from the
gastrointestinal tract. This limits the systemic toxicity of the drugs.
No data indicate that either drug is acutely toxic, which is the
type of toxicity of concern when considering whether CR packaging is
appropriate. Even in patients taking these drugs chronically, the
adverse effects are mostly minor, such as diarrhea, nausea,
constipation, flatulence, and dyspepsia.
Generally, chronic studies are not useful in determining whether a
drug should be in CR packaging (because CR
[[Page 8944]]
packaging is intended to protect against the child's access and likely
one-time use of the drug). Nevertheless, staff reviewed such data.
Animal studies involving 3 to 6 month administration of Welchol[supreg]
and Renvela,[supreg] respectively, resulted in hemorrhage. However,
this result was not related directly to the mechanism of action of the
drugs, but rather to a side effect involving the inhibition of vitamin
K absorption. Chronic administration of Welchol[supreg] and
Renvela[supreg] can cause an alteration in the absorption of vitamins
A, D, E, and K. Vitamin K is required by the liver to produce
functional blood clotting factors. When vitamin K levels are low,
nonfunctional blood clotting factors are produced, which can lead to
hemorrhage. This can occur following the chronic administration of a
drug that inhibits vitamin K, but not after the acute administration of
such a drug. Daiichi Sankyo's submission mentions one 4-year-old girl
who was prescribed Welchol[supreg] off-label to treat a skin irritation
secondary to liver disease. She died from an intracranial hemorrhage.
There are confounding factors in this case, and the death occurred
after chronic, not acute, exposure. Because of the confounding factors,
the death cannot be attributed solely to Welchol[supreg]. A trial of
Renvela[supreg] in a limited number of pediatric patients (18) for
eight weeks resulted in primarily minor GI effects. (Pieper A.K.,
Haffner D., Hoppe B., Dittrich K., Offner G., Bonzel K.E., John U.,
Frund S., Klaus G., Stubinger A., Duker G. and Querfeld U. (2006).)
Other effects, such as metabolic acidosis, can be attributed to the
underlying chronic kidney disease in these children. These effects
would occur after chronic, but not acute, exposure.
If a child were to ingest accidentally colesevelam hydrochloride
(Welchol[supreg]) or sevelamer carbonate (Renvela[supreg]), the
potential for the occurrence of mild to moderate GI discomfort, such as
indigestion, constipation, nausea, and vomiting does exist. However, a
review of relevant data indicates that an acute ingestion of these
drugs would not result in serious toxicity. Any serious toxicity would
result only after chronic administration.
As noted, the CPSC's CR packaging regulations exempt cholestyramine
and colestipol in powder form, two bile acid sequestrants that are
similar chemically to Welchol[supreg] and Renvela[supreg]. CPSC staff
has not found any articles in the medical literature describing toxic
effects following the acute ingestion of either cholestyramine or
colestipol from 1975 through 2010.
CPSC staff searched the following databases for incidents related
to Welchol[supreg] and Renvela[supreg] occurring between 2000 and 2009:
the Injury and Potential Injury Incident database (``IPII''), the
National Electronic Injury Surveillance System database (``NEISS''),
and the Death Certificates database (``DTHS''). Staff found one
incident involving Welchol[supreg] in the NEISS database. In that
incident, 11-month-old twin boys were taken to the emergency room after
they had been playing with their grandmother's prescription
medications. It is not clear how many, if any, pills the boys ingested,
but the children were treated and released from the hospital. CPSC
staff also searched Poisindex[supreg], Pub Med, and Google for
Welchol[supreg], Renvela[supreg], Colestipol, and Cholestyramine, and
found no incidents of acute poisoning in humans.
CPSC staff also analyzed Medwatch reports obtained from the FDA.
Medwatch is the FDA's program for reporting a serious adverse event,
product quality problem, product use error, or therapeutic
inequivalence/failure that may be associated with the use of an FDA-
regulated drug, biologic, medical device, dietary supplement, or
cosmetic. (See http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm.) There may be adverse events that have occurred and are
not reported in the Medwatch database. Also, the existence of a report
in the database does not mean necessarily that the product actually
caused the adverse event.
The FDA provided CPSC staff with 151 distinct incidents of adverse
events associated with colesevelam hydrochloride (Welchol[supreg])
reported through the Medwatch system. CPSC staff excluded incidents
where other medications may have caused the adverse event reported,
resulting in 22 adverse events. Most adverse events reported to
Medwatch were gastrointestinal or involved muscle pain, which is to be
expected considering the adverse effects reported from clinical trials
of Welchol[supreg].
