Laxative Drug Products for Over-The-Counter Human Use; Proposed Amendment to the Tentative Final Monograph

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