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[Federal Register Volume 76, Number 141 (Friday, July 22, 2011)]
[Rules and Regulations]
[Pages 43847-43851]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-18511]

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CONSUMER PRODUCT SAFETY COMMISSION

16 CFR Part 1700

[CPSC Docket No. CPSC-2011-0007]

Poison Prevention Packaging Requirements; Exemption of Powder 
Formulations of Colesevelam Hydrochloride and Sevelamer Carbonate

AGENCY: Consumer Product Safety Commission.

ACTION: Final rule.

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SUMMARY: The Consumer Product Safety Commission (``CPSC,'' 
``Commission,'' or ``we'') is amending its child-resistant packaging 
requirements to exempt powder formulations of two oral prescription 
drugs, colesevelam hydrochloride and sevelamer carbonate. Colesevelam 
hydrochloride, currently marketed as Welchol [supreg], is available in 
a 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 also available as a powder formulation and is indicated 
for the control of elevated serum phosphorus in chronic kidney disease 
patients on dialysis. The rule exempts these

[[Page 43848]]

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: The rule becomes effective on July 22, 2011.

FOR FURTHER INFORMATION CONTACT: John Boja, Office of Compliance, 
Consumer Product Safety Commission, Bethesda, MD 20814-4408; telephone 
(301) 504-7300; jboja@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 to children in the availability 
of the substance, by reason of its packaging, is such that special 
packaging is not required to protect children from serious personal 
injury or serious illness resulting from handling, using or 
ingesting the substance.

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]. The product, in 
tablet form, would continue to be in CR packaging.
    Welchol [supreg] 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] 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] 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 the FDA 
approved 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. Proposed Rule

    On February 16, 2011, we published a notice of proposed rulemaking 
(``NPR'') proposing to exempt from special packaging the powder forms 
of colesevelam hydrochloride (Welchol [supreg]) and sevelamer carbonate 
(Renvela [supreg]). 76 FR 8942. As explained in the preamble to the 
proposed rule, we considered the two exemption petitions together 
because Welchol [supreg] and Renvela [supreg] have similar chemical 
structures, biological properties, and powder formulations.

C. Toxicity and Human Experience Data

1. Summary of Data From Proposed Rule

    As noted in the preamble to the proposed rule (76 FR at 8943), the 
systemic toxicity of colesevelam hydrochloride and sevelamer carbonate 
is limited because they are not absorbed from the gastrointestinal (GI) 
tract. There is no data indicating that either drug is acutely toxic. 
Acute toxicity is the type of toxicity that is 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.
    If a child were to ingest accidentally Welchol [supreg] or 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.
    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] We have not found 
any relevant articles in the medical literature describing toxic 
effects following the acute ingestion of either cholestyramine or 
colestipol from 1975 through 2010.
    As discussed in the preamble to the proposed rule (76 FR at 8944), 
we 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''). We 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. We also searched Poisindex,[supreg] Pub 
Med, and Google for Welchol,[supreg] Renvela,[supreg] colestipol, and 
cholestyramine, and found no relevant incidents of acute poisoning in 
humans.
    Before publication of the proposed rule, and as noted therein, we 
also analyzed Medwatch reports obtained from the FDA. Medwatch is the 
FDA's program for reporting a serious adverse event, product quality 
problem, product

[[Page 43849]]

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 gave us 151 distinct incidents of adverse events associated 
with Welchol [supreg] reported through the Medwatch system. We 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]
    We also received reports from the FDA of 40 distinct incidents of 
adverse events associated with Renvela.[supreg] We 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 treatment with Renvela.[supreg] One of the five incidents involved 
intestinal obstruction and perforation, which the patient's physician 
thought were possibly related to the patient's treatment with 
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 
Renvela.[supreg]

2. Updated Injury Data

    We updated the injury data since publication of the proposed rule. 
We searched the IPII, NEISS, and death certificate databases from 2000 
through 2010, for incidents associated with Welchol,[supreg] 
Renvela,[supreg] and related drugs (i.e., cholestyramine (Questran 
[supreg]) and colestipol (Colestid [supreg])). We did not identify any 
incidents related to Renvela,[supreg] Questran,[supreg] or 
Colestid,[supreg] and identifed only one new Welchol [supreg]-related 
case. This incident occurred in July 2010, when a 19-month-old boy was 
found in his crib with an open Tylenol [supreg] bottle. The bottle was 
previously used for carrying Welchol [supreg] and other drugs. It was 
not clear from the report if any Welchol [supreg] tablets were in the 
bottle when the child accessed it. The child was taken to the emergency 
department, held overnight for observation, and then released the next 
day.
    Additionally, we searched Poisindex [supreg] (a comprehensive 
database which identifies the toxicity of commercial, biological, and 
pharmaceutical products), and the medical literature for updated 
information on colesevelam hydrochloride and sevelamer carbonate 
colestipol, and cholestyramine. We found no incidents of acute 
poisoning in humans through this search.