CPSC staff also received reports from the FDA of 40 distinct
incidents of adverse events associated with sevelamer carbonate
(Renvela[supreg]). CPSC staff excluded incidents where other
medications may have caused the adverse event reported, resulting in
five in-scope incidents. Two of the five incidents were deaths, which
most likely were related to the underlying disease and not sevelamer
carbonate (Renvela[supreg]) treatment. One of the five incidents
involved intestinal obstruction and perforation, which the patient's
physician thought were related to the patient's treatment with
sevelamer carbonate (Renvela[supreg]). In the two remaining incidents,
one patient experienced gastroenteritis, and the other (who had asthma
and chronic obstructive pulmonary disease) suffered severe breathing
problems while on Renvela[supreg]. Neither of these two results likely
was related to sevelamer carbonate (Renvela[supreg]).
CPSC staff also evaluated the likelihood of children younger than 5
years old ingesting powdered substances. The powdered form of these
substances makes them more difficult to ingest than medicines in other
forms and therefore, likely will keep children from ingesting
significant quantities. CPSC staff believes that it would be difficult
for children under 5 years old to eat large amounts of powder quickly
without aspirating or coughing. It would also be difficult for children
to mix powder thoroughly in a liquid, and the resulting lumpy quality
may be unappealing to children who try to drink it. Although children
are likely to be able to tear open the non-child-resistant packets used
for Welchol[supreg] and Renvela,[supreg] they are likely to spill much
of the contents; therefore, they would have to open a number of
packages to access a significant quantity of the drug. Most
unintentional poisonings among children occur during short lapses in
direct visual supervision. The difficulty posed by ingestion of powder
introduces a delay in the poisoning scenario, and supervision is likely
to resume before a child can take in a significant quantity.
The packages used with the powder formulations of Welchol[supreg]
and Renvela[supreg] also reduce the likelihood of child poisoning. Both
drugs are provided in small foil-lined packages containing individual
doses. The Renvela[supreg] package is easy to tear only at the notch.
Because the package must be opened at a precise location, it is less
accessible, especially to young children. The Welchol[supreg] package
does not have a notch and has uniform resistance to tearing, which
makes it more difficult to open than Renvela[supreg]. Although both
packages tear easily enough to be opened by children under 5 years of
age, the fine motor skills of this age group of children are still
developing, and children age 2 and younger are likely to spill most of
the powder.
C. Action on the Petition
After considering the information provided by the petitioner and
other available toxicity and human experience data, the Commission
concluded preliminarily that the degree and nature of the hazard to
children presented by the availability of powder formulations of
colesevelam hydrochloride (currently
[[Page 8945]]
marketed as Welchol[supreg]) and sevelamer carbonate (currently
marketed as Renvela[supreg]) do not require special packaging to
protect children from serious personal injury or serious illness
resulting from handling, using, or ingesting the substance. Therefore,
the Commission voted to grant the petition and begin a rulemaking
proceeding to exempt powder formulations of colesevelam hydrochloride
containing not more than 3.75 grams per package and sevelamer carbonate
containing not more than 2.4 grams per package from the special
packaging requirements for oral prescription drugs.
D. Regulatory Flexibility Act Certification
Under the Regulatory Flexibility Act, 5 U.S.C. 601 et seq., an
agency that engages in rulemaking generally must prepare initial and
final regulatory flexibility analyses describing the impact of the rule
on small businesses and other small entities. Section 605 of the Act
provides that an agency is not required to prepare a regulatory
flexibility analysis if the head of an agency certifies that the rule
will not have a significant economic impact on a substantial number of
small entities.
The Commission's Directorate for Economic Analysis prepared a
preliminary assessment of the impact of a rule to exempt powder
formulations of colesevelam hydrochloride (currently marketed as
Welchol[supreg]) and sevelamer carbonate (currently marketed as
Renvela[supreg]) from special packaging requirements.
Daiichi Sankyo, Inc., a subsidiary of the Japanese firm Daiichi
Sankyo Co, Ltd, the company that markets colesevelam hydrochloride
under the trade name of Welchol[supreg], employs approximately 1,500
people in the United States. Net sales of Welchol[supreg] were
approximately $243.1 million in 2008. Genzyme Corporation, the company
that markets sevelamer carbonate under the trade name of
Renvela[supreg], is a U.S. firm headquartered in Cambridge, Mass., with
more than 12,000 employees worldwide. Annual revenue for 2008 was $4.6
billion. Given that both firms that would be affected by a CR packaging
exemption for these drugs are large, the exemption would not have a
significant economic effect on a substantial number of small entities.
