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[Federal Register Volume 76, Number 32 (Wednesday, February 16, 2011)]
[Proposed Rules]
[Pages 8942-8945]
From the Federal Register Online via the Government Printing 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; 
alayton@cpsc.gov.

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
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