[Federal Register Volume 59, Number 62 (Thursday, March 31, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-7630]
[[Page Unknown]]
[Federal Register: March 31, 1994]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 334
[Docket No. 78N-036L]
RIN 0905-AA06
Laxative Drug Products for Over-The-Counter Human Use; Proposed
Amendment to the Tentative Final Monograph
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of proposed rulemaking.
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SUMMARY: The Food and Drug Administration (FDA) is amending the
tentative final monograph for over-the-counter (OTC) laxative drug
products to limit the OTC container size for sodium phosphate/sodium
biphosphate oral solution to not greater than 90 milliliters (mL) (3
ounces (oz)). FDA is limiting this container size because of reports of
deaths associated with an overdosage of sodium phosphate/sodium
biphosphate oral solution where the product was packaged in a larger-
size container and a larger than intended dose was taken inadvertently.
The agency is also adding a warning for all sodium phosphate/sodium
biphosphate products not to exceed the recommended dosage unless
directed by a doctor. This proposal is part of the ongoing review of
OTC drug products conducted by FDA.
DATES: Written comments on the proposed regulation by May 31, 1994;
written comments on the agency's economic impact determination by May
31, 1994. FDA is proposing that this portion of the final monograph be
effective 30 days after the date of publication of the final rule in
the Federal Register.
ADDRESSES: Written comments to the Dockets Management Branch (HFA-305),
Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., Rockville,
MD 20857.
FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug
Evaluation and Research (HFD-810),Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-5000.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of March 21, 1975 (40 FR 12902), FDA
published, under Sec. 330.10(a)(6) (21 CFR 330.10(a)(6)), an advance
notice of proposed rulemaking to establish a monograph for OTC
laxative, antidiarrheal, emetic, and antiemetic drug products, together
with the recommendations of the Advisory Review Panel on OTC Laxative,
Antidiarrheal, Emetic, and Antiemetic Drug Products (the Panel), which
was the advisory review panel responsible for evaluating data on the
active ingredients in these classes. The Panel recommended monograph
status for phosphate salts, such as sodium phosphate/sodium biphosphate
oral solution (40 FR 12902 at 12940), but did not recommend any
container size limitations.
The agency's proposed regulation, in the form of a tentative final
monograph, for OTC laxative drug products was published in the Federal
Register of January 15, 1985 (50 FR 2124). The agency also proposed
monograph status for sodium phosphate/sodium biphosphate oral solution
(50 FR 2124 at 2152 and 2155), but did not recommend any container size
limitations. The proposed dosage for adults and children 12 years of
age and over is 3.42 to 7.56 grams (g) of sodium phosphate and 9.1 to
20.2 g of sodium biphosphate in a single daily dose. In addition to its
use as an OTC laxative for the relief of occasional constipation,
sodium phosphate/sodium biphosphate oral solution is used as part of a
bowel ansing regimen in preparing a patient for surgery or for
preparing the colon for x-ray endoscopic examination. (See proposed
Sec. 334.80(a)(2), 50 FR 2124 at 2157.)
The major trade product containing sodium phosphate/sodium
biphosphate oral solution is marketed in 45 mL, 90-mL, and 240-mL
bottles (Ref. 1). The purgative dose or dose used for colonoscopy is 45
mL (1 1/2 oz). Because the product is available in three sizes, the
manufacturer's labeling advises physicians to prescribe by volumes and
not to prescribe by the bottle and not to exceed the recommended
dosage, as serious side effects may occur (Ref. 1). Despite this
labeling, the multiple container sizes available in the marketplace
have caused consumer confusion and appear to have been involved in
several consumer deaths.
II. Adverse Reactions and Deaths Associated with Sodium Phosphate/
Sodium Biphosphate Oral Solution
From January 8, 1987, to April 21, 1993, the agency has received 5
reports of death in elderly patients and 13 reports of other adverse
reactions related to the use of laxative drug products containing
sodium phosphate/sodium biphosphate oral solution (Refs. 2 through 6).
The five deaths involved elderly patients consuming the product in
preparation for x-ray or endoscopic examinations. The first death (Ref.
2) involved a 72-year-old woman who apparently was instructed to take
two sodium phosphate/sodium biphosphate enemas, but instead ingested 1
2/3 containers (size not known) of sodium phosphate/sodium biphosphate
oral solution on the morning of her scheduled testing. She experienced
cardiac arrest 1 hour after being admitted to the hospital and died
within 9 hours after consuming the laxative. The second death (Ref. 2)
involved an elderly male who was instructed by his radiologist to
purchase sodium phosphate/sodium biphosphate oral solution to prepare
for a barium enema. The patient purchased a 240-mL (8-oz) container and
ingested the entire contents, apparently without following the
directions on the label. The patient soon developed severe diarrhea and
collapsed, having no discernible pulse when the rescue squad arrived.