3. Powder Formulations Generally

    We 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. It would be difficult for children under 5 
years old to eat large amounts of powder quickly without aspirating or 
coughing. It also would 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.
    As noted in the preamble to the proposed rule (76 FR at 8944), 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 children in this age group are still 
developing, and such children are likely to spill most of the powder.

D. Response to Comments on the Proposed Rule

    We published a notice of proposed rulemaking in the Federal 
Register on February 16, 2011, to exempt colesevelam hydrochloride 
(Welchol [supreg]) and sevelamer carbonate (Renvela [supreg]) from the 
special packaging requirements of the PPPA. 76 FR 8942. The proposed 
rule would amend our existing regulations at 16 CFR Sec.  1700.14 by 
adding a new paragraph (a)(10)(xxii) to exempt coleselam hydrochloride 
in powder form in packages containing not more than 3.75 grams of the 
drug. The proposed rule also would create a new paragraph 
(a)(10)(xxiii) to exempt sevelamer carbonate in powder form in packages 
containing not more than 2.4 grams of the drug. We received 27 
comments, with 15 supporting the proposed rule. In general, the 
comments did not address the codified text; instead, they focused on 
issues relating to the drugs themselves. The comments are available at 
http://www.regulations.gov/#!docketDetail;rpp=50;po=0;D=CPSC-2011-0007. 
This section summarizes the issues raised by the comments and provides 
responses to those issues. Each summarized issue is identified below as 
a single comment, and the word ``Comment,'' in parentheses, will appear 
before the summary description of all comments on that issue, and the 
word ``Response,'' in parentheses, will appear before our response to 
the issue. We also have numbered each summarized issue as a separate 
comment to help distinguish between the different issues raised by the 
commenters and summarized by us. They are listed in no particular 
order.

1. Concern About Possible Harm to Children

    (Comment 1)--Some commenters were concerned about what they felt 
was a lack of data, and they thought that these drugs could be harmful 
to children (e.g., cause bowel obstruction, electrolyte/serum glucose 
imbalance, and death), particularly if ingested in large amounts. One 
commenter also questioned the use of adverse effect data from adults 
and animals in predicting toxicity from accidental poisoning in 
children.
    (Response 1)--We typically consider all available data in toxicity 
assessments, with human data taking precedence over animal data. While 
limited data are available on the acute toxicity of Welchol [supreg] 
and Renvela [supreg] in children, the adverse effects reported are 
similar to those in adults. Because these drugs are not absorbed

[[Page 43850]]

systemically, acute adverse effects typically are limited to the GI 
tract and are unlikely to be serious. An extension of these effects 
would be expected in an overdose scenario. Notably, intestinal 
obstruction has only been observed during therapeutic use of these 
drugs in patients whose health has been compromised otherwise (e.g., 
low birth weight, chronic kidney disease, and adhesions). Cases have 
been documented in infants and one child following treatment with a 
similar drug, cholestyramine. In addition, a 45-year-old male developed 
an intestinal obstruction, perforation, and an abdominal fistula 
(abnormal opening in the stomach or bowel, which allows the contents to 
leak) after several months of treatment with Renvela.[supreg] 
Intestinal obstruction has occurred very rarely after treatment with 
Welchol.[supreg] In fact, Welchol [supreg] has a greater specificity 
for bile acids than cholestyramine and colestipol and has been 
suggested to have greater gastrointestinal tolerance than the other two 
drugs.
    Based on all available information, an imbalance of electrolytes or 
glucose control is unlikely to occur following an acute exposure to 
Welchol [supreg] or Renvela.[supreg] No unexpected laboratory tests 
were seen following chronic administration of 3.75 grams g/day of 
Welchol [supreg] to pediatric subjects with heterozygous familial 
hypercholesteremia or 15 g/day of Renvela [supreg] to normal 
volunteers. Chronic administration of Welchol [supreg] decreased 
fasting glucose levels 3.9-15.9 mg/dl. Because a blood glucose goal is 
100-180 mg/dl for children, it is unlikely that acute administration of 
Welchol [supreg] would cause hypoglycemia (i.e., low blood sugar) in a 
child (less than 60 mg/dl).
    Moreover, as discussed in section C of this preamble, there are no 
available poisoning data showing that these drugs cause serious 
toxicity following an acute exposure.

