[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