The patient was hospitalized for symptoms of hyperphosphatemia and
hypocalcemia and died within 48 hours after consuming the sodium
phosphate/sodium biphosphate oral solution. Laboratory analyses 1 week
prior to death revealed normal electrolyte values. The third death
(Ref. 2) also involved an elderly male who was instructed by his
physician to purchase sodium phosphate/sodium biphosphate oral solution
in preparation for a colonoscopy. The physician was unaware that the
solution was available in containers larger than 90 mL and had
instructed the patient to drink one-half of the container in the
morning and to take the second-half of the container later in the
afternoon. The patient purchased the 240-mL container size and ingested
the entire contents. The patient subsequently developed nausea,
vomiting, and chills, followed by grand mal seizures, and was taken to
the hospital after being found unconscious at home. Upon admission, the
patient was treated for hyperphosphatemia and hypocalcemia, but did not
respond to electrolyte replacement therapy. During hospitalization, the
patient had several seizures, was placed on hemodialysis, eventually
developed adult respiratory distress syndrome, and died. Overdosage of
sodium phosphate/sodium biphosphate oral solution was considered the
contributing factor to this patient's death. The fourth death occurred
in an 80-year-old female nursing home patient (Ref. 3). The physician
had ordered a 45 mL dose of sodium phosphate/sodium biphosphate oral
solution to be given in preparation for an endoscopy exam. The nurse
inadvertently gave the patient a 240-mL dose, and the patient died the
next day. A fifth death involved a 71-year-old female (Ref. 4) admitted
to the hospital for rectal prolapse corrective surgery. The patient's
physician ordered a one-time dose of 240 mL of sodium phosphate/sodium
biphosphate oral solution for the purpose of cleansing the patient's
bowel prior to surgery. The pharmacist who filled the order questioned
the dose and notified the patient's nurse that 240 mL appeared to be an
unusual dose. The nurse discussed the dosage with the patient's
physician, and the nurse was told to administer the entire 240 mL in
one dose. The patient received the entire dose and died 2 hours later.
Four of the other reports of adverse reactions also involved
serious cases of accidental overdosage. The first (Ref. 2) involved a
64-year-old male who consumed 240 mL of sodium phosphate/sodium
biphosphate oral solution instead of the recommended dose of 45 mL.
After realizing his mistake, the man notified his pharmacist and
physician and was taken to an emergency room where his stomach was
pumped. The second (Ref. 2) involved an elderly male (age not given)
who consumed 300 mL of sodium phosphate/sodium biphosphate oral
solution in preparation for a barium enema and experienced intestinal
distress. The third (Ref. 5) was from a physician who instructed a
patient to ingest 180 to 240 mL of sodium phosphate/sodium biphosphate
enema solution in preparation for a colonoscopy (no details were given
regarding the patient's response to this dose). The report stated that
the enema was administered orally because the physician believed that
the enema could be used instead of the oral solution. The fourth (Ref.
6) involved an elderly woman (age not given) who had consumed 120 mL of
sodium phosphate/sodium biphosphate oral solution for treatment of
constipation. After 1 hour, she did not obtain her desired laxation
effect and she took another dose of 120 mL. She required
hospitalization for treatment of an episode of calcium tetany.
Other reports of death have appeared in the literature. McConnell
(Ref. 7) reported the death of a 48-year-old female who ingested sodium
phosphate/sodium biphosphate oral solution daily in large doses. (The
container size was not provided in the report.) The patient developed
severe hypotension, became semicomatose, and did not respond to
replacement electrolyte therapy for treatment of hypocalcemia and
hyperphosphatemia. Postmortem examination of the lungs revealed
congestion and edema. Although the kidneys showed hydropic degeneration
of the renal tubules, it was unclear whether this lesion was present
before the episode or was an organ complication from the overdosage of
the laxative solution. Wiberg, Turner, and Nuttall (Ref. 8) reported a
similar case of death caused by sodium phosphate/sodium biphosphate
oral solution. A male patient with a previously normal serum calcium
was admitted to the hospital for treatment of hypocalcemia after taking
sodium phosphate/sodium biphosphate oral solution to clean the bowel of
fecal material in preparation for a barium enema. However, the dose of
the laxative was not provided. As a consequence of the electrolyte
imbalance, the patient developed seizures and subsequently contracted
aspiration pneumonia and soon died.