2. Questions About Powder Form

    (Comment 2)--Some commenters argued that: (1) The powder may 
present a choking hazard to children; and (2) there is little support 
for claims that the powders are more difficult for children to ingest, 
access from the packet without spilling, and mix thoroughly in a 
liquid.
    (Response 2)--The low acute toxicity of Welchol[supreg] and 
Renvela[supreg] is a key factor for the exemptions. Additionally, 
CPSC's Human Factors staff considered relevant data and medical 
literature to conclude that powders generally present a low risk 
because they are more difficult to ingest, particularly in large 
quantities. Generally, with the exception of caustics, the primary 
exposure risk associated with powders is aspiration. Notably, any 
potential choking hazard with these drugs could also occur with any 
non-pharmaceutical powder formulation available in the household, such 
as soaps, baby powder, drink mixes, and food products.
    We maintain that a child would have difficulty opening the packet 
of either of these drugs and mixing the powder with a liquid because of 
the lack of precision and control required. Moreover, there are no 
available poisoning data with these or similar drugs (colestipol or 
cholestyramine) to indicate otherwise.

3. Mixing With Other Substances

    (Comment 3)--One commenter stated that he believes that ``the drug 
can potentially be mixed with something to create an adverse 
reaction.''
    (Response 3)--The commenter provided no evidence to suggest that 
this is a likely event, and no information or examples of a substance 
that would cause an adverse reaction when mixed with Welchol[supreg] or 
Renvela[supreg]. Although it is possible that a child might mix the 
powder with a liquid in imitation of an adult, it is highly unlikely 
that a child would do so repeatedly because a small child can drink 
only a limited amount of liquid at one time. In addition, the 
consistency of incompletely mixed powder is likely to deter repetition.

4. Benefits of the Exemptions

    (Comment 4)--Some commenters asserted that benefits from the CR 
exemptions are limited: increased profits for the manufacturers of the 
drugs; and ease of opening the package.
    (Response 4)--Exempting from CR requirements the powder forms of 
Welchol[supreg] and Renvela[supreg] may increase patient compliance. 
Poor adherence to medication regimens for chronic health issues is a 
well-established concern. Easier access to these drugs could benefit 
patients with minimal or no risk to children.

E. Effective Date

    This rule exempts two drugs that otherwise would be subject to CR 
packaging requirements under the PPPA. Because the rule grants an 
exemption, it is not subject to the usual requirement under the 
Administrative Procedure Act (``APA'') that a rule must be published 30 
days before it takes effect. 5 U.S.C. 553(d)(1). Therefore, it is 
appropriate for the rule to become effective upon publication in the 
Federal Register.

F. Regulatory Flexibility Act Certification

    Under the Regulatory Flexibility Act (``RFA''), 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 RFA 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.
    As noted in the preamble to the proposed rule (76 FR at 8945), the 
Commission's Directorate for Economic Analysis prepared a preliminary 
assessment of the impact of a rule to exempt powder formulations of 
Welchol[supreg] and Renvela[supreg] from special packaging 
requirements. Based on this assessment, we preliminarily concluded that 
the proposed amendment exempting powder formulations of Welchol[supreg] 
and Renvela[supreg] from special packaging requirements would not have 
a significant impact on a substantial number of small businesses or 
other small entities. We received no comments on this assessment or any 
additional information. Therefore, we conclude that 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.

G. 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. As 
discussed in the preamble to the proposed rule, 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 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.

H. Executive Orders

    According to Executive Order 12988 (February 5, 1996), agencies 
must state

[[Page 43851]]

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 rule exempting powder 
formulations of Welchol[supreg] and Renvela[supreg] from special 
packaging requirements preempts nonidentical state or local special 
packaging standards for the substances.

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 amends 16 CFR part 1700 
as follows:

PART 1700--[AMENDED]

0
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).

0
2. Section 1700.14 is amended by adding paragraphs (a)(10)(xxii) and 
(xxiii) to read as follows:

Sec.  1700.14  Substances requiring special packaging.

    (a) * * *
    (10) * * *
    (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: July 18, 2011.
Todd A. Stevenson,
Secretary, Consumer Product Safety Commission.
[FR Doc. 2011-18511 Filed 7-21-11; 8:45 am]
BILLING CODE 6355-01-P
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