Moreover, because the action at issue is an exemption from special
packaging requirements, it would allow companies to avoid the costs
associated with CR packaging.
Based on this assessment, we preliminarily conclude that the
proposed amendment exempting powder formulations of colesevelam
hydrochloride (currently marketed as Welchol[supreg]) and sevelamer
carbonate (currently marketed as Renvela[supreg]) from special
packaging requirements would not have a significant impact on a
substantial number of small businesses or other small entities.
E. Environmental Considerations
Pursuant to the National Environmental Policy Act, and in
accordance with the Council on Environmental Quality regulations and
CPSC procedures for environmental review, we have assessed the possible
environmental effects associated with the proposed PPPA amendment.
CPSC regulations state that rules requiring special packaging for
consumer products normally have little or no potential for affecting
the human environment. 16 CFR 1021.5(c)(3). Nothing in this proposed
rule alters that expectation. Therefore, because the rule would have no
adverse effect on the environment, neither an environmental assessment
nor an environmental impact statement is required.
F. Executive Orders
According to Executive Order 12988 (February 5, 1996), agencies
must state in clear language the preemptive effect, if any, of new
regulations.
The PPPA provides that, generally, when a special packaging
standard issued under the PPPA is in effect, ``no State or political
subdivision thereof shall have any authority either to establish or
continue in effect, with respect to such household substance, any
standard for special packaging (and any exemption therefrom and
requirement related thereto) which is not identical to the [PPPA]
standard.'' 15 U.S.C. 1476(a). A state or local standard may be
excepted from this preemptive effect if: (1) the state or local
standard provides a higher degree of protection from the risk of injury
or illness than the PPPA standard; and (2) the state or political
subdivision applies to the Commission for an exemption from the PPPA's
preemption clause and the Commission grants the exemption through a
process specified at 16 CFR Part 1061. 15 U.S.C. 1476(c)(1). In
addition, the federal government, or a state or local government, may
establish and continue in effect a nonidentical special packaging
requirement that provides a higher degree of protection than the PPPA
requirement for a household substance for the federal, state or local
government's own use. 15 U.S.C. 1476(b).
Thus, with the exceptions noted above, the proposed rule exempting
powder formulations of colesevelam hydrochloride (currently marketed as
Welchol[supreg]) and sevelamer carbonate (currently marketed as
Renvela[supreg]) from special packaging requirements, if finalized,
would preempt nonidentical state or local special packaging standards
for the substance.
List of Subjects in 16 CFR Part 1700
Consumer protection, Drugs, Infants and children, Packaging and
containers, Poison prevention, Toxic substances.
For the reasons given above, the Commission proposes to amend 16
CFR part 1700 as follows:
PART 1700--[AMENDED]
1. The authority citation for part 1700 continues to read as
follows:
Authority: 15 U.S.C. 1471-76. Secs. 1700.1 and 1700.14 also
issued under 15 U.S.C. 2079(a).
2. Section 1700.14 is amended by adding new paragraphs
(a)(10)(xxii) and (xxiii) to read as follows:
Sec. 1700.14 Substances requiring special packaging.
(a) Substances. The Commission has determined that the degree or
nature of the hazard to children in the availability of the following
substances, by reason of their packaging, is such that special
packaging meeting the requirements of Sec. 1700.20(a) is required to
protect children from serious personal injury or serious illness
resulting from handling, using, or ingesting such substances, and the
special packaging herein required is technically feasible, practicable,
and appropriate for these substances:
* * * * *
(10) Prescription Drugs. Any drug for human use that is in a dosage
form intended for oral administration and that is required by Federal
law to be dispensed only by or upon an oral or written prescription of
a practitioner licensed by law to administer such drug shall be
packaged in accordance with the provisions of Sec. 1700.15 (a), (b),
and (c), except for the following:
* * * * *
(xxii) Colesevelam hydrochloride in powder form in packages
containing not more than 3.75 grams of the drug.
(xxiii) Sevelamer carbonate in powder form in packages containing
not more than 2.4 grams of the drug.
Dated: February 10, 2011.
Todd A. Stevenson,
Secretary, Consumer Product Safety Commission.
[FR Doc. 2011-3437 Filed 2-15-11; 8:45 am]
BILLING CODE 6355-01-P