III. The Agency's Tentative Conclusions on Container Size
Limitations for Sodium Phosphate/Sodium Biphosphate Oral Solution
Sodium phosphate/sodium biphosphate oral solution is considered
safe when taken in the recommended dosage. The 45-mL and 90-mL
container sizes are often recommended and prescribed by physicians for
bowel cleansing purposes prior to surgery and diagnostic procedures of
the colon. However, consumer and health professional confusion with
resulting deaths have occurred as the result of the availability of a
240-mL container size. Unfortunately, life-threatening and fatal
adverse reactions have occurred following inappropriate or erroneous
ingestion of large amounts of this product. Following an overdose,
particularly in the elderly, a high likelihood exists for hypernatremia
(excessive amount of sodium in the blood) and hypocalcemia (reduction
of blood calcium below normal), as well as other fluid and electrolyte
imbalance. The reported cases (Refs. 2 through 6) illustrate the
serious and acute serum electrolyte imbalances created by ingestion of
large amounts of a sodium phosphate/sodium biphosphate oral solution.
Phosphorus-calcium imbalances are aggravated by the copious colonic
secretion of water, and are usually associated with a concomitant
secretion of potassium. The secondary severe hypocalcemia may lead to
heart block and tachyarrhythmias, which may cause sudden death.
The agency tentatively concludes that the OTC availability of the
240-mL container of sodium phosphate/sodium biphosphate oral solution
creates a potential safety risk, particularly for elderly persons who
are likely to use the product for bowel cleansing prior to surgery or a
diagnostic procedure involving the colon. Because of the reported cases
of accidental overdosing and the confusion that has occurred between
240-mL and 90 mL container sizes, the agency concludes that the 240-mL-
size container of sodium phosphate/sodium biphosphate oral solution
should no longer remain in the OTC marketplace. In the interest of
safety, the agency is proposing to limit the maximum OTC container size
for this product to 90 mL.
Based on the above, the agency is proposing to add new Sec. 334.25
Package size limitation to the tentative final monograph. This new
section will limit the OTC containers of sodium phosphate/sodium
biphosphate oral solution to a maximum of 90 mL. This container size
will provide enough laxative to use for bowel cleansing prior to
surgery or a diagnostic procedure involving the colon. Manufacturers
will continue to be able to market a 45-mL container.
The agency proposes that any final rule that may issue based upon
this proposal become effective 30 days after the date of publication of
the final rule in the Federal Register. However, the agency does not
believe that manufacturers should delay implementation until the OTC
laxative drug products rulemaking is completed. Manufacturers of OTC
laxative drug products are encouraged to comply voluntarily as soon as
possible after the date of publication of this proposal.
The agency is currently aware of only one major trade product of
sodium phosphate/sodium biphosphate oral solution available for OTC
use. The manufacturer of this product recently ceased manufacture and
shipment and instituted a market withdrawal of its 240-mL-size
container of this product (Ref. 9). The agency is not currently aware
of any other manufacturers with sodium phosphate/sodium biphosphate
oral solution products in the marketplace. However, any other
manufacturers of these products in container sizes greater than 90 mL
are encouraged to also voluntarily cease manufacture and shipment and
to withdraw them from the marketplace at this time.
The following information has been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
References
(1) ``Physicians' Desk Reference,'' 47th ed., Medical Economics
Co., Inc., Montvale, NJ, p. 1021, 1993.
(2) C. B. Fleet Co., ``Phospho-Soda Complaints,'' January 8,
1987 to January 3, 1991, copy in OTC vol. 090TFM3, Docket No. 78N-
036L, Dockets Management Branch.
(3) C. B. Fleet Co., ``Product Complaint Record No. 6675,''
March 4, 1993, copy in OTC vol. 090TFM3.
(4) United States Pharmacopeia (USP), ``Drug Problem Reporting
Program No. 16921,'' March 31, 1993, copy in OTC vol. 090TFM3.
(5) C. B. Fleet Co., ``Product Complaint Record No. 6337,'' July
21, 1992, copy in OTC vol. 090TFM3.
(6) C. B. Fleet Co., ``Product Complaint Record No. 6753,''
April 21, 1993, copy in OTC vol. 090TFM3.
(7) McConnell, T. H., ``Fatal Hypocalcemia from Phosphate
Absorption from Laxative Preparation,'' Journal of the American
Medical Association, 216:147-148, 1971.
(8) Wiberg, J. J., G. G. Turner, and F. Q. Nuttall, ``Effect of
Phosphate or Magnesium Cathartics on Serum Calcium,'' Archives of
Internal Medicine, 138:1114-1116, 1978.
(9) Market Withdrawal Letter from L. A. Farrar, C. B. Fleet Co.,
to Distributors of Fleet Phospho-soda Products, dated May 6, 1993,
included in OTC vol. 090TFM3.
IV. The Agency's Proposal for a Warning
The case reports clearly show that an overdose of sodium phosphate/
sodium biphosphate solution can cause an electrolyte imbalance. This
imbalance can cause severe reactions and result in death. Further, this
imbalance could occur if an excess dose of either the oral solution or
the rectal enema dosage form were used. To better protect consumers who
use products containing these ingredients, the agency believes that the
labeling should contain a warning alerting consumers not to exceed the
recommended dose unless directed by a doctor. The agency is also
including another sentence that alerts consumers that serious side
effects may occur from excess dosage. Such information is currently
included in the labeling of the oral dosage form of the major trade
product containing sodium phosphate/sodium biphosphate solution (Ref.
1). Accordingly, the agency is proposing to add the following warning
statements in Sec. 334.58(c)(2) for products that contain phosphates
identified in Sec. 334.16(d), (e), or (f): ``Do not exceed recommended
dose unless directed by a doctor. Serious side effects may occur from
excess dosage.'' Because of the dire consequences that can occur from
an overdose of phosphates, the agency is proposing that these warning
statements appear in boldface type as the first sentences under the
heading warnings.
Reference
(1) Labeling for Fleet Phospho-soda, in OTC vol. 090TFM3, Docket
No.78N-036L, Dockets Management Branch.
The agency has examined the economic consequences of this proposed
rulemaking and has determined that it does not require either a
regulatory impact analysis, as specified in Executive Order 12866, or a
regulatory flexibility analysis as defined in the Regulatory
Flexibility Act (Pub. L. 96-354). This rulemaking for OTC laxative drug
products is not expected to have an impact on small businesses. The
final rule will limit the OTC container size of one laxative drug
product (sodium phosphate/sodium biphosphate oral solution) to 90 mL.
This container size is currently allowed in the marketplace. Larger
size containers will not be allowed. The manufacturer of the only major
trade product marketed in a larger-size container has already withdrawn
that size product from the market. The final rule will also require the
addition of warning statements to product labeling. Manufacturers are
encouraged to add these warning statements at the next label printing
for affected products. Manufacturers will have a number of months until
a final rule becomes effective to implement this labeling. The impact
of a final rule appears to be minimal, therefore, the agency concludes
that this proposed rule is not a major rule as defined in Executive
Order 12866. Further, the agency certifies that this proposed rule will
not have a significant economic impact on a substantial number of small
entities as defined in the Regulatory Flexibility Act.
The agency invites public comment regarding any substantial or
significant economic impact that this rulemaking would have on OTC
laxative drug products. Comments regarding the impact of this
rulemaking on OTC laxative drug products should be accompanied by
appropriate documentation. The agency will evaluate any comments and
supporting data that are received and will reassess the economic impact
of this rulemaking in the preamble to the final rule.
The agency has determined under 21 CFR 25.24(c)(6) that this action
is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.
Interested persons may, on or before May 31, 1994, submit written
comments on the proposed regulation to the Dockets Management Branch
(address above). Written comments on the agency's economic impact
determination may be submitted on or before May 31, 1994. Three copies
of all comments are to be submitted, except that individuals may submit
one copy. Comments are to be identified with the docket number found in
brackets in the heading of this document and may be accompanied by a
supporting memorandum or brief. Received comments may be seen in the
office above between 9 a.m. and 4 p.m., Monday through Friday.
List of Subjects in 21 CFR Part 334
Labeling, Over-the-counter drugs.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR part 334 (as proposed in the Federal Register of
January 15, 1985 (50 FR 2124)) be amended as follows:
PART 334--LAXATIVE DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
1. The authority citation for 21 CFR part 334 continues to read as
follows:
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353,
355, 360, 371).
2. Section 334.16 is amended by revising the introductory text to
read as follows:
Sec. 334.16 Saline laxative active ingredients.
The active ingredient of the product consists of any of the
following when used within the dosage limits established for each
ingredient in Sec. 334.58(d) and when packaged according to
Sec. 334.25:
* * * * *
3. New Sec. 334.25 is added to read as follows:
Sec. 334.25 Package size limitation.
Due to the toxicity associated with sodium phosphate/sodium
biphosphate oral solution marketed in large size containers, any
product containing sodium phosphate/sodium biphosphate oral solution
shall not contain more than 90 milliliters per container.
4. Section 334.58 is amended by adding new paragraph (c)(2)(iv) to
read as follows:
Sec. 334.58 Labeling of saline laxative drug products.
* * * * *
(c) * * *
(2) * * *
(iv) Oral and rectal dosage forms. ``Do not exceed recommended dose
unless directed by a doctor. Serious side effects may occur from excess
dosage.'' [sentences in boldface type; sentences to appear as first
statements under the heading ``Warnings'']
* * * * *
Dated: March 22, 1994.
Michael R. Taylor,
Deputy Commissioner for Policy.
[FR Doc. 94-7630 Filed 3-30-94; 8:45 am]
BILLING CODE 4160-01-F